Herpes Simplex - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

HERPES SIMPLEX A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2003 by ICON Group International, Inc. Copyright ©2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Herpes Simplex: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83983-2 1. Herpes Simplex-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on herpes simplex. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON HERPES SIMPLEX ....................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Herpes Simplex ............................................................................. 7 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed .............................................................................. 100 CHAPTER 2. NUTRITION AND HERPES SIMPLEX ........................................................................... 147 Overview.................................................................................................................................... 147 Finding Nutrition Studies on Herpes Simplex .......................................................................... 147 Federal Resources on Nutrition ................................................................................................. 155 Additional Web Resources ......................................................................................................... 155 CHAPTER 3. ALTERNATIVE MEDICINE AND HERPES SIMPLEX ..................................................... 157 Overview.................................................................................................................................... 157 National Center for Complementary and Alternative Medicine................................................ 157 Additional Web Resources ......................................................................................................... 165 General References ..................................................................................................................... 170 CHAPTER 4. DISSERTATIONS ON HERPES SIMPLEX ....................................................................... 171 Overview.................................................................................................................................... 171 Dissertations on Herpes Simplex ............................................................................................... 171 Keeping Current ........................................................................................................................ 175 CHAPTER 5. CLINICAL TRIALS AND HERPES SIMPLEX ................................................................. 177 Overview.................................................................................................................................... 177 Recent Trials on Herpes Simplex ............................................................................................... 177 Keeping Current on Clinical Trials ........................................................................................... 189 CHAPTER 6. PATENTS ON HERPES SIMPLEX ................................................................................. 191 Overview.................................................................................................................................... 191 Patents on Herpes Simplex ........................................................................................................ 191 Patent Applications on Herpes Simplex .................................................................................... 215 Keeping Current ........................................................................................................................ 247 CHAPTER 7. BOOKS ON HERPES SIMPLEX ..................................................................................... 249 Overview.................................................................................................................................... 249 Book Summaries: Federal Agencies............................................................................................ 249 Book Summaries: Online Booksellers......................................................................................... 253 The National Library of Medicine Book Index ........................................................................... 255 Chapters on Herpes Simplex ...................................................................................................... 256 CHAPTER 8. MULTIMEDIA ON HERPES SIMPLEX .......................................................................... 271 Overview.................................................................................................................................... 271 Video Recordings ....................................................................................................................... 271 Audio Recordings....................................................................................................................... 271 Bibliography: Multimedia on Herpes Simplex........................................................................... 272 CHAPTER 9. PERIODICALS AND NEWS ON HERPES SIMPLEX ....................................................... 275 Overview.................................................................................................................................... 275 News Services and Press Releases.............................................................................................. 275 Newsletter Articles .................................................................................................................... 278 Academic Periodicals covering Herpes Simplex ........................................................................ 279 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 281 Overview.................................................................................................................................... 281 U.S. Pharmacopeia..................................................................................................................... 281 Commercial Databases ............................................................................................................... 283 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 287

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Overview.................................................................................................................................... 287 NIH Guidelines.......................................................................................................................... 287 NIH Databases........................................................................................................................... 289 Other Commercial Databases..................................................................................................... 292 APPENDIX B. PATIENT RESOURCES ............................................................................................... 293 Overview.................................................................................................................................... 293 Patient Guideline Sources.......................................................................................................... 293 Finding Associations.................................................................................................................. 299 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 303 Overview.................................................................................................................................... 303 Preparation................................................................................................................................. 303 Finding a Local Medical Library................................................................................................ 303 Medical Libraries in the U.S. and Canada ................................................................................. 303 ONLINE GLOSSARIES................................................................................................................ 309 Online Dictionary Directories ................................................................................................... 312 HERPES SIMPLEX DICTIONARY............................................................................................. 315 INDEX .............................................................................................................................................. 403

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with herpes simplex is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about herpes simplex, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to herpes simplex, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on herpes simplex. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to herpes simplex, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on herpes simplex. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON HERPES SIMPLEX Overview In this chapter, we will show you how to locate peer-reviewed references and studies on herpes simplex.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and herpes simplex, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “herpes simplex” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Diagnosis and Management of Recurrent Herpes Simplex Infections Source: JADA. Journal of the American Dental Association. 133(9): 1245-1249. September 2002. Contact: Available from American Dental Association. ADA Publishing Co, Inc., 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2867. Website: www.ada.org. Summary: Dentists are frequently asked by patients to diagnose and treat recurrent herpes infections, which are painful and disfiguring. This article explores the diagnosis and treatment of these commonly encountered viral conditions. Herpetic infections represent a reactivation of the herpes simplex virus, which is highly infectious to patients, their families, dentists, and staff members. The diagnosis of these conditions usually is based on case-specific historical findings, the characteristic clinical

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appearance, and the location of the lesions. Dentists often treat patients with a history of recurrent herpetic infections. Currently used topical antiviral agents, when used in a timely manner, are well-absorbed and quite effective in decreasing the severity and duration of herpetic episodes. The author stresses that until the herpetic lesions are completely healed, the dental team and patient should use management strategies to prevent spread of the virus, ensure adequate nutrition, and maintain appropriate oral hygiene practices. 3 figures. 1 table. 19 references. •

Case Study: Herpes Labialis Source: Access. 16(1): 38-42. January 2002. Contact: Available from American Dental Hygienists' Association. 444 North Michigan Avenue, Chicago, IL 60611. Summary: Herpes viruses are a group of DNA viruses that cause oral and systemic diseases. Eight types of human herpes viruses have been identified. This article describes a case report of herpes labialis (commonly known as fever blister or cold sores) confined to the vermilion (red) of the mandibular (lower) lip. Diagnosis and management of the condition were performed primarily by the client who had been educated to work with the dental receptionist and dental hygienist to schedule oral health care appropriately. The client, a 44 year old female, presented to a general dentistry practice with a known history of herpes labialis. She was hoping to find better ways to prevent recurrent lesions during times of higher exposure to ultraviolet radiation (sunlight). The author describes the patient's treatment plan that included pretreatment with acyclovir ointment and oral acyclovir; each was used at a different time. The author also discusses the importance of working closely with patients who have the knowledge, experience, and motivation that helps facilitate oral health education and care. The outcome for this patient remains to be seen, but the client left the dental practice feeling satisfied that her concern was taken seriously and addressed appropriately. 2 figures. 25 references.

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Update on Treatments for Oral Herpes Simplex Viral Infections (Cold Sores and Fever Blisters) Source: Today's Therapeutic Trends: The Journal of New Developments in Clinical Medicine. 19(1): 39-58. 1st Quarter 2001. Contact: Available from Communications Media for Education, Inc. PO Box 712, Princeton Junction, NJ 08550. (800) 221-3899. Fax (609) 275-8745. Website: www.cmeglobal.com. Summary: Infection with herpes simplex virus (HSV) 1 or 2, which causes cold sores or fever blisters on the mouth, is common and usually mild. This article offers an update on the treatments used for oral herpes simplex viral infections. Unlike other common viral infections, infection with HSV is lifelong. Recurrent outbreaks are troublesome and treatment has typically been limited to palliation of symptoms. However, recent advances in antiviral therapies, most notably a new non prescription (over the counter) agent docosanol (Abreva), promise to provide many more patients with effective treatment alternatives for cold sores. The author reviews the transmission and pathogenesis of HSV 1, the clinical manifestations of HSV 1 infection (during the stages of initial outbreaks, latency, and recurrence), diagnosis, and treatment options, including prescription and nonprescription treatments. The author notes that for most people, the social and emotional impact of herpes is greater than the physical distress. Patients need support and education in making an educated choice about treatment

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options. Appendices include information about practical treatment and transmission issues, answers to frequently asked questions about herpes simplex, and a list of web sites with information on herpes simplex. 2 tables. 42 references. •

Differentiating Herpes Simplex Virus and Recurrent Aphthous Ulcerations Source: Access. 17(2): 30-34. February 2003. Contact: Available from American Dental Hygienists' Association (ADHA). 444 North Michigan Avenue, Chicago, IL 60611. (312) 440-8900. E-mail: [email protected]. Website: www.adha.org. Summary: Recurrent oral ulcerations are commonly seen in dental office settings and are a source of discomfort and frustration for clients. It is often a challenge to distinguish one type of ulceration from another. Recurrent herpes simplex virus (HSV) and recurrent aphthous stomatitis (RAS) represent a classic example of lesions that are similar in clinical presentation and course. This article discusses the features of both ulcerative conditions, so dental hygienists can learn to differentiate between them. The author notes that these conditions share more similarities than differences clinically and thus are easy to misdiagnose. The author also discusses treatment considerations for each disease. 2 figures. 30 references.

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Salivary Defense Factors in Herpes Simplex Virus Infection Source: Journal of Dental Research. 81(6): 416-421. June 2002. Contact: Available from International Association for Dental Research. Subscription Department, 1619 Duke Street, Alexandria, VA 22314. (703) 548-0066. Fax (703) 548-1883. Summary: Saliva may contribute to a lowering of the infectious herpes simplex virus (HSV) dose during transmission and consequently abrogate infection or lead to decreased reactivation. To test this hypothesis, the authors of this article tested saliva for innate defense factors, immunoglobulin content, and the capacity to interfere with HSV infection. Serum or salivary anti-HSV IgG levels did not correlate with control of recurrent labial herpes (RLH) and were significantly higher in subjects with RLH compared with asymptomatic seropositive subjects. Although no differences in levels or output rate of innate defense factors between the groups were observed, the salivary neutralizing activity correlated with lactoferrin and hypothiocyanite concentrations in the asymptomatic seropositive group. The authors conclude that saliva contains factors, in addition to anti-HSV immunoglobulins, that neutralize HSV and may indirectly contribute to the control of RLH. 2 figures. 2 tables. 26 references.

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Effective Treatment of Herpes Simplex Labialis with Penciclovir Cream: Combined Results of Two Trials Source: JADA. Journal of the American Dental Association. 133(3): 303-309. March 2002. Contact: Available from American Dental Association. ADA Publishing Co, Inc., 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2867. Website: www.ada.org. Summary: This article reports on the combined results of two randomized, double blind, parallel group clinical trials that were conducted in Europe and North America to compare the efficacy and safety of topical 1 percent penciclovir cream with a placebo cream to treat herpes simplex labialis (cold sores on the lips). A total of 4,573 immunocompetent people with a history of recurrent herpes simplex labialis (HSL), with three or more episodes a year that typically manifested as classical lesions, were

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enrolled and prospectively dispensed medication: either 1 percent penciclover in a cetomacrogol cream base or a matching placebo. Patients self-initiated treatment and were required to apply study medication six times per day for the first day and every two hours while awake for four consecutive days. Of the 4,573 enrolled patients, 3,057 initiated treatment (1,516 with penciclovir and 1,541 with placebo). Combined data from two trials revealed that penciclovir recipients lost classical lesions 31 percent faster than did placebo recipients and experienced 28 percent faster resolution of lesion pain. Significant benefits were achieved with penciclovir use whether treatment was initiated in the early stages or the later stages. The authors conclude that penciclovir cream positively affects recurrent HSL, and dose frequency is vital to topical treatment. Even when penciclovir was applied late, it was effective in favorably altering the course of recurrent HSL. 4 tables. 14 references. •

Herpes Simplex Virus: Clinical Presentation and Treatment Source: Dentistry Today. 20(5): 65-67. May 2001. Contact: Available from Dentistry Today Inc. 26 Park Street, Montclair, NJ 07042. (973) 783-3935. Summary: This continuing education article familiarizes dental practitioners with the clinical presentation and treatment of herpes simplex virus (HSV). Topics include the virus and its pathogenesis, transmission, diagnosis, clinical presentation (symptoms), treatment of orolabial (mouth and lips) HSV infections, and the pharmacological (drug) treatment of orolabial HSV infections. The author stresses that practitioners should be aware of the 'asymptomatic virus shedding' phenomenon, in which a patient with HSV who does not have clinical symptoms is contagious approximately 4 percent of the time. Treatment with acyclovir (Zovirax) and valacyclovir (Valtrex) is common, however, neither product is labeled for use in orolabial herpes. Other treatment strategies include counseling the patient to determine infection triggers, modify lifestyle to reduce those triggers, wear a wide brimmed hat and use a sunscreen with greater than SPF 30, and consider the use of drug agents during the prodrome (preblister) stage. A brief posttest for continuing education credits is appended to the article. 2 tables. 13 references.

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Herpes Simplex Virus Type 1 in Brain and Risk of Alzheimer's Disease Source: Lancet. 349: 241-244. January 25, 1997. Summary: This journal article describes a possible association between herpes simplex virus type 1 (HSV1) and apolipoprotein E4 (apoE4) in Alzheimer's disease (AD). Researchers studied 84 brain samples from 46 AD patients and 75 brain samples from 44 people without dementia. DNA was extracted from the brain samples, and polymerase chain reaction (PCR) amplification was used to detect the HSV1 thymidine kinase gene and the host apoE gene. Multiple regression analysis suggests that the apoE4 allele frequency was significantly higher in AD patients positive for HSV1 in the brain (58.8 percent) than in the HSV1-negative AD group (10 percent), the HSV1-positive nondementia group (3.6 percent), or the HSV1-negative nondementia group (6.3 percent). The odds ratio for apoE4 compared with the HSV1-negative nondementia group was 16.8 in the HSV1-positive AD group, 1.67 in the HSV1-negative AD group, and 0.56 in the HSV1-positive nondementia group. In a separate comparison of apoE gene statuses in 40 people with and 33 without recurrent cold sores, the apoE4 allele frequencies were 36 percent and 9 percent, respectively. The authors conclude that the combination of HSV1 in the brain and the presence of an apoE4 allele appears to be a strong risk factor for AD. 1 figure, 5 tables, 26 references. (AA-M).

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Federally Funded Research on Herpes Simplex The U.S. Government supports a variety of research studies relating to herpes simplex. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to herpes simplex. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore herpes simplex. The following is typical of the type of information found when searching the CRISP database for herpes simplex: •

Project Title: A FEMALE MOUSE MODEL TO STUDY RECURRENT GENITAL HERPES Principal Investigator & Institution: Parr, Margaret B.; Professor; Anatomy; Southern Illinois University Carbondale 900 S. Normal Carbondale, Il 629014709 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: The purpose of this research is to further our understanding of immunity to sexually transmitted herpes simplex virus type 2 (HSV-2). In women, HSV-2 infects the mucosa in the genital tract and spreads to the nervous system where it persists in sensory ganglia as latent virus. Under conditions of stress, latent virus is activated and causes recurrent disease. Development of a vaccine to prevent HSV-2 infections in the genital tract and subsequent latency is problematic because it requires sterile immunity, but factors that suppress reactivation of latent irus deserve thorough investigation. The only animal model for studies of recurrent herpetic disease in the genital tract uses the guinea pig, but this species is less suitable for immunologic studies than mice. We propose experiments to establish a mouse model for studies of genital recurrent herpetic disease. The aims of this proposal are: Specific Aim 1: Tod etermine whether treatment with acyclovir and/or passive transfer of polyclonal HSV-2 antibody or monoclonal antibody to HSV- 2 glycoprotein D to naive mice after intravaginal infection with HSV-2 will prevent or attenuate neurological disease; Specific Aim 2: To demonstrate latent virus in lumbosacral ganglia in mice that survive infection. Specific Aim 3: To determine whether latently infected mice show spontaneous and induce recurrent infection. Specific Aim 4: To test the hypothesis that therapeutic immunization of latently infected mice will reduce or eliminate recurrent infection and to compare the effectiveness of vaccines that stimulate humoral immunity alone or both humoral and T cell mediated immunity. If therapeutic immunization reduced recurrent infections in women, it would reduce severe herpes infections in newborns, decrease the sexually transmitted spread of this virus throughout the population, and improve women's reproductive health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Project Title: AMELIORATION OF RECURRENT HERPES KERATITIS Principal Investigator & Institution: Stuart, Patrick M.; Assistant Professor; Ophthalmology and Visual Sci; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 31-MAY-2003 Summary: Herpes simplex keratitis is the leading cause of infectious blindness in the United States. Visual loss most commonly results from recurrent stromal disease, as opposed to primary herpes keratitis. Most experimental models have focused on primary rather than recurrent keratitis. The PI has created an animal model of recurrent herpetic keratitis in humans. The focal stromal opacification, regional neovascularization and endotheliitis produced in the recurrent keratitis model, is in distinct contrast to the keratinization, limbus to limbus opacification and exudative blepharoconjunctivitis that is seen in primary herpes simplex keratitis in NIH mice. While current data indicates that primary and recurrent herpes keratitis may share some common immune mechanisms, it is the PI's hypothesis that the considerable differences in the clinical pathology, viral antigen distribution within the cornea, and responses to vaccine therapy suggests that the immune responses in these two diseases will not be identical. The PI has proposed studies designed to test the hypothesis that recurrent HSK in NIH inbred mice is mediated by CD4+ T cells of the Th1 phenotype. In order to test this hypothesis he will: (1) define the cellular and costimulatory requirements for recurrent disease by selective depletion experiments; (2) characterize and compare the cytokine profile in corneal tissue during primary versus recurrent keratitis, using ELISA and RT-PCR analysis and then determine the relevance of these cytokines to recurrent disease by specifically targeting cytokines with monoclonal antibodies; (3) determine whether protective vaccination with a vhs-mutant strain of HSV-1 involves the selective stimulation of a Th2-mediated immune response. The information derived from these studies will lead to a better understanding of the biology of recurrent herpes simplex keratitis in mice and thereby this disease in humans. Furthermore, these studies could possibly suggest more specific and effective immunotherapies designed to ameliorate herpes simplex keratitis disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANALYSIS OF HSV 1 TEGUMENT PROTEINS AND VIRUS ASSEMBLY Principal Investigator & Institution: Courtney, Richard J.; Professor; Microbiology and Immunology; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2001; Project Start 01-JAN-1978; Project End 31-JAN-2006 Summary: The long-term goals of the research efforts within our laboratory have been to define the biochemical and immunological properties of selected herpes simplex virus (HSV) glycoproteins and tegument proteins and to provide new insight regarding their synthesis, processing, interactions, and functional roles within HSV-infected cells. As a significant extension to these studies, the overall objective of this competitive renewal application is to define the roles HSV-1 tegument and integral membrane proteins play in the envelopment/budding process. The working hypothesis for the proposed studies is that one or more specific tegument proteins are major participants in the initiation of the envelopment process (i.e. budding). It is also part of the working hypothesis that enveloped viruses in general are likely to use similar mechanisms to accomplish the envelopment process. The expertise and experience of two laboratories (Courtney and

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Wills) will join to address the goals of the project. The Courtney laboratory has for a number of years studied various aspects of HSV glycoproteins and tegument proteins. The Wills laboratory has defined, at the molecular level, specific amino acid domains that are responsible for the envelopment and budding of retroviruses. The proposed studies includes four specific aims that are interrelated, but are independent of each other. The first aim will focus on the expression and targeting of individual tegument proteins. Our working hypothesis is that targeting information within these tegument proteins plays a key role in the tegumentation of virus particles at internal membranes within virus-infected cells. These studies will dissect the targeting domains of tegument proteins and provide new insight as to what controls their localization within the cell. The second aim will-focus on the identification of the minimal budding machinery of HSV-1. The working hypothesis is that a subset of tegument/membrane proteins has the potential to mediate the envelopment/budding process. Two experimental approaches will be used. The first is to express selected tegument proteins, both individually and m various combinations and to determine if these proteins can mediate envelopment and egress of virus particle/vesicles into the media. In the second approach, the Rous sarcoma virus Src membrane-binding domain fused to tegument proteins will be used to target these proteins to the plasma membrane. This approach will allow us to investigate envelopment and release of enveloped particles from the plasma membrane and thus bypass events associated with the egress of enveloped particles to the extracellular space. The third aim focuses on the molecular dissection of two tegument proteins as an approach to define the packaging events that occur during assembly. The fourth aim will focus on the identification of retroviral M (membrane binding) and L (late) domain equivalents within HSV-1 tegument proteins. Recent studies have suggested that late domains interact with specific domains of cellular proteins and are required for the virus-cell separation event ("pinching off'). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIGEN MODULATION OF T CELL CYTOKINE PROFILE Principal Investigator & Institution: Evavold, Brian D.; Microbiology and Immunology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 01-JAN-1997; Project End 31-DEC-2001 Summary: The overall theme of this project is to identify the extent to which analogs of immunogenic peptide can influence and alter the phenotype of T helper cells. This is important not just for manipulation of the immune response, but also to deepen our understanding of the mechanisms responsible for the polarization of response towards a Th1 or Th2 phenotype. The fundamental hypothesis of this study is that the phenotype of T cells (cytokine response) will vary as a function of the stimulatory peptide ligand. In the following three aims, the goals are to identify mechanisms by which peptide shifts precursor Th0 cells in vitro (aim I), extend this information to model antigens in vivo (aim II), and apply our findings to a viral pathogen (aim III). AIM I- Analysis of the effect of partial agonists/ antagonists peptide variants on the differentiation of Th0 cells in vitro. The hypothesis underlying this aim is that analogs of immunogenic peptide can selectively activate Th0 cell functional responses and promote the differentiation into a defined Th1 or Th2 phenotype. The experimental approach will focus on three possible mechanisms by which peptide could drive the differentiation of Th0 clones which are: 1) the selective down-modulation of the IL-2 response (an anergic state), 2) the specific activation of the Th2 cytokine profile, and 3) alter the effective dose of antigen (antagonism). AIM II- Analysis of the effect of partial agonists/ antagonists peptide variants on the differentiation of Th0 cells in vivo. This aim will test the hypothesis that

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analogs of immunogenic peptide can selectively influence the Th response in vivo. The experimental approach will be to inject altered peptide ligands of the well-defined model antigens from aim I into inbred and TCR transgenic mice and determine the Th phenotype and precursor T cell frequency. AIM III- Analysis of a Herpes simplex-1 viral epitope and manipulation of the phenotype of the T cell response. This aim will continue to test the hypothesis that antigen can control Th response in vivo with the additional factor of influencing the response to the herpes simplex-1 pathogen. The goal of these experiments will be to apply the protocol(s) identified in aims I and II to the multi-antigenic HSV-1 pathogen. These aims are expected to accomplish our broad objectives through the use of variants of antigenic peptides to manipulate and control the Th cell response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTOPHAGY: A NOVEL ANTIVIRAL HOST DEFENSE PATHWAY Principal Investigator & Institution: Levine, Beth C.; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The process of autophagy, or bulk degradation of cellular proteins through an evolutionarily conserved autophagosomic-lysosomal pathway, is important in survival during nutrient stress, differentiation and development, and negative growth control. However, almost nothing is known about the role of this cellular pathway in defense against intracellular pathogens. The broad objective of this proposal is to evaluate the novel hypothesis that autophagy functions as an intracellular antiviral pathway that degrades viral particles and is antagonized by viral gene products required for disease pathogenesis. In support of this hypothesis, we have previously shown that the first identified mammalian autophagy gene, beclin 1, inhibits Sindbis virus replication and protects mice against lethal Sindbis virus encephalitis. In addition, our recent data demonstrate that the well-characterized IFNinducible antiviral molecule, PKR, is required for herpes simplex virus (HSV)-induced autophagy and that the HSV-l-encoded neurovirulence gene product, ICP34.5, antagonizes PKR-dependent autophagy in mammalian cells and Beclin 1-dependent autophagy in yeast. Together, these findings lead us to hypothesize a role for Beclin 1dependent autophagy in antiviral host defense and a role for ICP34.5 antagonism of Beclin 1-dependent autophagy in neurovirulence. In this proposal, there are four specific aims that investigate related sub-hypotheses, including: (1) the beclin 1 autophagy gene is required for HSV-l-induced autophagy; (2) HSV-1 ICP34.5 antagonizes autophagy in virally-infected cells through a direct interaction with the Beclin 1 autophagy protein; (3) Beclin 1-dependent autophagy functions as an antiviral host defense pathway by facilitating the degradation of intracytoplasmic viral particles and this function of Beclin 1 is antagonized by ICP34.5; and (4) HSV ICP34.5 regulates HSV-1 neurovirulence through a mechanism that involves antagonism of Beclin 1-dependent autophagy. To accomplish these aims, we will use an approach involving the combined use of host cells that are deficient in autophagy and expression of Beclin 1 protein and recombinant HSV-1 viruses that encode ICP34.5 mutant proteins that are deficient in antagonism of Beclin 1-dependent autophagy. We will use these reagents to investigate the role of Beclin 1-dependent autophagy in regulating viral replication and the role of ICP34.5 antagonism of Beclin 1-dependent autophagy in regulating viral neurovirulence. Together, these studies will provide novel insights about the role of autophagy in antiviral host defense and the role of viral evasion of autophagy in neurovirulence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BACTERIAL ARTIFICIAL CHROMOSOMES FOR HSV GENOMICS Principal Investigator & Institution: Leib, David A.; Associate Professor; Ophthalmology and Visual Sci; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Herpes simplex virus (HSV) is a significant and common human pathogen. HSV is a leading cause of nontraumatic blindness in the US with an accompanying ocular diseases ranging from dendritic epithelial keratitis, conjunctivits and blepharitis, to blinding necrotizing stromal keratitis. In addition, HSV causes cold sores, genital sores, and is a leading cause of viral encephalitis. The use of defined genetic alterations has become standard in many fields to gain insight into the functions of genes. Such genetic approaches -are often cumbersome, with the generation of genetically altered organisms often being far more time-consuming than the actual analysis of genetic function itself. There is, therefore, a need for the application of novel technologies to speed up the generation of mutants. This is certainly the case for the herpes viruses whose large DNA genomes, although amenable to reverse genetics by homologous recombination, complicate the generation of defined mutants. The goal of this proposal is to harness the power of bacterial artificial chromosome (BAC) technology to make HSV amenable to bacterial genetic approaches. For some other herpes viruses, BAC technology allows the generation of several mutants in less than a week. This is in contrast to current HSV recombination methodologies that allow generation of a single mutant in 2-3 months. BACs will therefore be generated for each of the three major laboratory strains of HSV-1 and two strains of HSV-2. Prior to their use as templates for mutagenesis, viruses will be regenerated from each of these BACs and their phenotypes compared carefully to their original parental strains. This will ensure that the propagation of such viruses as BACs does not inherently cause any undefined changes in the gene expression profiles, virulence, or pathogenesis of any of these viruses. Once established and characterized these reagents will be deposited with ATCC to allow all researchers access to this powerful technology. This work will represent a major advance in the field in allowing the rapid generation of HSV mutants in a standardized fashion for basic research, as well as for vaccine, anti-tumor agent, and gene delivery vector development. The successful outcome of this proposal, consistent with the R03 program objectives and strategic goals of the NEI's Corneal Diseases Program, will have a major impact on the research of all laboratories working on HSV infections and their blinding sequelae. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELLULAR MECHANISMS OF HSV REACTIVATION Principal Investigator & Institution: Greenberg, Michael E.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-JUL-2006 Summary: (provided by applicant): Herpes simplex virus (HSV) infections in humans result in sporadic but recurrent lesions that appear at the site of the initial infection, and are now known to be the result of the reactivation of latent virus that resides within sensory neurons. As a large percentage of the human population experience some form of HSV infection, this virus represents a significant health issue. In this application, we propose a series of experiments that will investigate the cellular mechanisms that control the reactivation of latent HSV in sensory neurons. Based on prior studies of the response of peripheral neurons to axotomy, and the finding that the axotomy of sensory neurons triggers HSV reactivation, we hypothesize that a combination of neurotrophin

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withdrawal and cytokine secretion triggers HSV reactivation. To test this hypothesis and to identify intracellular signaling mechanisms that control HSV reactivation, we propose the following aims: 1. To characterize the sensory neurons that support ESV reactivation from latency by examining the expression of neurotrophin and cytokine receptors in latently infected neurons that are induced to support HSV reactivation. 2. To use neurotrophins, cytokines, and specific blockers of these factors to examine whether neurotrophins and cytokines regulate HSV latency and reactivation. 3. To identify the intracellular signaling pathways that are activated by extracellular stimuli that induce HSV reactivation in latently infected neurons, and to determine if these specific pathways play a critical role in regulating HSV latency and reactivation. Taken together, these aims will provide new insight into the cellular mechanisms that control the reactivation of latent HSV and may allow the generation of new therapeutics that could help to inhibit the reactivation process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMBINED GENE THERAPY FOR METASTATIC BREAST CANCER Principal Investigator & Institution: Ojeifo, John O.; Assistant Professor; V T Lombardi Cancer Res Center; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2001; Project Start 07-SEP-2001; Project End 31-AUG-2006 Summary: (provided by Applicant) Recurrence and metastatic dissemination of breast cancers account for a significant morbidity and mortality in women, and effective means of treating this subset of patients remains elusive. In his post-doctoral studies, John Ojeifo, M.D., Ph.D., developed a novel t h e rapeutic drug delivery system that utilizes genetically-engineered endothelial cells to treat a variety of diseases. In this Mentored Career Development Award application, the candidate outlines a plan that will enable him to mature into a fully independent investigator studying the therapeutic efficacy and safety of intravenously (IV)-administered, genetically-modified endothelial cells (GMECs) transduced to express a cytokine and a suicide transgenes in metastatic breast cancer-bearing mice. During years 1 and 2 of the award, the candidate will benefit from the co-mentorship of Dr. Marc Lippman, a renowned expert in breast cancer biology and treatment, and Dr. Esther Chang, an expert in gene therapy. By year 3, Dr. Ojeifo will be a fully independent investigator. The broad goal of this application is to establish an independent laboratory studying: (I) the molecular and cellular mechanisms contributing to immune dysfunction in human cancers, and (ii) devising novel strategies for effective and safe genetic therapy and prevention of human cancers. To this end, the applicant first plans to test the hypothesis that a mixture of endothelial cells stably expressing herpes simplex virus thymidine kinase (HSV-TK) and h u man interleukin-2 (hIL-2) transgenes can target sites of pulmonary metastasis of breast tumors, induce an anti-tumor immune response at the local site, and abrogate the tumors in mice. The Specific Aims of this proposal are: Aim 1: To construct a bicistronic retroviral vector containing herpes simplex virus thymidine kinase (HSV-TK) and E. coli lacZ genes with intervening IRES fragment, and generate endothelial cells expressing the HSV-TK and lacZ transgenes. Aim 2: To determine (a) How well murine endothelial cells expressing HSV-TK transgene can target metastatic sites of breast tumors, and (b) the effects of HSV-TK gene expression upon tumor metastasis and animal survival. Aim 3: To determine whether the administration of a mixture of hIL-2 genetically-modified endothelial cells (GMECs) and HSV-TK GMECs followed by ganciclovir treatment can induce an effective, specific, and long-term anti-tumor immune response, and abrogate lung metastasis of breast tumors in mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONTROL OF VIRAL RNA SYNTHESIS IN HERPES VIRUS INFECTION Principal Investigator & Institution: Wagner, Edward K.; Professor of Virology; Molecular Biology and Biochem; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2001; Project Start 15-MAY-1978; Project End 31-JAN-2006 Summary: The differential stability of interactions between kinetic classes of HSV promoters and the basal transcriptional machinery of the cell combined with virusmediated compartmentalization of transcription machinery does much to explain the selective expression and repression of various kinetic classes of viral genes during the different phases of the productive replication cycle. We will expand and validate this model by accomplishing the following: 1. Analyze the biochemical interaction between a class of strict late promoters that contain a downstream activating sequence (DAS), as exemplified by the UL38 promoter, and the DNA binding subunits (Ku) of the multifunctional cellular enzyme DNA-dependant phosphokinase (DNA-PK). A major feature of this investigation will be the use of cultured cells in which components of DNA-PK have been functionally deleted, and purified TFIID. 2. Choose model promoters to investigate other modes that HSV utilizes to directly stabilize the interaction between late promoters and the TFIID complex. HSV DNA micro-arrays will be developed for this study. 3. Investigate how the kinetic class-specific promoter structure of HSV transcripts influences the strength of binding of the pre-initiation complex to influence time of maximal expression. We will use purified TFIID for biochemical studies, as well as in situ hybridization methods for analysis of differential gene expression in individual cells. 4. Use cell culture and mouse pathogenesis models to study of the precise role of time and level of maximal expression of selected required viral genes. This work has been started with viruses expressing kinetic alterations in the major capsid protein (VP5). We will also study kinetic modifications of expression of the VP19 capsid protein, the virion trans- activating protein, and the immediate-early ICP 27 promoter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--HISTOPATHOLOGY AND MICROSCOPY Principal Investigator & Institution: Ishov, Alexander; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-AUG-1986; Project End 31-AUG-2006 Summary: Description (provided by applicant) The Microscopy and Histopathology Laboratory provides a service to these members of the program project, whose work involves the evaluation of tissue or cell alterations that occur in response to HSV infection. Tissue will be embedded, sectioned, and stained. Microscopy services will be provided, including confocal microscopy. Dr Ehud Lavi, neuropathologist, will continue to provide anatomical advice on the sections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--LABORATORY Principal Investigator & Institution: Morrow, Rhoda A.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: The Virology Laboratory Core provides virologic, immunologic, and molecular laboratory testing for HSV and HIV in 3 well established, accredited

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diagnostic laboratories; each directed by University of Washington (UW) faculty involved in this Program Project: the UW Virology Laboratory at Children's Hospital and Medical Center (CHMC; directed by Dr. R Ashley), the UW Retrovirology Laboratory at University of Washington Health Sciences Center (directed by Drs. R. Coombs and L. Corey)) and the Molecular Virology Laboratory at the Fred Hutchinson Cancer Research Center (FHCRC; directed by Dr. L. Corey). The CHMC lab will perform HSV isolation, serology, and antiviral sensitivity testing to diagnose and characterize HSV infections in subjects enrolled in Project I-IV. The UW Retrovirology Lab will perform HSV PCR, in situ HSV PCR< and HSV restriction enzyme analyses. Lab testing at these 3 sites will be supplemented by specialized testing performed in the research laboratories of Dr. R. Ashley at CHMC (mucosal antibody testing) and Dr. D. Koelle at FHCRC (CD8+ pCTL testing). Testing performed in these 5 sites will follow uniform practices of quality assurance and quality control which are established and reviewed biannually by the College of American Pathologists for accreditation of our diagnostic testing services. Accesioning of specimens, specimen handling and banking, specimen retrieval, and reporting will be performed according to uniform guidelines to assure accurate test results as well as smooth electronic data transfer between laboratories and the data management team; between laboratories and investigators involved in Projects I-IV, and between data management and the Administrative Core. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--VECTOR 1--ADENOVIRUS/ADENO ASSOCIATED VIRUS HERPESVIRUS LIPOSOME Principal Investigator & Institution: Hackett, Neil R.; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2002 Summary: Core A (Vector 1) will provide assistance in the design, construction and struCtural verification of gene therapy vectors based on adenovirus (Ad), adenoassociated virus (AAV), herpes simplex virus I (HSV). The major role of the core is to provide knowledge and biological materials to the investigators so they may focus on the biological aspects of their projects rather than the technology of gene therapy. For this reason the core will fulfill the following roles: Perform large scale vector preparations for the participating projects (target 50 preparations /year) in accordance with the core usage allocations and resources available; Create new gene therapy vectors by importing improvements in the technology and / or new transgenes that are important for the participating projects (target 18 / year); Provide Standard Operating Procedures for all phases in the construction of all three types of viral vector; Education in construction of vectors through tutorials with senior core scientists and shadowing core technicians; Supply verified samples of biological materials for the vector construction including plasmids, cell lines and starting vectors, and maintain a database describing those materials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORNEAL DISEASE--MECHANISM OF LATENCY OF HSV-1 Principal Investigator & Institution: Mitchell, William J.; Assistant Professor; Veterinary Pathobiology; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2001; Project Start 01-AUG-1997; Project End 31-JUL-2003 Summary: The most common cause of infectious corneal blindness in humans in the developed world is herpes simplex virus induced keratitis. The available evidence

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indicates that HSV initiates and produces this corneal inflammatory disease. The pathogenesis of herpes stromal keratitis, requires that HSV-1 be maintained as a latent infection in the ophthalmic sensory neurons of the trigeminal ganglia and that it be periodically reactivated. The reactivated virus can either contribute to the corneal inflammatory disease or infect new hosts. the underlying basis of herpetic corneal disease is latent neuronal infection by HSV-1. The stimuli which cause reactivation of HSV usually involved changes in the physiology of the host cell. This coupled with a failure to demonstrate viral genes that control the latent and reactivated viral genome, leads to the hypothesis that neuronal transcriptional proteins control this process by activating or repressing viral immediate early (IE) gene expression. No suitable model for studying the regulation of HSV-1 latency exists in cultured cells. The application of transgenic technology offers a powerful way to test whether host transcriptional proteins control latent HSV infection of sensory neurons. The experiments described in this proposal are intended to delineate the underlying mechanism by which the virus is regulated by host cells during latent and reactivated infections. An understanding of this mechanism should lead to design of strategies or prevent HSV induced corneal disease. The objectives of these studies are: 1) Establish whether host transcriptional proteins can regulate HSV IE genes in neurons in vivo and whether viral IE genes can be regulated in a way that would be appropriate for controlling latent and reactivated infections. 2) Determine whether inhibition or stimulation of viral Ie gene expression will result in alteration of the ability of HSV to establish a latent infection and reactivate. 3)Determine whether host transcriptional regulatory proteins can modulate latent and reactivated HSV infections of sensory ganglia in tansgenic mouse models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DERG ENCEPHALITIS

(IMMUNOMODULATOR)

TREATMENT

OF

VIRAL

Principal Investigator & Institution: Rosenthal, Kenneth S.; Microbiology and Immunology; Northeastern Ohio Universities Coll Med P.O. Box 95 Rootstown, Oh 44272 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): The ultimate goal of this program is to develop a prophylactic or therapeutic agent (derG) for treatment of medically important viral and other infections for which there may not be treatment or the treatment is too toxic. DerG was identified as a new immunostimulatory peptide as a result of work on L.E.A.P.S.TM vaccine technology. The derG peptide is based on sequence from the beta chain of the MHC II molecule and is an altered peptide ligand of the CD4 molecule. Preliminary studies in different laboratories indicate that derG can induce protection against parasitic malarial sporozoite and herpes simplex virus challenge and act as an adjuvant for tumor vaccine therapy. Administration of derG within 3 days (or less) or up to 4 weeks in advance of infectious challenge elicited protection against HSV challenge. The proposed investigation will extend our studies of derG on HSV and determine by using mouse models whether derG protects against viral encephalitis by HSV and an arbovirus, S.A. AR86 sindbis-Iike alphavirus. Our specific aims are to: 1) establish the efficacy of derG against these viruses; 2) develop in vitro assays for derG activity to allow screening of analogues, other drugs and to maximize potential for the following aims; 3) determine the mechanism of action of derG; 4) design and prepare for evaluation derG analogues in vitro and in HSV challenge models and initiate procedures required to pursue FDA approval of derG for human therapy. This project is part of a continued collaboration between an academician and CEL-SCI Inc., a

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biotechnology-vaccine development company. CEL-SCI is committed to provide support including technological development, quality control, scale up to GMP level development, access to preclinical development, methods for toxicological and pharmacological testing, clinical testing and data management resources. Successful development of derG may provide a broad spectrum, immunoenhancing prophylactic and therapeutic treatment that can be provided in lieu of, or to enhance vaccination prior to travel or assignment to a region of high risk for exposure to infectious or bioterror agents upon short notice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA VACCINE EFFIICACY IN HERPES SIMPLEX VIRUS TYPE 2 Principal Investigator & Institution: Bernstein, David I.; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Adapted from Applicant's Abstract) Herpes simplex virus type 2 (HSV-2) infection is one of the most common sexually transmitted diseases. Following acute infection of the genital tract, the virus becomes latent and can reactivate to cause recurrent disease or be shed asymptomatically. Therefore vaccines can either be prophylactic, preventing or modifying the initial infection, or therapeutic, preventing or minimizing recurrent disease in those previously infected with HSV-2. To date neither vaccine strategy has been successful. One recent vaccine strategy utilizes DNA but this approach has not been optimized. In this application, we describe experiments designed to increase the effectiveness of HSV DNA vaccines. Because protection from both acute and recurrent HSV disease appears to be mediated by T cells, the initial aims are to evaluate HSV-2 glycoprotein B (gB) DNA vaccines targeted to the endosome/lysosome to increase MHC class II presentation and the CD4+ response (Aim 1). We also will characterize gB DNA vaccines targeted to the proteasome to increase MHC Class I presentation and the CD8+ T cell response (Aim 2). We will verify targeting, evaluate T cell responses, and assess these vaccines in our well-characterized small animal models of HSV-2 infection. In Aim 3, we will combine the best MHC class I and MHC class II targeted vaccines and evaluate their combined efficacy. In Aim 4, we will examine the effects of co-expressing gB with immune homing receptors. By targeting the antigen presenting cells to the lymph nodes we hypothesize that we will increase both the HSVspecific and innate immune response and protection. Our experience with the murine and guinea pig models as well as the virologic, clinical and immunologic endpoints make these models ideal for examining the strategies proposed. The experiments proposed will improve our understanding of the protective immune response for acute and recurrent disease, increase our knowledge of targeted DNA vectors for HSV-2 and other pathogens, and should result in improved DNA vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENGINEERED HERPES SIMPLEX VIRUS FOR TREATMENT OF GLIOMAS Principal Investigator & Institution: Markert, James M.; Professor; Surgery; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-SEP-1997; Project End 31-AUG-2002 Summary: The purpose of this Mentored Clinical Scientist Development Award application is to provide the necessary training for the principal investigator to develop into a fully independent investigator applying molecular medicine to diseases of the

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central nervous system (CNS). Specifically, the application proposes to engineer novel modifications into the genome of herpes simplex viruses (HSV) for the purpose of developing a safe and effective therapy for human gliomas. The development of these viruses will include foreign gene inserts to enhance the oncolytic activity of these viruses. Multiple genes from the HSV genome will he deleted to enhance the safety of this therapy. Double probes will be utilized to determine the distribution of both latent and actively replicating HSV in the CNS of treated animals. As virus constructs are developed, their biologic behavior will be evaluated in both in vitro and in vivo glioma models. This will include assessment of replication, antitumor activity, and the degree of foreign gene expression. In vivo evaluations will be conducted in both scid and c57BL/6 mice bearing intracranial gliomas to calculate the effects of immune response on tumor regression and host survival. Tissue sections will be examined to evaluate glioma eradication, neurovirulence, residual infectious virus, and immune response. Promising constructs will then be tested for neurovirulence in the HSV-sensitive simian primate, Aotus. The mentors who will direct this training proposal are international experts in herpes simplex virology and in glioma biology. The program is fully endorsed by the Division of Neurosurgery, which will provide all necessary resources. The candidate's career objective is to become a clinician-scientist who both 1) develops new models for the treatment of neurological diseases based on molecular medicine and 2) bridges basic science and clinical medicine by bringing such therapies into clinical use. An integral portion of the training program will thus be aimed at developing expertise in the design and administration of clinical trials. The candidate's immediate goals are to participate in an organized program that will provide the necessary training to become a fully independent investigator in this area while studying a novel therapy for brain tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FIDELITY OF HERPES SIMPLEX VIRUS DNA REPLICATION Principal Investigator & Institution: Hwang, Charles B.; Microbiology and Immunology; Upstate Medical University Research Administration Syracuse, Ny 13210 Timing: Fiscal Year 2001; Project Start 01-AUG-1992; Project End 31-DEC-2002 Summary: Herpes simplex viruses (HSV) are important pathogens affecting more than 50% of the general population HSV infections can cause aggressive intraoral and extraoral herpetic lesions. The successful treatment of HSV infections is complicated by the increasing prevalence of drug resistant mutants, which is becoming a clinical problem, especially in immunocompromised individuals. This possesses the need for new antiviral drugs and alternate therapeutic strategies against mutant viruses. An understanding of the mechanisms by which DNA is replicated and mutations evolve will be of value for future designs of new antiviral drugs and treatments. DNA polymerase (pol) is the pivotal enzyme involved in DNA replication. It plays the central role controlling the mutation rate by two major steps: selection of the correct nucleotides to be incorporated into the growing primer terminus, and proofreading or editing of the incorrectly incorporated nucleotides. Numerous mutagenesis and kinetic studies of a variety of Pols have already been conducted in vitro to reveal the mechanisms controlling the fidelity of DNA replication. HSV DNA replication has been proven to be an excellent model for the study of DNA replication, since HSV can be genetically amended for in vivo and in vitro characterization. Using this unique property, the effects of mutations in the pol gene can be analyzed in virus-infected mammalian cells. The in vitro characterizations of the same mutant Pol can also be studied by molecular biological and biochemical assays. Therefore, information obtained from the studies of a variety of mutant pols will be of value for a better understanding of the molecular

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mechanisms of DNA replication and replication fidelity. This information will also shed light on the structure-function relationship of Pol, which will be useful for future studies of new antiviral treatments. Our goals in this project include the following: 1. To examine the mutation spectra in different target genes induced by various HSV pols. 2. To examine sequence context effects on the misinsertion fidelity of HSV pols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FORMULATION OF COMBINATION MICROBICIDES Principal Investigator & Institution: Rohan, Lisa C.; Magee-Womens Hlth Corp Pittsburgh, Pa Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Description (provided by applicant): The overall goal of this proposal is to develop a formulated combination microbicide which will prevent the spread of human immunodeficiency virus (HIV) both vaginally and rectally utilizing multiple protective factors which inactivate the virus at different stages in its replication cycle. Inhibition of HIV attachment to the CD4 cellular receptor will be accomplished by formulating plantderived flavonoids with sulfated polysaccharides (carrageenans). There will therefore be redundancy built into the microbicide to inhibit HIV binding to its cellular receptor. Virucidal compounds, which destroy the viral envelope, will also provide redundant protection from infection. Both the antiviral ether lipid 1-0-octylsn- glycerol and citric acid will destabilize the envelopes of viral particles. Furthermore, the HIV reverse transcriptase will be inactivated by both antiviral flavonoids and a non-nucleoside reverse transcriptase inhibitor (Dr. Parniak, Project 1). Herpes simplex virus (HSV) will also be targeted by flavonoids, carrageenans, 1-0-octyl-sn-glycerol and citric acid to reduce genital ulceration and consequently the transmission of HIV to a greater extent than inactivating HIV only. Methods will be developed to quantify antiviral agents at each step in the pre-formulation and formulation process and physical and chemical pre-formulation data including solubility, stability, partitioning, and permeability data will be developed as part of these studies. Once active agents have been selected, their compatibility and toxicity with normal vaginal microflora and local tissues in both the isolated and formulated state will be determined. Following the initial formulation and development of a combination microbicide product, the microbicide will be optimized to maximize each antiviral mechanism and minimize toxicity in an iterative manner. The final formulated product will undergo stability testing, and product assessments will be made to ensure that the product has appropriate physical, chemical, microbiological, and antiviral properties during its shelf life. This project contributes to the program by producing new combinations of formulated microbicides based upon inhibition of viral replication using multiple and redundant antiviral mechanisms. Formulated combination microbicides produced in this project will be evaluated in vitro against HIV (Dr. Parniak, Project 1; Dr. Gupta, Project 2) and normal vaginal flora (Microbiology Core, Dr. Hillier), and as well as in humans (Dr. Landers, Project 4). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE ENGINEERING OF NERVE STEM USING HSV AMPLICON VECTOR Principal Investigator & Institution: Saeki, Yoshinaga; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2004

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Summary: (provided by applicant): The development of a novel strategy to genetically modify neural stem/progenitor cells (NSCs) both in vitro and in vivo will have a significant impact on the development of NSCs-mediated cell therapy for neurological disorders as well as on the advance of basic developmental neurobiology. We recently have developed a packaging system for herpes simplex virus (HSV)-based amplicon vectors free from helper virus contamination or viral gene expression. Using this technology, we have demonstrated that genomic DNA inserts over 100 kilobases can be packaged into HSV virions, delivered intact, and expressed in cultured cells in vitro. By adding Epstein-Barr virus (EBV)-based replicon elements, HSV amplicons with genomic DNA inserts (HSV/EBV/genomic vectors) were shown to replicate and be maintained as extra chromosomal elements in infected cells, and express functional gene products for a long period of time. The unique properties of this vector system lead us to hypothesize that HSV/EBV/genomic vectors can be a platform technology to achieve some of the long-term goals toward the development of NSCs-mediated cell therapy, namely: 1) Complementing genetic defects of diseased NSCs in vitro and in vivo to treat genetic neurological disorders, 2) stable and cell type-specific transgene expression in neurons and glial cells differentiated from the transduced NSCs, and 3) genetic engineering of NSCs for controlled proliferation, migration, and differentiation in vivo after transplantation. To evaluate the feasibility of this approach, this project proposes to: 1) Verify episomal replication and maintenance of HSV/EBV/genomic vectors and evaluate furictional transgene expression from the vectors in dividing NSCs in culture, and 2) verify stable and cell-type-specific expression of genomic transgenes in terminally differentiated neurons and glial cells both in vitro and in vivo. We will examine five human genes, hypoxanthine-phosphoribosyltransferase, nestin, myelin basic protein, glial fibrillary acidic protein, and microtubule-associated protein tau as a housekeeping, NSC-specific, oligodendrocyte-specific, astrocyte-specific, and neuronspecific gene, respectively. These studies will provide further understanding of HSV/EBV/genomic vectors and confirm the advantages of genomic transgenes and EBV elements, which then should provide a strong basis for genetic engineering of NSCs using HSV/EBV/genomic vectors Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR GLIOMA Principal Investigator & Institution: Lowenstein, Pedro R.; Director and Professor; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 90048 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Glioblastoma multiforme (GBM) is the most aggressive brain tumor and kills through intracranial growth and spread. We have previously shown (i) the efficiency of the herpes simplex virus type 1 thymidine kinase (HSV1-TK) and systemic ganciclovir (GCV) in eradicating an experimental syngeneic glioma model, (ii) 2-3 fold higher astrocyte- and glioma-specific high-level expression from the powerful 1.4kb major immediate early routine cytomegalovirus promoter (mCMV) compared to the human CMV equivalent, and (iii) unexpected long-term presence (12 months) of HSV1-TK in the brain. Although the efficiency of HSV 1-TK and GCV has been shown in a large variety of experimental models, the clinical results, while encouraging, remain inconclusive. The main reason thought to underlie this difference is the low levels of HSV1-TK expression from currently available vectors. Our experiments will address this issue by vastly increasing therapeutic transgene expression (through the use of a novel promoter) and reducing the viral vector toxicity (through the use of novel safer vectors of reduced toxicity). These findings will have

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important clinical implications and provide a blueprint for the implementation and design of Phase I clinical trials of gene therapy for GBM. We will validate the efficiency of a novel, safe, high capacity, helper dependent adenoviral vector (HC-Ad) expressing HSV1-TK under the control of the powerful mCMV promoter in a clinically relevant syngeneic experimental glioma model. HSV1-TK induces glioma cell death by phosphorylating the prodrug GCV, and killing both transduced and adjacent nontransduced, actively dividing cells. Killing of non-transduced cells, the 'bystander effect', amplifies this strategy's efficiency through cell-cell diffusion of cytotoxic intermediates (e.g. phosphorylated GCV), release of pro-apoptotic molecules, and immune stimulation. We hypothesize that our novel anti-tumor strategy will deliver high intraand peritumoral expression of the therapeutic transgene that, combined with systemic dosing of GCV, will lead to sustained and effective anti-tumor effect. Our long term aim is to translate this novel therapeutic approach into a Phase I clinical trial for GBM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR HEREDITARY TUMORS IN MODELS OF NF2 % TSC Principal Investigator & Institution: Breakefield, Xandra O.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 23-JAN-1987; Project End 31-AUG-2006 Summary: (provided by applicant): Studies will be undertaken to develop modes of gene delivery to experimental neural tumors for therapeutic intervention. Neoplastic lesions associated with tuberous sclerosis (TSC) including subependymal glial nodules, giant cell astrocytomas and cortical hamartomas, are believed to represent the consequences of loss of tumor suppressor genes on growth of astrocytes, neuroprogenitor cells and mesenchymal elements. Tumor models in the TSC2 heterozygous and conditional knock-out mice have been chosen as they are genotypically similar to mutations seen in patient cells and derive spontaneously from endogenous cells. They include liver hemangiomas, renal cell carcinomas, cortical hamartomas, and potentially subependymal glial nodules. Gene delivery to these tumor cells will be explored using three types of hybrid amplicon vectors derived from herpes simplex virus type 1 (HSV): one bearing a tetracycline (tet)-regulatable transgene cassette; one bearing elements of adeno-associated virus (AAV) to promote chromosomal integration; and one with both Epstein Barr virus (EBV), elements to promote episomal retention, and retrovirus vector elements (RV), to convert ampliconinfected cells into retrovirus producer cells. Vectors will be delivered through the intravascular route, either directly or via endothelial carrier cells to vascularized tumor foci; by intrathecal injection for brain lesions; and by direct intratumoral injection to large tumor masses. The efficiency and longevity of gene delivery to tumors in vivo will be established using reporter genes. Effective delivery modalities will incorporate therapeutic transgenes for anti-angiogenic and apoptosis factors, and consequences to tumor growth and pathology will be evaluated. In parallel, we will incorporate additional elements into these vector systems to increase the fidelity of regulatable transgene expression and to facilitate gene delivery to slowly growing tumors, typically seen in patients. This will include, in the first case, use of a tetracycline-silencer element and elimination of the VP16 transactivating protein from virions to achieve a "full off? state in the absence of drug, and, in the second case, replacement of RV elements in the HSV/EBV vector with components of lentivirus (LV) vectors, which are able to integrate transgenes into both dividing and non-dividing cells. TSC2 +/-transgenic and TSC1 conditional knock-out animals will be provided by Dr. Kwiatkowski (Project 12);

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pathologic expertise by Dr. Louis (Core C); assistance with vector engineering by Dr. Sena-Esteves; and MRI analysis by Dr. Weissleder. This project is designed to develop a strategy for reducing bulk in slow growing, benign tumors using vectors safe enough for eventual human use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY, STRESS AND HIPPOCAMPAL FUNCTION Principal Investigator & Institution: Sapolsky, Robert M.; Biological Sciences; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The hippocampus has been studied for its synaptic plasticity, role in cognition, and the neurogenesis that occurs in the adult hippocampus. With this has come an appreciation of endocrine modulators of hippocampal function. Specifically, glucocorticoids (GCs), adrenal steroids secreted during stress, disrupt [or] impair facets of synaptic plasticity and cognition, and inhibit neurogenesis. Estrogen, in contrast, enhances plasticity, cognition and neurogenesis. There has also been progress in the use of viral vectors to deliver transgenes into the CNS. We will use herpes simplex virus-1 vectors in a gene therapy strategy to protect the hippocampus from the disruptive effects of GCs and of stress, and to divert some of those GC effects into salutary estrogenic ones. We have constructed and wish to explore the protective potential of vectors expressing a) an enzyme which degrades GCs; b) a dominant negative GC receptor; c) a chimeric steroid receptor which binds GCs but has the genomic actions of an estrogen receptor. In Aim 1, we will alter these vectors to make them inducible by stress and GCs, as a means to have their expression triggered by insults. We will then characterize their patterns of expression. We will then examine the protective potential of these vectors, examining if the first two spare neurons from adverse GC effects, and if the chimeric vector also generates the salutary estrogenic effects when exposed to GCs. In Aim 2, the endpoint will be long-term potentiation in hippocampal slices generated from rats with differing pre-mortem regimes of GC exposure or stress. In Aim 3, we will study the effects of GCs, stress, and these vectors upon a hippocampal-dependent cognitive task. In Aim 4, we will study neurogenesis in vitro and in the adult hippocampus. We will characterize the effects of GCs, stress and estrogen upon it. We will then determine whether these vectors can protect neurogenesis from the inhibitory effects of GCs and, in the case of the chimeric vector, harness this to produce stimulatory estrogenic effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE TRANSFER FOR PREVENTION OF DIABETIC NEUROPATHY Principal Investigator & Institution: Fink, David J.; Professor; Neurology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2006 Summary: (provided by applicant): Polyneuropathy is a common and often debilitating complication of diabetes. In several animal models of diabetic neuropathy, it has been demonstrated that trophic factors administered by systemic injection may prevent progression or reverse signs of neuropathy. But translation of systemic trophic factor therapy to human disease has not succeeded, in large part because patients have proven to be unable or unwilling to tolerate the range of doses that are required to achieve a therapeutic effect. We have engineered and developed recombinant replicationincompetent genomic herpes simplex virus (HSV)-based vectors for gene transfer to the

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nervous system, and in the initial grant proposed to exploit the natural tropism of these vectors for peripheral sensory neurons of the dorsal root ganglion (DRG) to test the hypothesis that neurotrophin gene transfer to the DRG by means of an HSV-based vector can be prevent the progression of diabetic neuropathy. We now propose to extend these studies to accomplish two groups of specific aims, designed to explore the most effective strategy for the development of a novel therapy for diabetic neuropathy and to explore the molecular basis of that effect. Specific Aim 1. To define the time course of protection against diabetic neuropathy comparing transiently active promoter with a promoter that provides prolonged transgene expression. Specific Aim 2. To determine the dose-response characteristics of the vector-mediated effect. Specific Aim 3. To determine whether HSV-mediates gene transfer of IGF-1 or VEGF165 alone or in combination with NGF, is effective in preventing the progression of diabetic neuropathy. Specific Aim 4. To examine the effect of STZ diabetes on the alteration in gene expression in DR (neurons and Schwann cells in vivo, and to identify specific alterations in that expression that are reversed by vector transduction. Specific Aim 5. To construct a vector with a regulatable "switch" to control transgene expression safe). Diabetic neuropathy is a difficult complication of the primary disease. Factors of known therapeutic efficacy have been identified in animals models, and we have made substantial progress in constructing a vector to deliver these factors to the peripheral nervous system. The studies in this proposal are designed to allow the development of an effective therapy appropriate for the treatment of patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENERATION OF HERPES VIRUSES FOR IN VIVO OBSERVATION Principal Investigator & Institution: Maul, Gerd G.; Professor; Wistar Institute Philadelphia, Pa 191044268 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): The effect of viruses on the host can be observed at different levels of complexity and resolution depending on the technique used. The single-cell observation combined with various labeling techniques has provided great insight into host-virus interactions; however, the observations are made on fixed (dead) infected cells. We propose to develop an in vivo virus genome labeling system that will allow observation of virus genomes in live cells. Visualization of a viral genome in vivo requires tagging its DNA sequence. The construction of a "green" genome is possible by labeling a DNA tag in the viral genome as it enters the nucleus or before packaging with green fluorescent protein (GFP). Cells inducibly producing the GFP-fusion protein to bind to the DNA tag will be generated to assemble a system where upon virus entry into the nucleus or during packaging the viral genome is rendered "green" through very tight binding of the DNA tag and the reporter protein. These genomes can be visualized by confocal microscopy and documented in a time-resolved fashion by time-lapse microscopy. We propose to produce DNA-tagged recombinant herpes simplex virus and mouse cytomegalovirus. To complete the system, we will develop cell lines that inducibly produce GFP-labeled DNA-binding protein, where HSV-1 and MCMV can replicate and which are useful as quiescent ("latent") virus containing cultured cell model systems. Such a new system would recognize single viral genomes directly in the live cells and obviate in situ hybridization. The "green" viral genomes will open up new lines of inquiry into the dynamics of virus entry into the nucleus, the sequence of degradation by endonucleases and/or retention in a nuclease-resistant episome, replication and segregation by multiple observation of single cells or populations during

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quiescence, affinity immune separation of quiescent viral genomes and identification of viral genomes by immunoelectron microscopy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICALLY ENGINEERED VIRUSES FOR BRAIN TUMOR THERAPY Principal Investigator & Institution: Martuza, Robert L.; Chief of Neurosurgery; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-MAY-1994; Project End 31-MAR-2007 Summary: (provided by applicant): We have developed genetically engineered herpes simplex virus-1 (HSV-1) vectors that can selectively and efficiently infect and kill brain tumor cells in situ without harming surrounding brain cells and without causing systemic disease. Having taken one such vector into human clinical trial, we set forth testable hypotheses aimed at further understanding and improving this method of brain tumor therapy. In order to increase the efficacy of HSV oncolysis in brain tumor therapy, we hypothesize that: a.) HSV oncolytic therapy can be improved by using a HSV vector in conjunction with commonly used chemotherapeutic agents for brain tumors; b.) The efficacy of herpes vectors for brain tumor therapy can be improved through the use of a HSV backbone that replicates better in glioma cells while retaining the necessary safety features for clinical trials. In order to better understand and improve the delivery of HSV vectors for brain tumor therapy, we hypothesize that: a.) Some of the efficacy following intravascular or intratumoral HSV tumor therapy may be due to selective injury of tumor vasculature versus normal vasculature; b.) The timing of co-treatment with antiangiogenesis agents may either inhibit or augment the selective injury to tumor vasculature by oncolytic HSV vectors; c.) Prior anti-HSV immunity could alter the efficacy of intravascular delivery of oncolytic HSV but can be modulated with immunosuppressive agents. In order to further improve the anti-tumor immunity induced by HSV tumor therapy, we hypothesize that: a.) Defective HSV vectors expressing immune-modulatory genes will increase the survival of animals harboring intracranial tumors, b.) A recombinant virus can be constructed from an appropriate parent virus that will express a cytokine without down-regulating MHC-I thus enhancing the anti-tumor immune response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HERPES SIMPLEX VIRUS AND NGF DIFFERENTIATED PC12 CELL INTERACTION Principal Investigator & Institution: Block, Timothy M.; Professor and Director; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-AUG-1986; Project End 31-AUG-2006 Summary: Description (provided by applicant) This project is concerned with how neuronal cells manage HSV infection at the intracellular level. The intracellular details of HSV/neuronal cell interactions are difficult to study in vivo. Information regarding the mechanisms and kinetics of HSV genome physical organization following neuronal cell infection in vivo and even in vitro is extremely limited. We have, therefore, developed a tissue culture system of quiescent HSV infection using nerve growth factor (NGF) differentiated cells. This system will be used to determine the impact of HSV upon NGF differentiated cells and to track the fate and structure of viral DNA following infection. Briefly, NGF differentiated PC 12 cells have been shown to support long-term "quiescent" infections of HSV-1. NGF differentiated PC12 cells are not killed by virus

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infection and, surprisingly, persist longer than uninfected controls. There is little viral transcription and progeny is not detected in the culture medium, despite the presence of an inducible infectious genome. Strangely, the viral genome in quiescently infected PC12 cells persists as a linear form for several weeks before ultimately assuming an endless, presumably circular, state. These cells will, therefore, be used to study (a) if and how HSV can cause populations of PC12 cells to have a survival advantage over uninfected populations; (b) how linear viral genomes can be maintained intact, for weeks in neuronal like cells; (c) the mechanism(s) involved in their assumption of an endless, possibly modified, quiescent viral genomic state. Observations made in this in vitro system will be related to in vivo mouse models of latency by comparing the physical properties of viral DNA derived from tissue derived from infected mice with that from quiescently infected PC12 cells. This work will thus allow for the testing of hypotheses made about HSV latency seen in the vitro system, in mouse models of latency. Some of the information being uncovered in the in vitro, quiescent infection system has the exciting potential to influence our understanding of how HSV genomes are organized and "silenced". Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HERPES SIMPLEX VIRUS IN THE TREATMENT OF ORAL CANCER Principal Investigator & Institution: Shillitoe, Edward J.; Professor and Chairman; Microbiology and Immunology; Upstate Medical University Research Administration Syracuse, Ny 13210 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: We will develop new strains of Herpes simplex virus type-1 (HSV- 1) for use in the treatment of oral cancer. HSV- 1 has potential as a therapeutic tool for oral cancer since it infects oral epithelium as its natural host tissue, is highly cytotoxic, and spreads rapidly from one cell to another. The only disadvantage of HSV-1 is that it can spread to the nervous system, causing paralysis and death. To prevent this, we will develop a new strain of the virus whose replication is limited to oral cancer cells. This will be done by removing a promoter that controls expression of an essential viral gene, and replacing it with a promoter that is active in oral cancer cells but not in nervous- system cells. We will increase the anti-tumor effect of the virus by adding a gene for a cytokine. This will increase the local immune response to the infected tumor. We will then make the antitumor effect even stronger by exploiting the anti-tumor bystander effect that occurs when ganciclovir is activated by HSV-1. We expect that the triple combination of a tumor- restricted virus, enhanced local immune response, and anti-tumor bystander effect will be more effective in treatment of an experimental model of oral cancer than other treatments, and could lead to human trials in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HERPES SIMPLEX VIRUS INHIBITION OF CTL INDUCED APOPTOSIS Principal Investigator & Institution: Jerome, Keith R.; Laboratory Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JAN-1998; Project End 31-DEC-2001 Summary: The herpes simplex viruses (HSV) establish lifelong infection in their host. These viruses are thought to have evolved in parallel with their hosts, and therefore have developed intricate strategies for co-existing with the immune response. In preliminary studies for this proposal, I have demonstrated that HSV-1 inhibits the

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oligonucleosomal DNA fragmentation characteristic of apoptosis, including apoptosis induced by CTL. Since recent reports suggest that cells undergoing apoptosis are not suitable for viral replication, the induction of apoptosis may be a critical function for CTL control of viral infection. Inhibition of apoptosis would therefore promote viral replication. In contrast to its inhibition of DNA fragmentation, HSV has no effect on the membrane manifestations of apoptosis, such as phosphatidylserine exposure. In this proposal, the ability of HSV-2 to inhibit apoptosis will be evaluated. The HSV-1 and -2 genes mediating the anti-apoptotic effect will be identified, using compounds limiting HSV gene expression to individual transcriptional classes, followed by analysis of HSV deletion mutants. The cellular targets of each HSV anti-apoptotic gene will be identified using the yeast two-hybrid system. Finally, the ability of HSV to interfere with different apoptosis-inducing mechanisms of CTL will be determined using anti-Fas antibody and isolated perforin and cytotoxic granule components. The results of these studies will improve our understanding of HSV evasion of the immune response, and may suggest therapeutic strategies to circumvent this evasion. In addition, these studies will provide new probes and insight into the cascade of intracellular events following induction of apoptosis, especially the terminal effector events, since HSV inhibits nuclear but not membrane events of apoptosis. The work will also provide insights into how the manifestations of apoptosis vary depending on the inducing stimulus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HERPES SIMPLEX VIRUS TERMINASES Principal Investigator & Institution: Baines, Joel D.; Associate Professor; Microbiology and Immunology; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2001; Project Start 01-JAN-1995; Project End 31-DEC-2003 Summary: The long term goal of these studies is to elucidate the molecular mechanisms by which herpes simplex virus cleaves intranuclear concatameric viral DNA and packages the DNA into preformed intranuclear capsids. We and others have found that several proteins including UL6, UL15, UL17, and UL28 proteins are essential for DNA packaging but are dispensable for assembly of capsids. We hypothesize that procapsids (bearing UL6 in the outer shell and UL28 in the inner shell) are transported by action of UL17 protein to intranuclear sites containing the ATPase- bearing terminase subunit UL15. UL15 (bound indirectly to DNA) docks with UL6 protein in the capsid and is proteolytically cleaved. The cleaved protein binds the procapsid-bound DNA- binding subunit of the terminase, UL28 protein. The two subunit terminase then cleaves DNA that is looped into the capsid, scans DNA for a second cleavage site, and exits the capsid after this second cleavage. The goals of specific aims in this proposal are to test predictions of this hypothesis. Specific aim 1 will test the significance of UL15 proteolytic cleavage to cleavage and packaging, and test relevance of UL15 docking with capsid-bound UL6 protein. The pursuit of this aim will also include characterization of the UL15 docking site. Specific aim 2 will determine how UL28 associates with the capsid and test the relevance of detected DNA binding and cleavage activities of UL28 protein to DNA cleavage/packaging. The relevance and mechanism of interaction with UL15 protein will also be tested. The goals of specific aim 3 are to determine the role and mechanism of UL17 capsid/capsid protein transport in living cells and determine the relevance of this activity to cleavage/packaging. The relevance of the activities/interactions addressed in specific aims 1-3 will include identification of mutations that disrupt the activities/interactions in vitro, followed by testing proteins

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bearing such mutations for the ability to rescue viral null mutants lacking the respective proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HERPES SIMPLEX VIRUS, EARLY BRAIN INJURY AND EPILEPSY Principal Investigator & Institution: Eid, Tore; Neurosurgery; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Herpes simplex virus type 1 (HSV-1) is a common cause of acute and recurrent disease in humans. After the primary infection, which usually occurs in childhood, HSV-1 remains dormant in the nervous system. This proposal is aimed at exploring a novel hypothesis that early infection with HSV-1 plays a critical role in the genesis of temporal lobe epilepsy (TLE). The virus may contribute to this by creating a specialized brain focus involving alterations in neural circuitry and formation of a unique glial/microvascular substrate that promotes epileptogenesis and maintenance of seizures. Several observations suggest that HSV-1 may cause TLE. For example, survivors of HSV-1 encephalitis frequently develop epilepsy. HSV-1, when causing encephalitis, preferentially invades and lesions limbic structures, including the hippocampus, which also shows neuropathological changes in TLE. Moreover, patients with medically intractable TLE have a ten times higher rate of latent HSV-1 infection in their hippocampus than control subjects. To evaluate our hypothesis two approaches are proposed. (1) To critically explore the connection between HSV-1 and TLE by assessing the presence of viral DNA (by polymerase chain reaction) and virions (by immunohistochemistry) in surgically resected hippocampi from TLE patients, and correlating these with the specific neuropathological characteristics of TLE, i.e. (a) loss of hilar interneurons, (b) gliosis, and (c) vascular proliferation. (2) To assess the causal relationship of HSV-1 to the development of chronic seizures and neuropathology in TLE, rat models of HSV-1 infection will be studied and experimental modifiers of infection such as (a) viral strain, (b) age, (c) fever/febrile seizures, and (d) acute seizures, will be evaluated. The cellular/molecular mechanisms of viral-induced neuropathology and seizures will be explored by investigating the pattern and time-course of viral invasion during the infection. If a viral causation of TLE is established, then this would not only open new avenues for prevention and control of this disorder, but also improve our understanding of viral-induced brain injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HERPES SIMPLEX VIRUS-1 LAT PROMOTER ANALYSIS Principal Investigator & Institution: Garza, Hildegardo H.; Texas A&M UniversityKingsville 700 University Blvd Kingsville, Tx 78363 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: Recurrent herpes simplex virus type 1 (HSV-1) ocular infections are the leading infectious cause of blindness in industrialized nations. Fewer than 10% of clinical cases are primary acute infections; the remaining 90% are recurrences of latent HSV-1. Although HSV-1 can reactivate spontaneously, stress and trauma (e.g., hypoand hyperthermia, ultraviolet light irradiation, and ocular surgery) can also reactivate latent HSV-1. The latency-associated transcript (LAT) gene has been implicated as a component of the pathway that induces the conversion from latency to an acute infectious state. While the LAT gene is known to be the only gone that is abundantly transcribed during latency, it does not appear to code for any known protein.

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Furthermore, the LAT transcript that accumulates during latency is not the coding region, but is probably a stable 2.0 kb intron that is spliced out of the primary 8.5 kb LAT transcript. This proposal aims to dissect out the transcriptional control of the LAT promoter and its associated enhancer region from three distinct strains of HSV-1. These three strains of HSV-1 differ in their ability to undergo spontaneous and stress-induced reactivation. If the pathway by which the virus senses and responds to adrenergic stimuli can be established, it should prove to be a rich source of therapeutic targets. This is desirable since antiviral therapy merely delays the onset of blindness and viruses may become resistant to treatment. The specific aims that will address this issue are: 1) To assess the efficacy of the three LAT promoter regions in driving luciferase production in neuronal and fibroblast cell cultures, 2) To assess the effect of the three LAT enhancer regions on luciferase production in neuronal and fibroblast cell cultures, and 3) To assess the effect of different combinations of LAT promoters and enhancers on luciferase production in neuronal and fibroblast dell cultures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HERPESVIRUS PERSISTENCE AND ONCOGENICITY Principal Investigator & Institution: Shenk, Thomas E.; Professor & Howard Hughes Investigator; Molecular Biology; Princeton University 4 New South Building Princeton, Nj 085440036 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: Changes in cellular biochemical pathways are fundamental to herpesvirus persistence and oncogenicity. We will employ new global approaches to identify viral genes that modulate cellular pathways and to identify the pathways that are altered, and then we will elucidate the mode of action of these altered pathways within the infected cell. Our approach will be comparative. The program will include the study of viruses in each of the three families of herpesviruses: alpha, herpes simplex type 1 virus and pseudorabies virus; beta, human cytomegalovirus; and gamma, Epstein- Barr virus and Kaposi sarcoma-associated herpes virus. Some herpes viruses contribute to human cancers (Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus), while others are not known to do so. Consequently, our program will compare tumor viruses with closely related non-tumor viruses. The long-term objective of the program is to better understand the mechanisms by which herpesviruses persist and contribute to oncogenesis in the infected host. We will search for additional viral genes that mediate persistence and oncogenicity, and we will study the mechanism of action of new genes that are identified. We also will identify cellular genes whose level of expression change after infection, and test the hypothesis that some of these altered cellular genes influence the outcome of the virus-host interaction, contributing to the persistence and/or oncogenicity of the viruses. The individual research projects are as follows. Project 1, Roizman. Comparative role of cellular functions in herpes simplex type 1 virus infection. Project 2, Enquist Comparative alpha-herpesvirus (herpes simplex type 1 virus and pseudorabies virus) infection of the nervous system. Project 3, Shenk: Viral and cell gene function in human cytomegalovirus replication and latency. Project 4, Moore: Viral and cellular gene regulation in Kaposi sarcoma-associated herpesvirus-associated tumors. Project 5, Kieff: Epstein-Barr virus and cell gene expression in latency and oncogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HETEROCONJUGATE VACCINES AGAINST HERPES SIMPLEX VIRUS Principal Investigator & Institution: Zimmerman, Daniel H.; Cel-Sci Corporation 8229 Boone Blvd, Ste 802 Vienna, Va 22182 Timing: Fiscal Year 2001; Project Start 01-JUN-1998; Project End 31-AUG-2004 Summary: The primary goal of this program is the development of L.E.A.P.S.(TM) heteroconjugate peptide vaccines against herpes simplex virus) to prevent or treat human infection. The heteroconjugate vaccines are constructed of peptides which contain defined T cell epitopes and peptides which are predicted to bind to T cells or antigen presenting cells. The T cell epitopes that are being used are from the ICP27, glycoprotein B, and glycoprotein D of HSV-1. Our Phase I studies proved the principle behind this new technology by showing that incorporation of a viral peptide epitope into a L.E.A.P.S. construct based vaccine can enhance and define the type of immune response which is elicited to promote the development of protective and not detrimental immune responses. A L.E.A.P.S. vaccine can then be formulation with LEAPS constructs assembled with adjuvants to produce defined immune responses to defined epitopes. The major goal of the Phase II studies will be to optimize the vaccine formulation with respect to L.E.A.P.S. peptide (or mixture), the adjuvant and other components to allow progression to human trials. In addition, we will study the mechanism of action by which the L.E.A.P.S. peptide potentiates the immune response. The HSV vaccines are also prototypes for the development of heteroconjugate vaccine to treat or prevent disease caused by other infectious agents. The ultimate goal of our study will be to develop sufficient data to allow progression to human trials. PROPOSED COMMERCIAL APPLICATION: Heteroconjugate peptide vaccines use proprietary new technology called L.E.A.P.S. (Ligand Epitope Antigen Presentation System) to provide treatment and/or prophlysis against herpes simplex virus (HSV) infection and disease. HSV is a common oral pathogen and sexually transmitted disease which also causes serious disease. An estimated 40 to 60 million Americans are infected with HSV with approximately 600,000 new cases occurring per year. The HSV vaccine will be prototypes for the development of heteroconjugate vaccines to treat or prevent disease by other infectious agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIGH-TITER HELPER VIRUS-FREE HSV-1 VECTORS Principal Investigator & Institution: Geller, Alfred I.; Associate Professor of Neurology; Neurology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): HSV-1 vectors are attractive for gene therapy of aging disorders that affect the brain because HSV-1 can persist indefinitely in neurons in the latent state and large HSV-1 vectors can coexpress multiple genes. This laboratory has developed a Herpes Simplex Virus (HSV-1) plasmid vector system for gene transfer into neurons. Using this system, we have begun to explore gene therapy approaches to specific aging disorders that affect the brain, such as Parkinson's Disease (PD). We have shown that delivery of a HSV-1 vector that expresses human tyrosine hydroxylase into the partially denervated striatum in the 6-hydroxydopamine rat model of PD results in long-term (1 year) biochemical and behavioral correction. Other investigators have demonstrated the potential of using this vector system for gene therapy for a number of other neurological disorders. We developed a helper virus-free packaging system for

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these HSV-1 vectors. This improvement substantially reduces the cytopathic effects and the inflammatory response previously associated with gene transfer. Furthermore, we and others have recently identified specific promoters that support long-term expression in rat forebrain neurons. However, the relatively low titers remain one of the primary barriers to the use of this vector system for human gene therapy of aging disorders that affect the brain. The goal of this proposal is to develop a packaging cell line that can produce high-titer helper virus-free HSV-1 vector stocks. High-titer retrovirus, lentivirus, and adenovirus vector stocks have been produced using packaging cell lines, and these vector stocks have been used in human gene therapy. The first specific aim will isolate a cell line that stably maintains an HSV-1 genome that does not express any immediate early (IE) genes and lacks a packaging site. The second specific aim will produce high-titer, helper virus-free HSV-1 vector stocks by using an HSV-1 vector that contains the 3 essential IE genes flanked by lox sites. This packaging system is based upon standard genetic complementation. High-titer vector stocks will be produced by serial passaging. To excise the IE genes from the vector, the final passage will use a cell line that expresses Cre recombinase. The third specific aim will evaluate the safety features of this packaging system. The fourth specific aim will use these high-titer vector stocks to achieve gene transfer to large numbers of cells in the rat striatum. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIV RISK REDUCTION THROUGH HSV-2 PREVENTION WITH N-9 Principal Investigator & Institution: Padian, Nancy S.; Professor; Ob, Gyn and Reproductive Scis; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: Viral sexually transmitted infections (STIs) are a significant health burden and in particular, women have limited options to protect themselves against them. Herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus (HIV) are two of the most prevalent viral STIs. Neither of these infections is curable, or preventable with available vaccines. Both have serious sequelae and implications for reproductive health. While HIV and HSV-2 infection have been demonstrated to be highly associated with each other, it has been postulated that infection with each virus may be a risk factor for infection with the other. Although both behavior change and the consistent use of condoms appear to protect against HIV, no prevention strategies for HSV-2 have been demonstrated to be effective. While this lack of effective prevention strategies may in part reflect the inadequacy of studies to date, the biology of HSV-2 -the fact that viral shedding occurs over a wide anatomic area in the genital region -suggests that condoms may be less effective for preventing transmission of HSV-2 than for preventing STIs associated with transmission through urethral and cervical secretions. Nonoxynol-9 appears effective in preventing HSV-2 infection in animal models, however, little is known about the effect of nonoxynol-9 in preventing HSV-2 infection in humans. This AIDS-FIRCA proposal is primarily aimed at determining if HSV-2 infection is an independent risk factor for HIV acquisition, and at defining the effect of intravaginal use of nonoxynol-9 in preventing HSV-2 acquisition. This proposal outlines a 3 year prospective cohort study of 1200 HIV uninfected women attending the Spilhaus family planning clinic in Harare, Zimbabwe. Baseline clinical, microbiologic, and laboratory data, including HIV and HSV-2 serologic tests will be obtained. If we establish that infection with HSV-2 increases susceptibility to HIV, and that nonoxynol-9 prevents transmission of HSV-2, we will have revealed a modifiable risk factor for HIV, as well as an inexpensive means of preventing HSV-2 infection and its attendant

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sequelae. By simply adding an additional tube of blood and a diagnostic test to an established phase III trial in Zimbabwe, the study being proposed here may answer these important questions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HSV AMPLICON VECTORS FOR HIV VACCINE DEVELOPMENT Principal Investigator & Institution: Dandekar, Satya W.; Professor & Chair; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 15-SEP-2001; Project End 31-AUG-2004 Summary: (Provided by Applicant) The development of an effective prophylactic vaccine for HIV-1 will likely need an immunogen that can induce neutralizing antibody, and CD4 and CD8 T cell activity. Viral vector systems that infect cells and allow intracellular expression of HIV-1 gene products have the ability to activate T cells through MHC class I and II presentation. Herpes simplex virus type-1 (HSV-1) amplicons possess many of the desirable features of such a viral vector system. They are non-replicating, induce robust CD8+ T cell responses in mice, are easily manufactured, and infect a variety of antigen presenting cells, including dendritic cells. The HSV-1 amplicon can incorporate large segments of DNA, express more than one gene product, are not contaminated by helper virus, and are under development and evaluation as gene therapy tools. In initial experiments, HSV-1 amplicons expressing HIV-1 MN gp120 were shown capable of inducing interferon gamma-producing T cells at a number equivalent to that induced by live herpesvirus vectors, and far exceeding that of a modified vaccinia Ankara vector. In addition, the amplicons induced large anti-Env antibody responses. Building upon these observations, three specific aims are proposed. The first will be to construct amplicons which express codonoptimized clade C env, gag, and tat genes, and evaluate the protein expression from such vectors in vitro. In the second aim, the optimum route of parenteral and mucosal delivery, the dose and duration of immunity, and the effect of prior immunity to HSV will be evaluated. Lastly, the immune responses induced by the clade C amplicon will be evaluated in BALB/c and mapped in HLA-A2/human beta2 microglobulin transgenic mice. Overall, it is anticipated that these experiments will generate sufficient data to warrant moving the HSV-1 amplicon vaccine concept into non-human primate and human vaccine trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HSV US11 MEDIATED EVASION OF HOST SHUTOFF Principal Investigator & Institution: Cassady, Kevin A.; Pediatrics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2003 Summary: The Mentored Clinical Scientist Development Award will provide the opportunity to extend the applicant's intensive molecular virology training and develop an expertise in protein biochemistry and cellular biology. These skills will enable the applicant to become a fully independent research scientist and to address studies that dissect the molecular and genetic basis of viral infection and human disease. The mentor who will direct this training is an expert in herpes simplex virology. The candidate's career objective is to become a pediatrician- scientist who provides insights into viral pathogenesis which ultimately will improve the therapeutic and management decisions for patients with viral infections. Research interests of the applicant focus on the molecular and genetic basis for viral pathogenesis: specifically, how viruses evade

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intrinsic and immune host defense systems. This proposal examines how second-site mutations in avirulent herpesviruses enable progeny to reacquire their pathogenic potential and evade an intracellular host defense system, the interferon induced protein kinase (PKR). Studies have identified that a change in the kinetic expression of an HSV gene flanking the second site mutations (US11) contributes to the renewed pathogenicity of these viruses. These studies have not resolved a significant paradox: the early synthesis of US11 protein enables viral evasion of PKR but pre-made protein carried in with the virus is ineffective. The working hypothesis of this proposal is that while these functional differences in PKR inhibition may reflect inherent biochemical differences between the pre-made and synthesized US11, it is more likely that this reflects the relative ability of synthesized US11 to recruit accessory infected cell proteins. Biochemical techniques (chromatography, 2-D electrophoresis, in vivo phosphorylation) will be used to isolate and analyze virion-associated and synthesized US11. This will be followed by tests for functional differences using a PKR in vitro kinase assay. Affinity studies using both biochemical (immunoprecipitation, protein affinity) and genetic methods (yeast two hybrid system) will evaluate if US11 or PKR recruit participating infected cell proteins that modify the PKR pathway. An in vitro PKR kinase assay will test the functional significance of the identified proteins. Finally, biologic function will be evaluated by creating a cell line expressing the US11 and identified gene with an avirulent virus and examining for phenotypic changes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN EXPLANT CULTURES AND A MOUSE TO EVALUATE SAMMA Principal Investigator & Institution: Cara, Andrea; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 26-SEP-2001; Project End 31-JUL-2005 Description (provided by applicant): Approximately 90% of new human immunodeficiency virus (HIV) infections are acquired through sexual contact. The development of safe, effective, and affordable topical microbicides for vaginal or rectal use could play a critical role in reducing HIV transmission rates worldwide. Clinical, epidemiological and molecular studies strongly support the role of herpes simplex virus (HSV) as a major cofactor for the transmission of HIV. Genital ulcers lead to breaks in the epithelial barrier and HSV induces the expression of pro-inflammatory cytokines that are known to enhance HIV replication. The goal of the proposed studies is to characterize the effects of sodium dimandelic acid ether (SAMMA) and its leading derivatives on HIV and HSV infection utilizing relevant biologic culture systems. SAMMA has excellent anti-mV and anti-HSV activity, while exhibiting no cytotoxicity in cell culture. While cell cultures may provide important information for the evaluation of microbicides, they may not adequately simulate events that occur in vivo. Human explant cultures (endocervical, ectocerivcal, vaginal and rectal), biologic fluids (cervicovaginal secretions and semen) and a mouse genital herpes model will be used in this Project to assess anatomic, physiologic, and immunologic factors that might impact on the activity of this novel class of compounds. Building on the in vitro cell culture data of Projects I, II and IV, the applicant will study the most active derivatives/isomers of SAMMA using biologic culture systems. In Aim 1, the most active derivatives will be evaluated for efficacy against HIV-1 infection of primary macrophages using human genital tract fluids and mucosal explant cultures. In Aim 2, mucosal explant cultures and a mouse model will be used to determine the efficacy of SAMMA to block HSV infection of epithelial cells. Inflammatory cells and cytokines will be measured to study the effects

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Herpes Simplex

of SAMMA on the innate immune system (Aims 1,2 and 3). The interrelationship between HIV and HSV and the efficacy of SAMMA to inhibit dual infection will be studied in Aim 3. Efficacy and safety data in relevant biologic culture systems may provide compelling support for advancing SAMMA or one of its derivatives to clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN RESISTANCE TO HERPES SIMPLEX VIRUS INFECTIONS Principal Investigator & Institution: Posavad, Christine M.; Associate Professor; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Herpes simplex virus type 2 (HSV-2) is the major cause of genital herpes, one of the most frequent sexually transmitted diseases. The worldwide prevalence of genital HSV-2 continues to increase and the limited success of HSV-2 glycoprotein subunit vaccines underscores the urgency of defining innate resistance and protective immune responses to HSV-2 in humans. Because of the high seropositivity rate of HSV throughout the world, evidence of innate or acquired resistance to HSV was not previously suspected, We have, however, in the last year identified a group of individuals who are seronegative to HSV by repeated analyses using the most sensitive serologic assays but who possess CD4+ and CD8+ T cell responses to HSV at multiple time points over the course of prospective follow-up. Preliminary study revealed no evidence of HSV infection in these subjects. The goal of this proposal is to determine whether HSV-seronegative subjects who are chronically exposed to HSV-2 from infected partners exhibit acquired and innate mechanisms of resistance to HSV infection. These subjects are classified as immune seronegative, IS, if they possess HSV-specific T cell responses or as exposed-seronegative, ES, if they do not possess HSV-specific T cell responses. Specific Aim #I will identify IS subjects from HSV-2 discordant couples and evaluate if HSV-specific T cell responses differ qualitatively or quantitatively from those observed in HSV-infected persons with frequently reactivating genital herpes. We will characterize systemic and local T cell responses to HSV using standard chromium release assays, Elispot, intracellular cytokine staining and tetramer analysis. We will also determine if local antibody responses develop in ES and IS subjects. Specific Aim #2 will determine if polymorphisms exist in 3 HSV entry receptor genes, HVEM, nectin-1, and nectin-2 to evaluate whether one mechanism of resistance to HSV-2 infection could be analogous to the receptor mutations detected in some HIV-1-resistant persons. All 3 genes will be sequenced from ES and IS subjects and relevant HSV-2 infected subjects. If coding polymorphisms are present, we will determine whether these changes alter the efficiency of viral entry. Specific Aim #3 will explore a role for CD8-derived chemokines, MIP-lalpha, MIP-1beta and RANTES, in resistance to HSV infection. Preliminary data suggest that these chemokines are secreted at higher levels in IS subjects compared to non-IS subjects and further, that MIP-la inhibits HSV infection. We will determine if Beta-chemokines inhibit the binding of HSV to cell surface glycosaminoglycans, which binding is know to facilitate HSV entry. The results of these studies will improve our understanding of effective immune defense against HSV-2 infection and may identify a mechanism of genetic resistance to HSV. The data generated will be relevant to designing and evaluating strategies for HSV-2 preventative vaccines and immunotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFICATION OF NOVEL ANTIVIRAL TARGETS USING RNAI Principal Investigator & Institution: Pachuk, Catherine J.; Nucleonics, Inc. 26 Spring Mill Dr Malvern, Pa 19355 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAR-2004 Summary: (provided by applicant): The goal of this project is to develop a selection strategy using RNA interference (RNAi) to identify novel therapeutic targets for the treatment of cytolytic virus infection. RNAi is a cellular process that causes targeted elimination (silencing) of mRNA. Nucleonics, Inc. has developed platform technologies to exploit RNAi for development of therapeutics and genomic applications. These technologies provide powerful new tools for targeted elimination of specific mRNAs. RNAi will be used to selectively silence genes required for cytolytic virus replication thereby producing cells that will be resistant to infection. Repeated rounds of selection (infection with cytolytic virus) and enrichment (isolation of RNAi-inducing sequences in surviving cells) will identify genes that are potential therapeutic targets for treatment of virus infection. Phase I of this application focuses on ( i ) optimizing vectors and delivery systems for inducing RNAi in mammalian cells and (ii) "proof-of-concept" tests using these vectors and delivery systems to silence viral and cellular genes known to be required for cytolytic virus replication. Two cytolytic viruses will be tested in this system, a DNA containing virus, human herpes simplex virus type I (HSV-1), and an RNA containing virus, bovine viral diarrhea virus (BVDV). BVDV is a tissue culture surrogate for hepatitis C virus. Phase II of this proposal focuses on using this selection to identify novel genes required for cytolytic virus infection and validate these novel targets in cell culture and animal models of infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IL-6 IN HERPES SIMPLEX VIRUS TYPE 1 OCULAR REACTIVATION Principal Investigator & Institution: Kriesel, John D.; Associate Professor; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2001; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: There are approximately 50,000 cases of new or recurrent ocular HSV disease per year in the U.S., with stromal scarring of the cornea leading to reduced visual acuity in about 6,000 patients per year. Acute and recurrent herpes simplex keratitis are leading indications for corneal transplantation in this country. Ultraviolet light (UV) exposure, fever, hyperthermia, hypothermia, dental trauma and surgical manipulation of the trigeminal ganglion are stimuli associated with reactivation of HSV-1. The sequence of HSV gene activation during productive infection is well known, but the mechanism by which reactivation stimuli, including UV light, stimulate latent virus to replicate is unknown. Studies by the principal investigator have shed new light on this mysterious process, implicating the inflammatory cytokine interleukin-6 (IL-6) and its associated cellular transcription factor STAT3 in the pathogenesis of ocular HSV reactivation. New supporting data presented in this application demonstrates that ocular UV exposure induces IL-6 production in explanted corneas. By contrast, the same UV stimulus induces and activates the transcription factor STAT3 in the trigeminal ganglion, the site of the latent viral infection, where this factor is hypothesized to initiate HSV-1 gene transcription. This specific aims of this proposal are to: 1)Investigate the role of IL-6 in the murine keratitis model by: a) directly injecting IL-6 into the conjunctiva of latently infected mice and b) studying the ability of IL-6 knockout mice to reactivate HSV-1. 2)Explore the hypothesized IL-6STAT mechanism of induced HSV ocular reactivation. Based on supporting data, studies are proposed: a) to detect

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activated, phosporylated STAT transcription factors and b) determine whether these factors specifically bind important HSV-1 genes. 3)Directly investigate the hypothesis that IL-6 drives HSV-1 gene transcription. A collaborative effort is outlined to study this using HSV-1 transient expression and/or reporter construct assays. Novel and specific viral mutants will be constructed based on the results of HSV-DNA binding and transient expression assays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMAGING TRANSGENE EXPRESSION IN GENE THERAPY PROTOCOLS Principal Investigator & Institution: Blasberg, Ronald G.; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 30-JUL-2002; Project End 31-MAR-2006 Summary: (Applicant's Description) We propose to assess transgene expression by noninvasive imaging in patients undergoing gene therapy. Four separate components, involving four different clinical trials, are included in this proposal in order to provide a broad clinical spectrum for assessing the benefits and limitations of imaging transgene expression in a clinical setting. Three different viral vectors (adenovirus, Herpes Simplex Virus, and retrovirus) will be used in these clinical trials and this will provide the opportunity to obtain comparable imaging data for each of the three vectors. Two of the components will involve patients in existing clinical trials at Mount Sinai Medical School in New York. One clinical trial involves patients with hepatic metastases from colorectal cancer, and the other involves patients with local prostate cancer; both trials involve direct intratumoral injection of an adenoviral vector (ADV-tk) expressing the Herpes Simplex Virus thymidine kinase gene (HSV1-tk), followed by intravenous ganciclovir treatment. The third and fourth components will involve both preclinical and clinical imaging studies at MSKCC, and will also involve patients with colorectal hepatic metastases. The third component involves an experimental treatment protocol where a replication restricted Herpes Simple Virus type-1 (mHSV1; G207 or R7020) is injected into the hepatic artery to induce selective cytolysis of dividing tumor cells (hepatic metastases). The fourth component will involve hepatic artery injection of a retrovirus (DCSV or SFG) containing a fusion gene which includes dihydrofolate reductase (DHFR) and HSV1-tk cDNA. The treatment rationale is based on data showing that exposure of transduced tumor cells to trimethotrexate (TMTX) will lead to amplification of DHFR and consequently, to amplification of the HSV1-TK as well; in turn, this will make the transduced cells more sensitive to ganciclovir. HSV-TK imaging will be performed using positron emission tomography (PET) and 124-I labeled FIAU (2'-fluoro-1-beta-D-arabinofuranosyl-5-iodo-uracil); we have previously demonstrated that [124I]-FIAU PET imaging of HSV-TK activity following retroviral and adenoviral (ADV-tk) transduction is feasible, selective and quantitative. The preclinical studies in this proposal will: 1) extend these studies and demonstrate selective vector imaging, 2) provide a comparison between mHSV1 (G207 and R7020) and retroviral (DCSV and SFG) vectors in appropriate experimental animal models, and 3) provide imaging data that could support and justify the initiation of clinical trials. The clinical studies are the focus of this proposal and will demonstrate that noninvasive imaging of transgene expression in target tissue can be used to monitor and facilitate the evaluation of gene therapy by defining the location, magnitude and persistence of transgene expression over time. It would also provide the opportunity to assess the spread of the vector to nontarget tissue and organs using whole body imaging techniques, and it could define the optimal time and duration of time for effective pro-drug administration.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNIZATION TO REDUCE GENITAL AND NEONATAL HERPES Principal Investigator & Institution: Bourne, Nigel; Associate Professor; Pediatrics; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): The control of genital herpes will require widespread use of effective vaccines. However, if herpes simplex virus (HSV) vaccines do not achieve sterilizing immunity (prevent virus replication at the entry site) the virus will establish latency, rendering the host potentially contagious during reactivation, and allowing continued transmission. While animal studies with a variety of vaccines show that immunization does not prevent virus replication in the genital mucosa following high titer challenge, a HSV type 2 glycoprotein D vaccine protected 39-46% of seronegative women against infection in a recent clinical Trial. Since much of the spread of genital herpes occurs during periods of asymptomatic shedding when relatively little virus is present, we believe that the protection resulted because immunization increased the virus inoculum required to infect the genital mucosa. In Aim 1 we will explore this hypothesis by determining the effect of immunization with the clinical study vaccine on the virus inoculum required to infect the genital mucosa in a mouse model. In Aim 2 we will again use the threshold of infection to measure efficacy and determine whether DNA prime glycoprotein boost improves protection compared to DNA or glycoprotein only immunization. These studies are relevant because an effective vaccine will need to induce T helper type 1 (Th1) responses in addition to antibody and DNA vaccine priming with protein boosting has been shown to increase Th1 responses compared to protein only immunization. While a vaccine that increases the threshold of infection will reduce the incidence of transmission, it will not provide universal protection. In Aim 3 we will use conditions that overcome protection from infection to examine the impact of immunization on the magnitude of latent infection and recurrent disease (both clinical recurrences and virus shedding into the genital tract). These studies will provide new information about the risks of transmission from immunized hosts who become infected. Taken together, the studies in this proposal will yield new information about the capacity of HSV vaccines to reduce the spread of genital herpes. These study designs may become standard for preclinical evaluation of HSV vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTERACTIONS

IMMUNOBIOLOGY

OF

ANTIRECEPTOR

RECEPTOR

Principal Investigator & Institution: Greene, Mark I.; Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-MAY-1986; Project End 31-OCT-2001 Summary: The PI work is concerned with the study of manipulation of corneal cell growth and the diminution of T cell dependent inflammatory responses in corneal injury and a model of uveitis. He has developed a new class of structurally designed immunologic mimetics for these studies. the compounds were designed from discrete complementarily determining regions of a particular anti-receptor antibody and another member of the immunoglobulin gene family, CD4. These molecules operate via novel mechanisms and offer the opportunity to study agonist and antagonistic effects on receptor specific functions. The small CDR form designed from the anti-receptor antibody stimulates corneal cell growth and accelerates corneal would defect closure.

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This CDR form has an opposite affect on activated T cells in which it inhibits activation. This compound will be studied in corneal damage associated with herpes simplex disease and in other studies dealing with corneal defects. The compound developed from CD4 has the ability to inhibit T cell activation. This compound will be studied in models of T cell dependent corneal inflammation and in models of uveitis. These compounds have many chemical and immunologic benefits over the intact macromolecules from which they were derived. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICROGLIA

IMMUNOREGULATION

OF

HERPES

ENCEPHALITIS

BY

Principal Investigator & Institution: Lokensgard, James R.; Assistant Professor; Minneapolis Medical Research Fdn, Inc. 600 Hfa Bldg Minneapolis, Mn 55404 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Herpes simplex virus 1 (HSV) is an important opportunistic pathogen in HIV-1-infected patients as well as the cause of a devastating CNS infection in normal hosts. Although immune responses to HSV have been the subject of intense investigation, the role of immune-mediated pathology in HSV-related brain damage is unknown. In this proposal, the central hypothesis to be tested is that chemokines produced by microglial cells in response to HSV infection initiate a cascade of neuroimmune responses that result in the serious brain damage seen during herpes encephalitis. To test this hypothesis, chemokine production in the brains of HSVinfected mice will be compared to that in cultures of highly purified murine glial and neuronal cells, and in murine organotypic brain slices infected with HSV. This approach will allow us to differentiate microglial cell chemokine production from that of cells of the somatic immune system. Additionally, the use of organotypic brain slice cultures will enable us to specifically deplete microglial cells for "loss-of-function" experiments. We will then investigate the neurotoxic effects of microglial cell-produced immune mediators on cultured murine neurons. Microglia-driven leukocyte trafficking into the brain will be investigated by determining if neutralizing antibodies to chemokines inhibit T-cell infiltration. The neuropathogenic role of T-cell infiltration will be studied by determining if depletion of T-cells in vivo will delay encephalitis and whether adoptive transfer of HSV-specific lymphocytes restores the encephalitis phenotype. Comparing neuropathology in brain slice cultures with and without the transfer of HSV-specific CD4 + and CD8 +lymphocytes, will allow us to distinguish between injury generated by viral infection and brain damage provoked by immunopathogenic mechanisms. Downregulation of microglial cell chemokine production through peripheral benzodiazepine (BDZ) receptor-mediated cellular deactivation will then be examined. We will determine if deactivation of microglia with BDZs suppresses the production of neurotoxic factors. Finally, we will study the effects of BDZ ligands on chemokine production, T-cell trafficking, and the development of encephalitis in vivo. These in vivo, in vitro, and ex vivo models will provide us with the ability to investigate neuropathogenesis, neuroinflammation, neurotoxicity, and neuroimmune-mediated pathology occurring during herpes encephalitis. Knowledge gained from these studies will increase our understanding of the role of microglial cells and chemokine networks that regulate brain inflammation during herpes encephalitis with the ultimate goal of finding new therapy for this serious brain infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INDUCTION OF PROTECTIVE IMMUNITY AGAINST MULTIPLE STDS Principal Investigator & Institution: Eko, Francis O.; Professor; Morehouse School of Medicine Atlanta, Ga 30310 Timing: Fiscal Year 2002; Project Start 30-SEP-1987; Project End 31-JUL-2006 Summary: (provided by applicant): Sexually transmitted diseases (STDs) are of major medical and social importance worldwide and co-infection by more than one STD is common in high-risk populations. Genital infections caused by Chlamydia trachomatis and herpes simplex virus type 2 (HSV-2) rank among the highest STDs in the world. In fact, genital chlamydial infection is the most common bacterial STD in the United States and may cause severe irreversible complications in women, including pelvic inflammatory disease, fallopian tube scarring, ectopic pregnancy and infertility. Genital infection caused by HSV-2 is prevalent worldwide causing genital ulcerations and severe complications such as neonatal herpes and central nervous system involvement. Considering the worldwide prevalence of these STDs, vaccines offer the best approach for controlling these infections. Besides, a combination vaccine that can be administered as a single regimen to protect against multiple STDs would be highly desirable to control the rampant co-infections among STDs. Despite considerable effort, the development of an efficacious vaccine against either Chlamydia or herpes using conventional approaches has been difficult. The current paradigm for designing efficacious vaccines against these pathogens requires identification of appropriate antigens and development of effective delivery vehicles capable of eliciting high levels of Th1 response that can confer long-lasting protective immunity. The chlamydial major outer membrane protein (MOMP) and the glycoprotein D2 (gD2) of HSV-2 are highly immunogenic proteins that have been targeted as potential vaccine candidates; these proteins possess both neutralizing and T cell epitopes. We have designed a novel recombinant bacterial ghost delivery system which has inherent adjuvant properties and capable of simultaneously presenting multiple antigens to the immune system. The ultimate aim of the proposed project is to genetically design a recombinant multivalent subunit vaccine composed of Vibrio cholerae ghosts co-expressing the MOMP of C. trachomatis and the gD2 of HSV-2. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INNATE CORNEAL CELL IMMUNITY TO VIRUS INFECTION Principal Investigator & Institution: Taylor, Jerry L.; Microbiol & Molecular Genetics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Infection of the cornea with herpes simplex virus (HSV) initiates an innate immune response that plays a major role in limiting virus spread. Production of interferon (IFN) and IFN-induced proteins is an important component of this innate response. Some of the IFN-inducible proteins localize to nuclear structures termed ND1Os, which are the sites of viral DNA localization and initiation of viral transcription. The aims of this grant focus on determining the mechanism of action of two of these IFN-induced proteins, PML and SP100, and the regulation of their expression in human cornea (HCS) cells. Each protein exists in multiple forms as a result of variable mRNA splicing. Our studies show that SP100B is a potent inhibitor of two HSV transcriptional transactivating proteins, VP16 and ICP4. The specificity of SP100B's inhibitory activity will be characterized by examining the action against basal expression and transactivation of a number of viral and cellular

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promoters. Using the yeast two-hybrid system we will identify cellular protein(s) that function as mediators between SP100B and ICP4. The region of SP100B that confers repression is within a 29 amino acid domain that has the potential to be highly phosphorylated. This region will be mapped to determine whether specific amino acid phosphorylation is essential for activity. We will determine whether localization to the ND1O structure and transcriptional repressive activity are linked. The second protein to be examined is PML, a structural component of ND1Os. Two forms of PML will be evaluated alone and combined with SP100B for their contribution to the transcriptional regulation of HSV genes. The interaction of PML with the viral general transcriptional transactivator ICPO, a protein known to disrupt ND1s, will be characterized by transcription assays in transiently and stably transfected cells and by microscopic localization of green fluorescent protein-tagged forms of PML. HCS cells appear to contain high levels of PML localized to ND1Os, potentially acting to provide an elevated innate immune response. Monoclonal antibodies specific for forms of PML and SP100 will be prepared and used to identify the forms of PML and SP100 naturally present in these corneal cells and determine the changes that occur in their expression in response to IFN treatment and virus infection. These studies will characterize a potent transcriptional repressive mechanism we have identified and determine its contribution to corneal inhibition of HSV replication. This knowledge may be utilized to enhance this innate antiviral response and thereby limit initial and recurrent viral infections in the eye. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF LATENCY OF HERPES SIMPLEX VIRUS Principal Investigator & Institution: Fraser, Nigel W.; Professor; Microbiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-AUG-1986; Project End 31-AUG-2006 Summary: (provided by applicant) Herpes Simplex virus (HSV) can cause a wide range of diseases, including skin lesions, which are common, encephalitis which is rare, an HSV infection of the eye, which is a leading cause of blindness in the USA (400,000 cases). The seroprevalence of HSV in the U.S. adult population is very high (approximately 70%). Herpes virus infections are characterized by the ability of the virus to form latent infections in the nervous system. It is this ability, which leads to recurrent episodes of the disease causing much human suffering, which is the focus of our application. The overall goal of this proposal is to understand the mechanism of HSV latency using both a mouse model system and tissue culture studies. We have previously used a mouse model system of HSV latency to study physical state of the latent viral genome, and to initiate studies on viral gene expression during latency. From our data, we have formulated models for the mechanism of HSV-1 latency. We now wish to continue to refine these models using the techniques of molecular virology. The program consists of three scientific projects, and an administrative and two scientific cores. The scientific projects are titled: 1. Gene Expression during HSV-1 Latency and Reactivation; 3. The Role of Cellular Transcription Factors in the Regulation of HSV-1 Latency and Reactivation; 4. Herpes Simplex Virus and Neuronal Cell Interactions. Successful completion of these studies will permit the mechanisms of HSV latency to be described in more detail, allowing formulation of new strategies for the prevention of latency and recurrence. In addition, it is anticipated that the knowledge gained will continue to be of use to the fields of gene therapy and cancer therapy in the nervous system, and continue to provide more patentable findings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM OF LATENCY OF HERPES SIMPLEX VIRUS Principal Investigator & Institution: Schaffer, Priscilla A.; Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-JUL-2006 Summary: (provided by applicant): The long-term objectives of the Program Project are to identify the viral and cellular factors involved in the establishment, maintenance and reactivation of herpes simplex virus type 1 (HSV-1)/ latency and to determine the roles of these factors in the latency process To achieve these objectives, the following four projects are proposed. Project 5 (Knipe) will define the mariner in which the host immediate response induced by specific viral antigens affects latent infection by HSV-1. Special emphasis will be placed on the duration of cytokine expression and the T cell response following immunization. The identity of the viral functions required for longterm effects on neuronal gene expression will be determined using mutant viral strains. The mechanisms by which the LATs down-regulate productive-cycle gene expression and ICP8 stimulates accumulation of viral DNA in neurons will also be investigated. Project 6 (Coen) will investigate the mechanisms by which various recognized blocks to viral gene expression, including the LATs, are involved in maintaining HSV-1 latency. The molecular and genetic basis for the ability of an ACVr, TK- clinical isolate to establish and reactivate from latency will be investigated to identify viral functions able to compensate for TK in latency. Changes in host cell gene expression and factors affecting these changes during HSV-1 latency in mice will also be examined. Project 4 (Schaffer) will determine the kinetics and order of viral gene expression relative to the initiation of viral DNA replication in reactivating mouse TG. The roles of oriL and oriS, and specifically the 0BP and GR binding sites in these origins, in the initiation of DNA replication during reactivation in mouse TG and in rabbits will be investigated. The identity of cdks required for reactivation of HSV-1 from latency and the effects of cdks on the transactivating activity and post- translational modification of lCP0 will be identified. Project 7 (M. Greenberg) will characterize the neurotrophins, cytokines and neuropeptides in TG neurons that support HSV replication and determine whether these molecules can regulate HSV-1 latency and reactivation in TG cell cultures. The intracellular signaling pathways activated by stimuli that induce HSV-1 reactivation, and that mediate NGF withdrawal induced reactivation in sympathetic neurons will also be investigated. Collectively, the results of these studies will provide new insights into the mechanisms by which HSV-1 latency in established, maintained and reactivated in neurons. In turn, these insights will reveal novel strategies for intervening in this poorly understood aspect of HSV-1 pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF HERPES SIMPLEX VIRUS RETINITIS Principal Investigator & Institution: Atherton, Sally S.; Professor and Chair; Cellular Biology and Anatomy; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2001; Project Start 30-SEP-1985; Project End 31-AUG-2003 Summary: (Adapted from applicant's abstract): Following uniocular anterior chamber inoculation of the KOS strain of HSV-1 in euthymic BALB/c mice, extensive virus infection accompanied by a massive inflammatory response is observed in the anterior segment of the injected eye. However, in spite of the virus infection in the anterior segment, virus does not infect the retina of the inoculated eye. In contrast, the retina of the uninoculated eye becomes infected with virus beginning on or about day 7 p.i., and the retina of this eye is destroyed by 14 days p.i. Although there is mild anterior uveitis,

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Herpes Simplex

the anterior segment of the uninoculated eye does not become infected. The overall goal of the studies proposed in this application is to elucidate the pathogenesis of HSV-1 infection in the injected eye, the brain, and the uninjected eye following uniocular anterior chamber inoculation of HSV-1. Three specific aims will define (1) the mechanism by which direct anterior-to-posterior spread of the KOS strain of HSV-1 is prevented following uniocular anterior chamber inoculation of BALB/c mice, (2) the mechanism which prevents virus that has spread to the brain in euthymic BALB/c mice from infecting the optic nerve and retina of the injected eye, and (3) the role of T cells and cytokines during HSV-1 infection of the retina of the uninoculated eye. Information about early protection in the injected eye following anterior chamber inoculation may provide clues about why patients with HSV-1 keratitis, many of whom also have viral anterior uveitis, do not normally develop retinitis in the afflicted eye. Information about limitation of virus spread in the hypothalamus may provide insight into why virus that reaches the brain in pathways other than the trigeminal may be unable to spread to the optic nerve and retina and may help to explain why such a small number of patients with HSV-1 develop retinitis. Studies of how T cells and cytokines contribute to retinitis once virus has infected an eye may aid in design of specifically-targeted therapies to modulate an established infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF MUCOSAL IMMUNITY TO HERPES SIMPLEX VIRUS Principal Investigator & Institution: Morrison, Lynda A.; Associate Professor; Molecular Microbiol and Immun; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract): Herpes Simplex virus (HSV) causes several serious human diseases including a sexually transmitted disease that significantly effects maternal and child health and may be a cofactor in the acquisition of other STDs such as AIDS. Once infected with HSV, individuals retain the virus in a latent state, from which periodic reactivation causes recurrent disease and provides an opportunity for transmission. The means to protect against HSV infection by inducing potent immune responses that can act quickly at the site of infection remains elusive. Replication-defective mutants of HSV offer a safer alternative to live virus vaccines. Because the infection does not spread in the host, these viruses also provide a unique tool to examine the induction of antiviral immune responses. Mice immunized subcutaneously or intranasally with an HSV-2 mutant virus generate immune responses that protect mice from disease and lethal infection upon genital challenge with a heterologous HSV-2 strain. It is hypothesized that immunization with replicationdefective HSV-2 generates an immune response protective against genital HSV-2 that is principally mediated by CD4+ Th1 cells. In addition, it is also hypothesized that the provision of B7 co-stimulatory molecules in infected cells will augment the immunogenicity of the replication-defective virus and improve protective capacity. In Aim 1, histochemical analysis of the vaginal mucosa and the analysis of latent genomes in the ganglia will identify the stage of pathogenesis that is blocked by the protective immune response. In Aim 2, the components of the immune response that are protective against genital challenge will be identified using knockout mice, T cell subset depletions, and cytokine analyses. In Aim 3, the role of costimulation in the induction of immune response to replication-defective virus will be investigated by construction of recombinant viruses that encode B7 molecules. This information will facilitate

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41

developent of immunization strategies against HSV and possibly other pathogens of the genital tract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF THE HSV-1 UL42 PROTEIN Principal Investigator & Institution: Parris, Deborah S.; Professor; Medical Microbiol & Immunology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2001; Project Start 01-JUL-1986; Project End 31-MAR-2003 Summary: There is amazing conservation in the requirements for and mechanism of DNA replication among highly diverse organisms. Herpes simplex virus type 1 (HSV-1) is an excellent model system for eukaryotic DNA replication since the virus encodes most of the proteins required for this essential process and can be manipulated genetically with greater ease than higher eukaryotes. DNA polymerases are central to the process of DNA replication. A general requirement of replicative DNA polymerases is that they copy the template genome with rapidity and reasonable fidelity. A major means by which they achieve the necessary rate required for genome duplication is the use of accessory proteins to increase their processivity. The HSV-1 DNA polymerase (pol) forms a stable and specific complex with an accessory factor, UL42. Like other pol accessory proteins, UL42 increases the processivity of its cognate pol, but differs in several important ways. Its lack of requirement for clamp loading proteins distinguishes it from the toroid sliding clamps, such as PCNA and E. coli pol III beta. Furthermore its intrinsic ability to bind to DNA is unique among all other known processivity factors, including those which don't require clamp loaders, such as thioredoxin, the processivity factor for T7 bacteriophage pol. The latter ability also presents an apparent paradox for known mechanisms of processivity, in that UL42 could also serve as a brake to elongation. The major long-term goal of the proposed studies is to elucidate the mechanism by which UL42 increases pol processivity, and the resulting impact this mechanism has on other properties of the pol, including parameters required for fidelity of DNA replication. A combination of biochemical, biophysical, and genetic approaches will be used to address four specific aims: 1) To determine the effect of reduced DNA binding by mutant UL42 proteins on rates of elongation and pol processivity using transient kinetic analysis and direct binding studies; 2) To determine the effect of processivity and proof-reading capability on the individual parameters which affect fidelity in vitro, including nucleotide selection, failure to extend mismatched termini, and excision of mismatched primer termini, using kinetic analysis to dissect these processes; 3) To determine the biological impact of changes in fidelity parameters (caused by changes in processivity) on the frequency and types of mutations which occur during origin (ori)- dependent DNA replication in vivo; 4) To determine the ability of the ori-binding protein, UL9, which interacts with UL42, to facilitate the assembly and/or processivity of pol/UL42 complexes on blocked synthetic primer/templates. Functional analogs of HSV-1 pol and UL42 are encoded by all human herpesviruses, including Kaposi sarcoma-associated virus (HHV-8), Epstein Barr virus, and human cytomegalovirus, all of which are significant human pathogens, particularly for cancer and immuno- suppressed patients. It is important to understand an the mechanism of UL42 action since disruption of the pol/UL42 complex has been proposed for development of antivirals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

42

Herpes Simplex

•

Project Title: MOLECULAR ANALYSIS OF HSV-I REACTIVATION FROM LATENCY Principal Investigator & Institution: Sawtell, Nancy M.; Associate Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2001; Project Start 01-JAN-1992; Project End 31-DEC-2002 Summary: The long term goal of the proposed research is to define the molecular mechanisms involved in the transition from latent to lytic herpes simplex virus (HSV) gene transcription. They previously developed the hyperthermic stress (HS) reactivation model which is unique in that the production of infectious virus is detectable within 1214 hours after the induction stimulus. Using this model, they have identified what is likely to be a key event in the regulation of reactivation, namely the up regulation of ICPO within 1 hour post HS. Insight into the molecular regulation of reactivation must ultimately be obtained from analysis of individual latently infected neurons. They have developed a new method, contextual expression analysis, CXA, to obtain quantitative information about the DNA and RNA in individual cells within solid tissues. In this proposal, the power of PCR and RT PCR will be harnessed through CXA to construct a molecular definition of latency and reactivation. Their ability to precisely quantify the number of latently infected neurons in the ganglia and examine the RNA and DNA content will allow them to meaningfully evaluate wild type and genetically engineered mutant strains to achieve the following specific aims: (1) Determine the impact of the number of latently infected neurons and/or the number of viral genome copies within individual latently infected neurons and/or the number of viral genome copies within individual latently infected neurons upon the initiation and progression of HS inducted reactivation in vivo; (2) Utilize CXA-RNA strategies to characterize viral transcription during latency and following HS induced reaction at the neuronal population and single cell level; (3) Determine the biological significance and biochemical basis of the rapid up regulation of the ICPO gene following HS induced reaction in vivo. Defining the regulatory mechanisms by which the "latent" repository of viral genetic information periodically give rise to infectious virus is central to understanding this important aspect of the viral life cycle. Insight into these viral functions could contribute significantly toward our ability to design effective vaccines, develop treatments for the prevention of recurrent disease, and efficiently transfer, maintain and regulate foreign genes in the human host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MOLECULAR GENETICS OF HSV 1 CAPSIDS Principal Investigator & Institution: Desai, Prashant; Pharmacol & Molecular Sciences; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-DEC-1993; Project End 31-AUG-2003 Summary: A genetic and biochemical study of herpes simplex virus type 1 (HSV-1) capsids is proposed. Major goals of the proposed experiments are to identify conformation changes in capsid structure that occur during B capsid maturation, to identify residues in the molecules that cause the changes, and to identify interactions between the molecules through which the changes may be mediated. Capsid shells are composed of three essential proteins; VP5, the major capsid shell component, and VP19C-VP23, a complex which interacts with and stabilizes VP5. The UL26 (VP24 and 21) and the more abundant UL26.5 (22a) gene products specify the protease activity (VP24), and the scaffold (22a and probably 21) on which the shell is assembled via interactions with VP5. Specific Aim 1. Residues of UL26 and UL26.5 gene products

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43

known to interact with VP5 will be altered that (1.1). block protease cleavage at the maturation site, or (1.2). prevent essential interactions with VP5. Compensatory genetic changes, presumably in VP5, will be selected that allow the blocks to be overcome. Specific Aim 2. Changes in shape (spherical to icosahedral) may accompany B capsid maturation. Mutant viruses possibly blocked at steps in the maturation process will be examined during infection of non-permissive cells by electron microscopy, cellular immunofluorescence using a VP5 specific antibody, and by SDS-PAGE analysis of capsid proteins following sedimentation analysis. Specific Aim 3. The size, shape and oligomeric status of the major scaffold molecule (22a) will be determined. The yeast GCN4 and HIV-1 gp160 residues that specify basic leucine zipper motifs may be used to replace the self-interactive domain. The transdominance of mutant viruses will be evaluated. Specific Aim 4. Residues of VP26 that interact with VP5 will be identified using VP26-negative capsids incubated with wild-type and mutant forms of VP26 synthesized in vitro. Specific Aim 5. Studies will be pursued to determine the structure of the VP19C-VP23 complex by x-ray crystallography. A number of insertions in VP19C coding sequences will aid the identification of residues of VP19C that interact with VP23 and with VP5. In vitro synthesized products of VP19C and VP23 will be assayed by coimmunoprecipitation and a capsid binding assay, respectively. Specific Aim 6. Experiments are proposed to package viral DNA into capsids, and to determine the direction of packaging of DNA into capsids. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETICS OF HSV REACTIVATION Principal Investigator & Institution: Bloom, David C.; Assistant Professor; Molecular Genetics & Microbiol; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: provided by applicant): Herpesviruses are ubiquitous and are responsible for significant human mortality and suffering both in terms of initial infections and (even more so) recurrences. In addition, with increasing occurrences of immunosuppressive disorders, a corresponding increase in the frequency of clinically significant initial and latent herpesvirus infections arise. Therefore, the long-term objective of this project is to gain a functional understanding of the herpesvinis-encoded genes involved in latency and reactivation - knowledge that is fundamental to the rational design of interventive therapies. We have identified a region of the genome termed the "reactivation critical region" (rcr) that is required for epinephrine-induced reactivation. The primary focus of this proposal is to characterize the functional role sequence elements in the rcr of the Herpes simplex virus type 1 (HSV- 1) genome play in reactivation of infections latent in sensory ganglia neurons. The overriding hypothesis of this study is that the HSV rcr facilitates reactivation by regulating gene expression from the latent genome allowing the initiation of acute gene expression during reactivation. Using a molecular genetic approach involving specifically engineered viral recombinants, we will follow the transcriptional and replicative processes of HSV- 1 reactivation in the rabbit corneaepinephrine model to link viral genetics with processes in animals. Specifically, the proposed studies will test three potential mechanisms by which the rcr functions to facilitate reactivation: a) the rcr acts as a modulator of transcription which facilitates reactivation by regulating the expression of LAT, ICPO and/or ICP4, b) the rcr is a target of methylation and/or cellular factors that regulate transcription during latency and reactivation, and c) the rcr acts as a non-coding functional RNA that regulates gene expression via a dosage compensation-like mechanism. These three mechanisms are not mutually exclusive and it is likely an interplay between these regulatory elements is

44

Herpes Simplex

necessary for the maintenance of and reactivation from latency. This work will lead to the identification of viral target(s) of host factors that communicate stress stimuli leading to reactivation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISEASES

MOLECULAR

MECHANISMS

OF

STRESS-RELATED

ORAL

Principal Investigator & Institution: Chambers, Donald A.; Professor & Head; Molecular Biol/Oral Diseases; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Our long term goals are to understand the molecular interactions governing neuroimmunology and their relationship to infectious oral diseases, e.g., recurrent Herpes simplex virus infection, HIV and periodontal diseases, and wound healing: processes associated with stress and/or enhanced fluxes of catecholamines (CAs) and immune dysfunction. Previous studies by others and us demonstrated association between CAs and diminished immune function. These investigations focus on the hypothesis that the nervous system interacts with the immune system in part through the agency of CAs, sympathetic neurotransmitters most closely associated with immune cells and their reservoirs. This grant investigates specific molecular mechanisms involved in CA-mediated immune gene expression; in particular, the CA-mediated downregulation of mRNAs necessary for regulated Tcell function. To do this, we will use well characterized cloned murine cells of T cell lineage (S49 lymphosarcoma, EL-4 cells and a CD8+ cell line) to study the CA-mediated dynamics of mRNAs of genes associated with immune regulation (the Beta-adrenergic receptor and the cytokines TNFa, IL-2 and IFN-y) down-regulated by cAMP, the second messenger associated with CA-beta-adrenergic signaling. Specific Aim I determines whether these genes are down-regulated by CA exclusively through mRNA destabilization or in concert with other mechanisms and continues investigation of our paradigm for mRNA destabilization that a (CA/cAMP/PKA) protein kinase mechanism is central to regulation of mRNA stability this Aim will a) identify the RNA target sites in CA/cAMP/PKA modulated mRNAs that affect their stability and b) investigate the mechanisms through which CAs modulate mRNA destabilization in T cells by characterizing the proteins that affect mRNA stability. Specific Aim II will explore new data that suggest the hypothesis that CM modulates specific gene products involved in the activation and function of Herpes simplex (HSV) specific cytotoxic T lymphocytes. Completion of these Specific Aims provides insight into exciting and unique mechanisms whereby CAs down-modulate mRNAs for effector proteins of immune cells to decrease the capacity of these cells to respond to external signals and HSV infection and could allow development of peptides and oligonucleotide therapies designed to inhibit the effect of endogenous stressors and/or enhance immune function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINES

NEUROENDOCRINE

REGULATION

OF

HSV

1

INDUCED

Principal Investigator & Institution: Ortiz, Griselle C.; Periodontology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2001; Project Start 01-AUG-1998; Project End 31-JUL-2003

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Summary: Herpes simplex virus type 1 (HSV-1) infections lead to misery and discomfort for millions of persons worldwide. Cell-mediated immunity has been pointed out as an important component of the host's defense against herpes simplex virus. It has been demonstrated that the activation of the hypothalamic-pituitary-adrenal axis by stressful events results in an elevation of corticosteroids in the serum that may impair immune function. Although the skin is the primary site for recurrent HSV-1 infections we still do not understand the immunological mechanisms in which stress modulates immune responses toward cutaneous herpes simplex virus infections. Cytokines are important mediators of inflammation and viral clearance in herpes virus infections, but despite their importance in antigen specific recruitment of immune cells and in the inflammatory process, little is known about local cytokine expression during the course of a cutaneous herpes viral infection. During stress events, activation of the hypothalamic-pituitary-adrenal axis occurs and catecholamines and glucocorticoids are produced. Glucocorticoids have an immunosuppressive action such as inhibiting the activities of neuropeptides and cytokines. The hypothesis that we intent to test in this proposal is that restraint stress will induce changes in the pathophysiology of a HSV-1 infection by depressing early inflammatory mediators which will lead to a severe and longer lasting infections. Gene expression of pro-inflammatory cytokine will be downregulated leading to a decrease in inflammatory cell infiltrate, which will lead to an increased number of infective viral particles at the site of the infection. We also hypothesize that restraint stress will induce a down-regulation of the gene expression of Th1 derived cytokines, causing a shift into a Th2 mediated response. Shifting to a h2 mediated response has been shown to make the host more susceptible to severe HSV-1 infections. An elevated level of glucocorticoids in plasma is the underlying factor in the depressed immune response. The following specific aims have been developed in order to test the hypothesis: In Specific Aim I, we will evaluate and characterize the HSVinfection severity and healing time in restrained animals. We will perform histological evaluations of the inflammatory cells present in the tissues at different times during the course of the infection; we will also evaluate for the presence of viral particles at the site of the infection, and we conduct assays to determine infectious viral titers. Later in Specific Aim II, we will focus our attention on the gene expression of pro-inflammatory cytokines and Th1 and Th2 cytokine profiles. We will study the gene expression of IL1alpha, TNF-alpha, pro-inflammatory cytokines involved in the recruitment of inflammatory cells; Th1 profile cytokines IL-2, INF-gamma, which have important proliferative functions for T-cells and potent antiviral effects, respectively, Downregulation of IL-2 and INF-gamma may induce shifting of a TH1 mediated response to a Th2 dominated response. Correlations of the clinical, histological, and immunological findings will be done in order to understand the mechanisms in which restrain stress modulates HSV-1 infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL MICROBIOCIDES FROM CARRAGEENAN Principal Investigator & Institution: Phillips, David M.; Senior Scientist; Population Council 1 Dag Hammarskjold Plaza New York, Ny 10017 Timing: Fiscal Year 2001; Project Start 27-SEP-2001; Project End 31-JUL-2005 Description (provided by applicant): This Project will study the efficacy of two novel carrageenan-based formulations, zinc- carrageenan (Zn-carrageenan) and lignosulfonic acid (LSA) carrageenan (LSA-carrageenan). Preliminary results indicate that these formulations are significantly more efficacious than carrageenan in blocking HIV in vitro and herpes simplex-2 (HSV -2) infection in mice. Since there is no known assay that

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Herpes Simplex

is predictive of a microbicide's efficacy, the applicant proposes to utilize a number of different in vitro assays and animal systems. In vitro assays will involve a peripheral blood mononuclear cells (PBMC) assay and another assay that employs an established epithelial cell line derived from the human cervix. Because there is a variety of different HIV strains that are sexually transmitted, as well as the fact that the viral genome is constantly changing, the formulations will be assayed for activity against a number of different strains and clades of HIV. Additionally, formulations will be evaluated in a number of animal systems. The HSV-2/mouse system has proven to be a straightforward and consistently reproducible method for evaluating several parameters. Formulations will be evaluated in this system for vaginal and rectal antiviral activity, duration of activity, and efficacy in protecting against pre- and post-viral challenge. Another system, developed by the PL, has shown that lymphocytes and macrophages can traffic from the vaginal vault and subsequently be detected in lymph nodes and spleen. This finding supports the concept that HIV -infected mononuclear cells in semen may infect women by study by Masurier et al. (J. Virol. 1998:72:78227829), which presented evidence that when active or inactivated virus is instilled into the vagina of a mouse, it can subsequently be detected by RT -PCR in the lymph nodes. The applicant will utilize his modified HIV/Mouse system and the Cell Trafficking system to compare Zn-carrageenan, LSA-carrageenan, and the carrageenan-only formulation, Carraguard for efficacy in preventing HIV transport and cell trafficking from the vaginal vault. The applicant feels that the proposed in vitro assays and animal systems in conjunction with the proposed research of our co-investigators is the most well rounded approach to the pre-clinical development of novel microbicide against HIV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OCULAR HSV INFECTION-LATENCY AND PATHOGENESIS Principal Investigator & Institution: Thompson, Richard L.; Molecular Genetics, Biochemistry & Microbiology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: Herpes simplex virus (HSV) is the leading infectious agent causing blindness world wide. This human viral pathogen invades the nervous system, seeding host neurons with viral genetic information. This genetic information is a stable repository from which the virus reinitiates lytic infection which can result in recurrent or persistent corneal inflammation, scarring and ultimately blindness. The molecular mechanisms underlying this process are not well understood but remain central to the prevention and control of HSV. The long-term goal of the proposed research is to define the molecular mechanisms involved in the establishment of herpes simplex virus (HSV) latency. Using a novel single cell PCR assay to obtain quantitative information about the number of neurons containing the viral genome, we have demonstrated that a 2.3kb fragment residing within the latency associated transcript (LAT) gene provides a critical function for the establishment of latent infections (Thompson and Sawtell J.Virol.71 :5432, 1997). Data has been recently generated indicating a significant increase in neuronal death in ganglia infected with mutants lacking this 2.3kb fragment. Consistent with the decreased neuronal survival in the peripheral nervous system, LAT null mutants are more neuroinvasive. Pfu/LD50 experiments demonstrate LAT null mutants in strain l7syn+ are 100-fold more virulent when compared to wild type or genomically rescued isolates. Our ability to precisely quantify the number of latently infected neurons in the ganglia and the number of viral genomes in those individual neurons

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will be exploited to evaluate genetically engineered mutant strains to define the regulatory mechanisms by which locus attenuates virulence increases the latent repository of viral genetic information, and promotes reactivation and thereby recurrent disease. The information gained in these studies will permit the design of more effective vaccines and interventive drug therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OCULAR COSTIMULATION

HSV-1,

STROMAL

KERATITIS,

&

T

CELL

Principal Investigator & Institution: Kwon, Byoung S.; Professor; Ophthalmology; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Herpes simplex virus type 1 (HSV-1) corneal infection leads to establishment of a latent infection in the sensory and autonomic ganglia. HSV-1 reactivates at intervals and causes recurrent corneal infection. Repeated inflammation in the corneal stroma can lead to herpetic stromal keratitis (HSK), an immune inflammatory process that results in blindness. For optimal activation, T cells require costimulation in addition to antigen receptor signals. Constitutive receptors such as CD28 are known to provide costimulation to naive T cells. We have also shown that 4-1BB, an inducible receptor, provides costimulation to activated and memory T cells. However, whether costimulatory receptors play a role in acute, latent, and recurrent HSV-1 infection, and in HSK, is not known. It is also not known whether induction of Tcell energy by blocking costimulation can prevent HSK. Our goals are to determine the role of T-cell costimulatory molecules in herpes infection, to identify factors involved in the pathogenesis of HSK, and to investigate the therapeutic potential of blocking costimulation in HSK. Three specific aims are proposed: 1] Test the hypothesis that the costimulatory receptors, 4-1BB and CD28, are involved in modulating acute HSV-1 infection, latency, and recurrence using 4-1BB- and/or CD28-deficient mice. 2] Determine the roles of the costimulatory receptors 4-1BB and CD28 in the pathogenesis of HSK. 3] Test the hypothesis that blocking costimulation is effective in preventing HSK. This approach (inhibition of costimulation) should be both specific and nontoxic, compared to the use of immunosuppressive drugs. These studies will aid in understanding the immunological mechanisms involved in the blinding eye condition, HSK, and allow development of strategies for the treatment of this and other ocular inflammatory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEPTIDE INHIBITION OF HSV ENTRY Principal Investigator & Institution: Brandt, Curtis R.; Professor; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2005 Description (provided by applicant): Herpes simplex virus remains a significant public health threat despite the availability of antivirals to treat HSV infections. The incidence of genital HSV infection has doubled in the last decade and it is estimated that 22% of all people over 12 years of age in the US are infected with HSV-2. HSV infection also is a significant risk factor for acquisition of HIV infection. It has been known for some time that the presence of ulcerative genital disease increases. Since both HIV and HSV cause persistent infections, the ideal control strategy is to prevent infection. Many people choose not to use condoms and nonoxynol-9 enhances HIV infection by damaging the

48

Herpes Simplex

vaginal mucosa. Alterative preventative strategies are desperately needed. The applicant has discovered a series of peptides that block HSV infection in vitro and one, EB, which is virucidal, also blocks infection in vivo. The applicant?s collaborators have shown that the peptides also block HIV and HPV infection. The first overall goal of Project II is to further the development of the lead peptides that the applicant has discovered and move them closer to clinical trials. He will determine the mechanism of action of the peptides, screen derivatives to identify more potent peptides, test in vitro toxicity in several cell types, and test efficacy in an animal model of HSV epithelial disease. The second overall goal is to use the peptides as tools to study processes involved in HSV entry. The applicant will test binding of the antiviral peptides to the purified entry proteins of HSV(gB, gD, and gH/gL), use the peptides to block entry and analyze the step or steps that are blocked. He will use phage display methods in conjunction with Core A to identify peptides that specifically bind to the purified glycoproteins. These peptides will then be tested for antiviral activity and used in studies to determine the role of the proteins in entry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTECTION OF GENITAL MUCOSA AND GANGLIA AGAINST HSV-2 Principal Investigator & Institution: Milligan, Gregg N.; Associate Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2001; Project Start 01-FEB-1999; Project End 31-JUL-2001 Summary: Greater than Herpes simplex virus type 2 (HSV-2) now infects the genital tracts of approximately one in five Americans. Strategies to prevent new HSV-2 infections are complicated by its ability to initiate a latent infection in the sensory ganglia, periodically reactivate, and cause recurrent lesions or asymptomatic virus shedding in genital tissues thus increasing its chances of infecting new hosts. Effective vaccines are needed to prevent the establishment of latency within the sensory ganglia. Unfortunately, little is known about the immune mechanisms which protect the sensory ganglia. In animal models, previous genital inoculation with HSV-2 elicits immunity which protects the sensory ganglia from reinfection, thus serving as a paradigm for an effective HSV-2 vaccine. The long term aims of this proposal are to use a murine model of genital HSV-2 inoculation to understand the types of immune mechanisms responsible for protection, how these mechanisms work at the molecular level, and how to elicit these responses to provide long term protection. The results of these studies will provide important information for the rational design of vaccines to protect against HSV-2. In the first aim, a recombinant HSV-2 strain expressing green fluorescent protein (HSV-2 gfp) will be used as a marker to determine if HSV-specific T lymphocytes prevent HSV-2 from reaching the sensory ganglia, thus preventing the establishment of latency. Quantification of HSV-2 gfp infected ganglionic neurons by UV microscopy and HSV-2 gfp genomes in the ganglia by quantitative PCR will be used to demonstrate the role of specific T cell subsets in preventing acute and latent HSV-2 infection of the ganglia. In the second aim, an antibody deficient strain of mice (muMT) will be used to determine the role of HSV-specific antibody in protection of the sensory ganglia. Purified IgG and IgA fractions of HSV-specific sera will be administered to HSVimmune muMT mice to determine the efficacy of specific antibody isotypes in completing the protection of HSV-immune muMT mice against the establishment of latent HSV-2 infection. In the third aim, the ability of immune responses elicited by inoculation of distal mucosal or systemic sites to protect the sensory ganglia will be tested. The ability of inoculation at these sites to elicit long term memory immune

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responses within the vaginal mucosa and associated genital lymphoid tissue which can be rapidly recalled for protection of the vaginal mucosa and sensory ganglia will be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RANDOMIZED TRIAL OF HIV/STI PREVENTION IN ZIMBABWE YOUTH Principal Investigator & Institution: Cowan, Frances M.; U of L University College London University College London London, Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The aim of the project is to implement and rigorously evaluate an innovative adolescent HIV/STI prevention program involving school students, professional peer educators, teachers, parents, rural health clinics and the wider community, by means of a community randomized trial. Primary objective: To measure the effectiveness of an adolescent HIV prevention intervention delivered to secondary school students and the wider community in reducing the incidence of HIV1, Herpes simplex virus type 2 (HSV2) and unintended pregnancy among the students. Secondary objectives: I) To use a combination of quantitative and qualitative research methods to explore the evolution of sexual behavior in adolescents in rural Zimbabwe. II) To assess the impact of the intervention on knowledge and attitudes regarding reproductive and sexual health, reported behavior, and measures of self-efficacy. III) To determine through rigorous process evaluation whether these programs are delivered as intended. IV) To refine and assess the validity of research instruments for measuring sexual behavior in Zimbabwean adolescents. V) To examine through rigorous process evaluation acceptability and feasibility of providing VCT in rural community settings. VI) To study the epidemiology of HSV2 infection among adolescents, and to measure the extent to which HSV2 facilitates acquisition of HIV infection. Trial Design: 30 communities (60 schools) will be randomly allocated to either early or deferred program implementation. The impact of the program will be measured in a cohort of 6,600 students aged >12 (median age 15), who will be followed for 4 years (median age 19). Participants will be surveyed at the start of the project, after 30 months and after 4 years. At each survey they will complete a questionnaire and provide a saliva sample (and females a urine sample). The impact of the program on cumulative incidence of HIV-1 and HSV2 infection, and unintended pregnancy as well as on reported sexual behavior will be determined. A detailed process evaluation of the program will be conducted to inform wider program implementation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: REGULATION OF GENE EXPRESSION BY DNA BINDING LIGANDS Principal Investigator & Institution: Dervan, Peter B.; Professor; None; California Institute of Technology Mail Code 201-15 Pasadena, Ca 91125 Timing: Fiscal Year 2001; Project Start 01-JUL-1989; Project End 31-MAR-2003 Summary: Sequence specific DNA binding small molecules that can permeate human cells could potentially regulate transcription of specific genes. When one considers the fact that within the next few years the entire human genome will be mapped and sequenced and, coupled to the remarkable discoveries in biology and human medicine which link human disease to specific genes, fundamental research on these DNA binding ligands could lead to reagents for research in functional genomics and, importantly, a new class of human therapeutics. Our objective has been to elucidate

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Herpes Simplex

chemical principles for the design of small molecules which bind predetermined doublehelical DNA sequences with the affinity and specificity of proteins in order to target predetermined sites within the human genome. The Py-Im-Hp polyamides, the result of a 20-year chemistry program to understand the physical organic principles for DNA recognition, are cell permeable ligands only a few percent the size of a protein which have the affinity and specificity of transcription factors. These synthetic DNA binding ligands have been shown to penetrate human cells, traffic to the nucleus, find the promoter DNA sequences of transcriptionally active genes and inhibit gene expression. In this next funding period, the scope and limitations of this approach with regard to polyamide configuration, size, cell types, and different families of transcription factors will be examined. Cancer and viral genes important in human health will be targeted. With regard to specific aims, polyamides will be designed and synthesized to: (1) inhibit transcription of human breast cancer oncogenes (Her-2/neu), (2) inhibit transcription of Herpes Simplex Virus (HSV), (3) regulate c-fos promoter activity in a mouse, (4) upregulate transcription by creation of polyamide-peptide conjugates as artificial transcription activators, (5) inhibit DNA replication in E coli and yeast, (6) chemically modify coding regions of genes by the design of polyamide-mitomycin and nitrogen mustard conjugates, (7) inhibit viral integration of murine leukemia virus into a host chromosome, and (8) enhance cell uptake further by polyamides with membrane translocation peptide sequences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF GENE EXPRESSION IN HSV INFECTED CELLS Principal Investigator & Institution: Wilcox, Kent W.; Associate Professor; Microbiol & Molecular Genetics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2001; Project Start 01-JUL-1980; Project End 31-MAR-2003 Summary: Herpes simplex virus (HSV) infection often results in a recurrent disease that manifests as skin lesions in the facial or genital area. Herpes virus infections are a leading cause of blindness and fatal endemic enecphalitis. Reactivation of herpes is a serious problem for individuals with immune systems compromised by chemotherapy or HIV infection. Productive infection and the consequent cell destruction by herpes virus requires activation of viral gene expression by a viral protein designated ICP4 (IE175, Vmw175). Initial characterization of the structure and function of ICP4 suggests that it is an ideal target for anti-viral drugs. ICP4 has been conceptually divided into 5 regions on the basis of comparative sequence analysis with related members of the alphaherpesvirus family. These proteins share extensive homology in regions 2 and 4. There is evidence for a transactivation domain in region 1, a DNA binding domain in region 2, and nuclear localization signal in region 3. Although all 5 domains are required for full ICP4 activity, no specific functions have been assigned to regions 4 and 5. The long-term goal of this investigation is to define the structural basis for the functions of ICP4. The specific aims of this project are (1) to characterize the ICP4 during productive infection; and (4) to investigate interactions between ICP4 and a component of the 20S proteasome. The roles of TAD-1 in productive infection and pathogenesis will be determined by infection of cells and animals with a TAD-1 negative mutant. TAD-1 will be further defined by analysis of the effect of point mutations in TAD-1 on transactivation. Coimmunoprecipitation assays with mutant proteins will be performed to define the residues in region 4 that are responsible for TBP/TFIIB interactions. The biological significance of the TBP/TFIIB binding sites in region 4 will be investigated by complementation assays and analysis of viral mutants. Interactions between ICP4 and

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proteasomes will be investigated in transfected and infected cells. The results of these analysis will be integrated into a working model for ICP4. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF HSV GENE EXPRESSION DURING LATENCY Principal Investigator & Institution: Coen, Donald M.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-JUL-2006 Summary: (provided by applicant): The long-term objective of this project has been to investigate the roles of viral DNA replication, replication proteins, and gene expression in the interaction of herpes simplex virus (HSV) with the mammalian nervous system, especially virus latency. Latency is the most fascinating biological property of the virus and its most important clinical feature. Understanding HSV latency is sure to reveal novel features of HSV and the nervous system. Such information is highly relevant to antiviral drugs that target DNA replication, vaccines, and potential agents to cure HSV infections. The proposed research will investigate regulation of viral gene expression during latency (aim 1). Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assays will be used to measure expression of different classes of transcripts and potential regulatory molecules in ganglia and single cells. Cloning of cDNAs will complement the RT-PCR studies. These assays, mutant viruses from the Schaffer and Knipe laboratories, and transgenic mice overexpressing viral sequences will be used to study mechanisms of repression mediated by the HSV latency-associated transcript locus. Anti-HSV drugs will be used to test a model for regulation of viral gene expression by DNA replication. The mechanisms by which drug resistant mutants retain pathogenicity will be explored (aim 2). Frameshift mutations in the thymidine kinase gene that arise in clinical isolates will be tested for effects on latency. Cosmid-based methods will be used to map alleles of clinical isolates that compensate for loss of TK in latency. Finally, changes in host gene expression, which may affect latency, will be studied in collaboration with the Knipe laboratory and Millennium Pharmaceuticals (aim 3). Array technologies will be used to identify changes in host gene expression and RT-PCR assays and viral mutants will be used to examine the time-course, localization, and requirements for these changes. The proposed experiments should shed light on viral and cellular factors involved in the establishment, maintenance, and reactivation of HSV latency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF THE LAT-ICP0 LOCUS IN REGULATING HSV LATENCY Principal Investigator & Institution: Halford, William P.; Microbiology and Immunology; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Recurrent infections with herpes simplex viruses (HSV) are a significant clinical problem. Fundamental to understanding the nature of recurrent herpetic disease is determining precisely how HSV alternates between the two phases of its dual life cycle, latency and reactivation of productive infection. The LATICP0 locus plays a central role in the regulation of HSV-1 latency and reactivation. The genes that encode for the latency-associated transcripts (LATs) and infected cell polypeptide 0 (ICP0) form a continuous locus in the repeated regions of the HSV genome. Specifically, the LAT and ICP0 genes lie on opposite strands of HSV-1's doublestranded DNA genome and share a significant overlap. Thus, the abundant LATs can

52

Herpes Simplex

hybridize to 0.75 kilobases of complementary sequence in ICP0 mRNA. While the antisense arrangement of the LAT-ICP0 locus has long been recognized, the hypothesis that LAT RNAs serve as "antisense repressors" of ICP0 gene expression has not been rigorously analyzed. The juxtaposition of the LAT and ICP0 genes mirrors their opposing roles in latency. While LAT RNAs facilitate the maintenance of HSV latency, expression of ICP0 is necessary and sufficient to induce HSV-1 reactivation. Conversely, failure to express ICP0 is highly conducive to HSV genomes entering a transcriptionally repressed state. Thus, antisense repression of ICP0 mRNA translation is one mechanism by which LATs may facilitate the maintenance of latency. The goal of this research proposal is to evaluate the concept that LAT RNAs and ICP0 form a pair of mutually dependent, opposite regulators that are the yin and yang of HSV latency. Specifically, genetic evidence will be obtained to test the hypothesis that "All viral proteins that induce HSV-1 reactivation in the trigeminal ganglion cell culture model achieve this phenotype via (a) induction of ICP0, (b) suppression of LAT transcription, or (c) both." Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SEROPREVALLENCE /INCIDENCE OF GENITAL HERPES IN UGANDA Principal Investigator & Institution: Nakku-Joloba, Edith; New Mulago Hospital Po Box 5346, Std Clinicward 12 Kampala, Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Prevalence of herpes simplex type 1 and 2 virus (HSV-1 and 2) infection is high worldwide and is highest in developing countries like Uganda. International and local health organizations have called for studies to characterize genital herpes epidemiology in sub-Saharan Africa. Population estimates are needed for policy, for planning interventions, for valid measures of the effect of interventions and for research on new therapies and potential vaccines. The overall goal of this study is to determine the burden of infection and assess the modifiable risk factors associated with Herpes simplex types 1 and 2 infection in Kampala, Uganda with an aim of prevention of spread and relief of those who suffer with genital herpes. The proposed study will aim i) To estimate the age and sex specific prevalence of Herpes simplex type 1 and 2. ii). To estimate the incidence of Herpes simplex type 1 and 2 in an inception cohort of HSV-2 negative persons in an urban population in Uganda and iii) to identify modifiable risk factors associated with Herpes simplex types 1 and 2 prevalence and incidence in this population. The proposed study will be a twostage stratified random population sample survey of female and male participants 15 to 65 years old in Kawempe division of Kampala District. To estimate prevalence of HSV-1 and 2, a cross-sectional serological survey at baseline will be done using type specific ELISA tests for herpes simplex type 1 and 2. Incidence will be assessed in an inception cohort of HSV-2 negative persons by 6 monthly testing for HSV-2. Risk factors for genital herpes will be assessed using a standardized questionnaire to collect information on age, sociodemographic characteristics, sexual behavior, sexual partner characteristics such as age differentials, and HIV infection status. Incidence densities and relative risks will be calculated from new HSV-2 infection and risk factors that predispose to HSV-2 incidence such as age, sex, (gender), sexual behavior, and HIV infection analyzed in a Cox proportional hazards model. By conducting a population study in an urban area in a country where rural studies show high prevalence we will describe the epidemiology genital herpes, gaining new knowledge about genital herpes in urban Uganda and highlighting the modifiable risk factors which can be targeted for effective interventions.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SPECIFICITY OF HEPARAN SULFATE FOR HERPES INFECTION Principal Investigator & Institution: Liu, Jian; Medicinal Chemistry and Natural Products; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 15-JUL-2001; Project End 31-MAY-2005 Summary: (provided by applicant) The long term goal of this project is to understand the roles of cell surface heparan sulfate in contributing herpes simplex viral infection. Heparan sulfate is a highly sulfated polysaccharide with very complicated saccharide sequences, and is present on the mammalian cell surface and in the extracellular matrix in a large quantity. Although heparan sulfate is a known important cell-surface molecule involved in assisting herpes virus infection for a long time, the relationship between the saccharide structure and its role in assisting herpes viral infection is poorly understood. We propose to conduct a series of biochemical studies to elucidate the structural specificity of the 3-O-sulfated heparan sulfate, which is generated by three different heparan sulfate 3-O-sulfotransferase (3-OST) isoforms, for the binding to herpes envelope glycoprotein D (gD). In particular, we plan to carry out the following projects: 1. Isolation and characterization of the gD-binding oligosaccharides generated by isoform 3 (3-OST-3). We plan to prepare the gD-binding oligosaccharide by incubating purified 3-OST-3 enzyme with a heparan sulfate oligosaccharide library. The gD-binding oligosaccharide will be purified using anion exchange HPLC and gDaffinity column. The structure of the gD-binding oligosaccharide will be determined by chemical and enzymatic degradation approaches coupled with matrix assisted laser desorption/ionization mass spectrometry. We also plan to examine the effect of the purified gD-binding oligosaccharide on viral entry into the cell using a cell-based assay. 2. Characterization of the structures of the gD-binding sites generated by isoform 2 and isoform 4 (3-OST-2 and 3-OST-4). We plan to express and purify 3-OST-2 and 3-OST-4 enzymes. We will also determine the structures of the gD-binding sites within 3-OST-2 and 3-OST-4 modified heparan sulfate. Both 3-OST-2 and 3-OST-4 have recently proved to assist herpes simplex virus 1 entry into the cells, suggesting that 3-OST-2 and 3-OST4 provide binding sites for gD. In addition, studies of the distribution of 3-OST-2 and 3OST-4 revealed that both enzymes are highly expressed in human brains. We speculate that herpes virus may utilize 3-OST-2 and 3-OST-4 modified heparan sulfate to infect human brains. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STUDIES OF HERPES SIMPLEX VIRUS GLYCOPROTEINS Principal Investigator & Institution: Cohen, Gary H.; Professor and Chair; Microbiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-1981; Project End 31-JUL-2005 Summary: (Adapted from the Investigator's abstract) For the two herpes simplex viruses (HSV-1 and HSV-2), four glycoproteins designated gB, gD and a complex of gH/gL are essential for virus entry. A fifth glycoprotein, gC, though not essential, is important for facilitating initial attachment by binding to cell surface heparin sulfate proteoglycans. gD triggers entry by interacting with one of several different cellular receptors. gB and gH/gL are necessary for fusion of the envelope with the plasma membrane. The long-term objective of the research efforts of Drs. Cohen and Eisenberg is to understand the mechanism by which these glycoproteins interact with each other

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and with cell molecules to mediate HSV entry. Within this proposal, they propose three specific aims: 1) to study immunological and biochemical properties of soluble gD, alone or in combination, with two of its receptors, HveA (a TNF receptor) or HveC (an adhesion molecule in the Ig superfamily); 2) to study the gD-receptor interaction when either the ligand or the receptor (or both) is membrane bound; and 3) to study events in virus entry that occur as a consequence of gD-receptor interactions. The investigators suggest that downstream interactions of the virus with the plasma membrane may involve gB and gH/gL of the virus and may additionally involve other cellular molecules. They have cloned the ectodomains of gD, gB, gH/gL, HveA and HveC into a baculovirus expression system and/or mammalian cells and have expressed and obtained purified proteins. In Aim 1, they will use these proteins to solve the structure of gD alone and/or in combination with receptor and/or antibody by X-ray diffraction analysis. They will map antibody and receptor binding domains on gD and look for conformational changes in gD that occur as a result of receptor binding. In Aim 2, they will use quantitative assays that present gD or its receptor in the context of a membrane and study the interaction of the other protein as a soluble form. One approach will be to bind HSV to an ELISA plate and then determine if added soluble receptor inhibits the infection of cells that are added in fluid phase. Such studies will indicate that they are evaluating receptor binding to a viable virus. In a second approach, they will bind virions to a biosensor chip and flow soluble receptor across the chip to measure receptor-virus interactions. A third approach will be to express the receptor in the murine leukemia virus (MuLV)-receptor pseudotype system and use these particles to study binding of gDt. In Aim 3, they will look for interactions among soluble forms of gD, gB and gH/gL in the presence and absence of gD receptors. In addition, they will study a series of gD/gH hybrid molecules for their ability to function in HSV infection in place of gD or gH/gL. Finally, they will study mutant forms of HSV including those that no longer require HveA or HveC for entry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDIES OF MECHANISM OF ACTION AND BIOAVAILABILITY Principal Investigator & Institution: Birt, Diane; Professor and Chair; Iowa State University of Science & Tech Ames, Ia 500112207 Timing: Fiscal Year 2002; Project Start 22-JUL-2002; Project End 31-MAY-2007 Summary: Aims: 1) Evaluation of the effects of Echinacea and Hypericum in animal models: non-specific and specific immune responses to herpes simplex-1 virus, inflammation and cell proliferation. 2) Explore the mechanisms of action of the above using cell culture systems 3) Evaluate the bioavailability of constituents of Hypericum (hypericin, pseudohypericin) and Echinacea (alkylamides, echinacoside). Researchers on this project include Diane Birt as the PI and 5 co-PI's (Susan Carpenter, Joan Cunnick, Suzanne Hendrich, Marian Kohut and Patricia Murphy). The bulk of the work will be done by two assistant scientists and one associate scientist. This project includes in vitro, in vivo and human studies. Facilities for this project are located in several buildings on the Iowa State University Campus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TARGETTING DIFFUSE LIVER METASTASES WITH HERPES VIRUS Principal Investigator & Institution: Tanabe, Kenneth K.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 07-JAN-2000; Project End 31-DEC-2002

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Summary: Current therapuetic modalities for patients with liver metastases are clearly inadequate. To date, virtually all cancer gene therapy research using viruses have focused on replication- incompetent viruses. However, replication-competent herpes simplex virus type 1 (HSV) holds promise as a potentially effective oncolytic agent. The principal anti-tumor activity of replication-competent HSV results from viral replication within tumor cells, resulting in cell destruction, as well as production of progeny virions that can directly infect adjacent tumor cells. In addition, HSV thymidine kinase activation of the prodrug ganciclovir enhances the antitumor activity. The strategy of restricting HSV replication to cancer cells represents a novel paradigm. The hypotheses to be examined are 1) HSV can be genetically modified to restrict its replication to CEAexpressing cells; 2) Treatment of diffuse liver metastases with intrasplenic administration of HSV will result in significant tumor reduction with limited spread of viral infection; and 3) Pre-existing immunity to HSV will limit spread of viral infection without reducing anti-tumor efficacy. In Specific Aim 1 construction of an HSV mutant (designated HSVceaalpha) will be completed. This vector is engineered such that an immediate-early gene that is critical for HSV replication is regulated by the human CEA promoter, thereby limiting HSVceaalpha replication to CEA-expressing cells. The ability of HSVceaalpha to replicate and cause cytopathic effects will be examined in primary cultures of normal human tissues, CEA- positive and CEA- negative colon carcinomas, and in human skin xenografts. In Specific Aim 2 the efficacy and toxicity of treating liver metastases with replication-conditional HSV will be examined. Several complementary assays will be used to detect HSV replication in tumor and non-tumor tissues after intrasplenic HSV administration to mice bearing diffuse liver metastases. The effects of viral dose, systemic ganciclovir administration, and initial tumor volume on spread of viral infection and animal surivival will be measured. In Specific Aim 3 we will analyze the effect of the host immune system on treatment of liver metastases with replicationconditional HSV. We will first examine how pre-existing immunity influences both the spread of HSV infection after treatment of liver metastases and the anti- tumor efficacy. We will subsequently examine the effect of individual components of the immune system on viral spread and anti-tumor efficacy. In concert, these studieds will provide a basis for development of clinical trials with HSV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE GENETICS OF HSV-1 REACTIVATION Principal Investigator & Institution: Feldman, Lawrence T.; Associate Professor; Microbiology and Immunology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: Herpes Simplex Virus Type I (HSV-1) infects humans orofacially, causing a gingivostomatis of the mouth and a keratitis of the eye. HSV-1 infections are highly prevalent in the population. Approximately eighty percent of adults in the U.S. are seropositive for HSV-1. Following a primary infection, this virus establishes a latent infection of the trigeminal from which it can reactivate causing a recurrence of the disease. Our present understanding of the pathogenesis of both latency and reactivation at the molecular level is incomplete. Research to date has established the importance of the LAT region in viral reactivation from the latent state. However no clear molecular role for the LAT region's contribution to reactivation has been defined, nor has the role of the LAT region in establishing a latent infection been determined. This proposal is aimed at the construction of more precisely defined mutations within the LAT region. Current viral mutants are defective in more than one function. A second goal of the

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proposal is to employ a variety of PCR and non-PCR-based techniques to study the ability of these mutant viruses to establish a latency infection when compared with the wild type virus. The final area of interest is to construct recombinant viruses which are unable to reactivate from the latent state and to learn from the structure of those viruses how the LAT region contributes to a reactivation event. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF ATP HYDROLYSIS IN HSV-1 TERMINASE ACTIVITY Principal Investigator & Institution: Duffy, Carol L.; Microbiology and Immunology; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The goal of this project is a thorough analysis of the ATPase activity associated with the herpes simplex virus type 1 packaging enzyme, or terminase. The process of DNA packaging is both conserved among members of the Herpesviridae and distinct from cellular processes. Thus studies on the HSV-1 terminase will provide knowledge important for the generation of anti-viral agents for herpesviruses associated with a number of life-threatening diseases. The hydrolysis of ATP is required for herpesvirus DNA packaging. The UL15 and UL28 proteins have been proposed to comprise the HSV-1 terminase and, therefore, to possess the many activities required for DNA packaging including ATPase activity. The specific aims of this proposal utilize biochemical and genetic approaches to identify and analyze the ATPase center of the HSV-1 terminase. Purified UL15 and UL28 proteins will be tested for ATPase activity and the kinetics of ATP hydrolysis will be determined. ATPinteracting residues will be identified through the sequencing of protease-derived peptides from 8-N3-[alpha-32p]ATP-photolabeled protein. Proteins containing amino acid changes in ATP-interacting residues will be generated, purified, and studied to confirm the importance of those residues to ATP hydrolysis. Finally, HSV-1 mutants carrying the above mutations will be generated and examined in vivo to identify specific DNA packaging activities that require the newly discovered ATPase center. These studies will greatly increase the understanding of the process of DNA packaging by all herpesviruses and will extend our knowledge of ATP-driven molecular motors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THERAPEUTIC RECURRENCE

VACCINES

TO

REDUCE

OCULAR

HSV

Principal Investigator & Institution: Nesburn, Anthony B.; Director; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 90048 Timing: Fiscal Year 2001; Project Start 01-JAN-1992; Project End 31-DEC-2003 Summary: (Adapted from the applicant's abstract): This proposal proposes to reduce the incidence of herpes induced blindness through therapeutic vaccination. In the previous research period, the investigator has indicated therapeutic vaccine efficacy in terms of statistically significant that reduced recurrent HSV-1 ocular disease and HSV-1 shedding. The investigator has hypothesized that the therapeutic vaccine efficacy seen is due to local ocular/mucosal immune response rather than a systemic immune response. The investigator's group has produced four papers directly related to their work on therapeutic vaccination. All papers have been submitted at this time (none accepted). The specific aims to be addressed in the present application are (1) to test the hypothesis that therapeutic vaccine efficacy and duration against recurrent ocular HSV-1 can be extended by periocular booster inoculations with a subunit vaccine, or with HSV-1 DNA

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ocular vaccines or live HSV-1 ocular vaccines; (2) to test the hypothesis that therapeutic vaccine efficacy against recurrent ocular HSV-1 is due to common mucosal immunity rather than just local ocular mucosal immunity; and (3) to verify the hypothesis that sIgA is the specific mucosal immune response most important for therapeutic vaccine efficacy against recurrent ocular HSV-1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSCRIPTIONAL REGULATION Principal Investigator & Institution: Herr, Winship; Assistant Director/Dean; Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2002; Project Start 21-MAR-2002; Project End 31-DEC-2006 Summary: (provided by applicant): Tumor progression involves changes in transcriptional regulation that result in altered states of gene expression. Central to the process of transcriptional regulation is the activation of transcription by RNA polymerases I, II, and III. This transcriptional activation involves the interplay of sitespecific activators bound to sites near or far from the transcriptional start site with basal factors bound to core-promoter elements located near the transcriptional start site. This project represents the fusion of two current projects-Enhancer Function and Viral Transactivation-and its overall goal is to understand how site-specific activators and core-promoter-binding basal factors communicate amongst themselves and with each other to regulate transcription. We use herpes simplex virus (HSV) to probe these mechanisms. When HSV infects a cell, the infecting virion deposits a transcriptional activator called VP16 into the infected cell. VP16 initiates a cascade of viral gene transcription by directing formation of a multiprotein-DNA complex, called the VP16induced complex, with two cellular coregulators-Oct-1, a POU-domain transcriptional activator, and HCF-1, a chromatin-associated regulator of cell proliferation-on HSV immediate-early promoters. In uninfected cells, Oct-1 plays important roles in activation of RNA polymerase II and III transcription by different core-promoter-binding basal factors in different promoter contexts and HCF-1 plays one or more important roles in promoting cell proliferation through association with chromatin. We study these cellular and viral proteins together and separately to understand the mechanisms of transcriptional regulation in human cells. We will determine the structure and function of the herpes-simplex-virus VP16-induced complex and its constituent members, HCF-1, Oct-1, and VP16; elucidate the roles of basal core-promoter-binding factors in both RNA polymerase II and III transcription; and identify mechanisms of transcriptional activation domain function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRANSPORT OF HERPES SIMPLEX VIRUS IN OCULAR TISSUES Principal Investigator & Institution: Lavail, Jennifer H.; Professor; Anatomy; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2002; Project Start 01-JUL-1978; Project End 31-MAR-2007 Summary: (provided by applicant): Understanding the mechanisms of axonal transport of neurotropic viruses is the key to understanding and controlling their spread in the nervous system. To multiply and spread, to move initially from the site of entry and later to the site of release, Herpes simplex virus (HSV) must use neuronal host cell proteins and mechanisms. Our understanding of the interplay of specific viral proteins that piggyback on the mechanisms and of the neuronal proteins that are exploited, is critical but almost nonexistent. In this application we continue to focus on the

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anterograde transport of HSV. Based on our previous results, our hypothesis is that the nucleocapsid and envelope components of HSV are independently transported in the axon and that the components require specific kinesin related proteins. 1) We have begun to examine the transport of the nucleocapsid and envelope components. To do this we have developed two viral mutant strains and revertants that will facilitate our research into these transport mechanisms. 2) In this proposal we shall continue these studies and carry out co-immunoprecipitation assays to identify the motor proteins associated with the nucleocapsid component. 3) We shall also determine whether or not the virus egresses from the cell by budding, after the envelope proteins are delivered to the axon membrane and the nucleocapsids cluster near that region of membrane. These results will provide important new cell biological information about the recognition signals of particular organelles. They will also have significant clinical benefits. The anterograde transport of HSV to the cornea in human herpetic keratitis results in severe consequences, including corneal scars, glaucoma and possibly encephalitis. Our results will provide new insight into the identification of viral and host proteins necessary for viral envelope and nucleocapsid transport and a rational basis for the design of innovative antiviral drugs for prevention and intervention. Furthermore, the genome of HSV can be altered to serve as a vector for introduction of novel genes into the nervous system. Our results will elucidate the mechanisms that target the vector to particular neuron types and to particular regions of infected neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: USE TRANSMISSION

OF

MODIFIED

LACTOBACILLI

TO

BLOCK

HSV

Principal Investigator & Institution: Chang, Chia-Hwa; Osel, Inc. Suite 14 Santa Clara, Ca 95054 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-AUG-2003 Summary: (provided by applicant): Genital herpes infection is extremely common throughout the world and continues to increase in incidence, Genital herpes is caused by the sexual transmission of herpes simplex virus type 2 (HSV-2), although a smaller, but increasing, percentage of cases are caused by herpes simplex virus type 1 (HSV-1) Genital herpes infection is associated with a range of clinical sequlae, including many that are serious in nature. The lack of effective measures to impede HSV transmission underlies the widespread escalation of the genital herpes epidemic. We are developing a novel approach to block HSV transmission in women. This approach, termed MucoCept HSV, involves genetic modification of human vaginal isolates of lactobacilli, the common bacterium found within the vaginal mucosal microflora of healthy women. These bacteria are being modified to produce a decoy HSV receptor that has the capacity to bind, trap, and inactivate HSV within the mucosal layer before it is transmitted to host cell and tissues. As such, this represents a novel and potentially powerful approach to prevent the transmission of HSV. As outlined in the present application, we propose to genetically modify vaginal-derived lactobacilli to express the HSV receptor, HveC, either covalently attached to the cell wall of the bacterium, or secreted into the surrounding biofilm matrix. This approach will use technology that has already been used by our group for the successful expression of other heterologous mammalian proteins in these same strains of lactobacilli. We propose to subsequently demonstrate the capacity of the expressed HveC protein to neutralize HSV infectivity of susceptible cultured cell lines. If achieved successfully, these studies will position us to undertake Phase II studies to assess the efficacy of these modified bacteria to reduce HSV

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transmission in vivo, as well as to optimize stable expression of the HveC protein as a major component of the clinical development plan for this product. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRAL AND MOLECULAR CHEMOTHERAPY OF MALIGNANT CNS TUMORS Principal Investigator & Institution: Buchsbaum, Donald J.; Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-MAY-2007 Summary: This multi-disciplinary group of investigators has several years' experience working together designing and characterizing viral vector approaches to gene therapy of malignant brain tumors. A major focus has been producing and testing both nonreplicative and replicative adenovirus (Ad) and conditionally replicative herpes simplex virus (HSV) vectors that express foreign gene products within infected tumor cells. These studies have been conducted at both the in vitro and in vivo levels to demonstrate proof-of-principle, safety and efficacy in experimental mouse models of intracranial gliomas. We have conducted Phase I and III clinical trials using retrovirus, Ad and HSV administered intratumorally in patients with malignant gliomas. In keeping with the translational theme of this SPORE application, this project seeks to design and deploy effective viral vector therapies of malignant glioma by utilizing rational combinations of foreign gene-viral vectors, oncolytic virus and irradiation., defined by additive, synergistic or antagonistic interactions determined for these various modalities. Aim 1 seeks to optimize the timing and dose of irradiation to achieve greater viral replication and spread and/or enhanced foreign gene expression in glioma cells and in intracranial experimental gliomas. In athymic nude mice. Aim 2 will develop and characterize both replicative HSV and replicative Ad that expression the pro-drug converting enzyme cytosine deaminase and optimize its use in intracranial preclinical models of malignant gliomas in combination with systemic 5-fluorocytosine. Other genetic constructs (uracil phosphoribosyl transferase) and drugs (dihydropyrimidine inhibitors) that facilitate appropriate 5-FU incorporation into host cell DNA synthesis pathways will also be tested to improve the therapeutic effect. Further, the radiation sensitization properties of certain pro-drugs products (5-FU) will be characterized to achieve a greater anti-glioma effect. Aim 3 will combine findings in Aims 1 and 2 to design and test strategies that rationally combine intratumoral viral vector injection, systemic pro-drug administration and low dose external beam irradiation to achieve the most effective and safe antiglioma therapy (ies). Aim 4 will translate our findings in preclinical models for brain tumor therapy into pilot, Phase I and Phase II clinical trials in patients with malignant gliomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIRION HOST SHUTOFF PROTEIN OF HERPES SIMPLEX VIRUS Principal Investigator & Institution: Ross, Jeffrey; Professor and Chair; Oncology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-MAY-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Herpes Simplex

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Project Title: VIRUS-CELL INTERACTIONS & HERPES SIMPLEX VIRUS INFECTION Principal Investigator & Institution: Montgomery, Rebecca I.; Inst for Molecular Virology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: (provided by applicant): The ultimate goal of this project is to define the mechanism of herpes simplex virus (HSV) invasion of human cells to establish productive infection. The two serotypes of HSV combined, infect -80 percent of the world adult population. Once infected, a person is infected with these viruses for life. HSV causes a variety of diseases: cold sores, genital lesions resulting from sexually transmitted virus, blindness from ocular infection, severe disseminated disease in newborns, and encephalitis. Disease can resuk from initial infection or re-occurring infection by HSV. Understanding how the virus gains entry into cells to initiate infection can lead to new therapies to block virus infection, prevent disease due to re-occurring infection, or help in the design of vaccines to promote inimunity to HSV infection. In this grant we will further characterize the HveA co-receptor, a human protein that mediates HSV entry into cells, to determine areas of the molecule necessary for virus interactions and promotion of virus entry. We will identify biologically relevant glycosaminoglycans and proteoglycans that enhance virus entry via HveA and characterize their role in the HSV entry pathway. In addition, we will continue the search for other cell products used by HSV to gain entry into cells. The results obtained from these studies will advance our understanding of the cellular components HSV interacts with to gain entry into cells, the cell-virus interactions that promote entry, and methods of enhancing or preventing HSV entry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “herpes simplex” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for herpes simplex in the PubMed Central database: •

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A 371-nucleotide region between the herpes simplex virus type 1 (HSV-1) LAT promoter and the 2-kilobase LAT is not essential for efficient spontaneous reactivation of latent HSV-1. by Perng GC, Slanina SM, Ghiasi H, Nesburn AB, Wechsler SL.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190031

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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A 437-base-pair deletion at the beginning of the latency-associated transcript promoter significantly reduced adrenergically induced herpes simplex virus type 1 ocular reactivation in latently infected rabbits. by Hill JM, Garza HH Jr, Su YH, Meegalla R, Hanna LA, Loutsch JM, Thompson HW, Varnell ED, Bloom DC, Block TM.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191932

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A Gene Capable of Blocking Apoptosis Can Substitute for the Herpes Simplex Virus Type 1 Latency-Associated Transcript Gene and Restore Wild-Type Reactivation Levels. by Perng GC, Maguen B, Jin L, Mott KR, Osorio N, Slanina SM, Yukht A, Ghiasi H, Nesburn AB, Inman M, Henderson G, Jones C, Wechsler SL.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135864

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A Herpes Simplex Virus Type 1 [gamma]34.5 Second-Site Suppressor Mutant That Exhibits Enhanced Growth in Cultured Glioblastoma Cells Is Severely Attenuated in Animals. by Mohr I, Sternberg D, Ward S, Leib D, Mulvey M, Gluzman Y.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114924

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A Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutant with Increased Virulence and Reduced Spontaneous Reactivation. by Perng GC, Slanina SM, Yukht A, Drolet BS, Keleher W Jr, Ghiasi H, Nesburn AB, Wechsler SL.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103911

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A Multicenter Phase I/II Dose Escalation Study of Single-Dose Cidofovir Gel for Treatment of Recurrent Genital Herpes. by Sacks SL, Shafran SD, Diaz-Mitoma F, Trottier S, Sibbald RG, Hughes A, Safrin S, Rudy J, McGuire B, Jaffe HS.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105979

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A Net + 1 Frameshift Permits Synthesis of Thymidine Kinase from a Drug- Resistant Herpes Simplex Virus Mutant. by Hwang CB, Horsburgh B, Pelosi E, Roberts S, Digard P, Coen DM.; 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44015

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A Novel Cellular Protein, p60, Interacting with both Herpes Simplex Virus 1 Regulatory Proteins ICP22 and ICP0 Is Modified in a Cell-Type-Specific Manner and Is Recruited to the Nucleus after Infection. by Bruni R, Fineschi B, Ogle WO, Roizman B.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104158

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A novel function for human factor C1 (HCF-1), a host protein required for herpes simplex virus infection, in pre-mRNA splicing. by Ajuh P, Chusainow J, Ryder U, Lamond AI.; 2002 Dec 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136956

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A Novel Herpes Simplex Virus Type 1 Transcript (AL-RNA) Antisense to the 5[prime prime or minute] End of the Latency-Associated Transcript Produces a Protein in Infected Rabbits. by Perng GC, Maguen B, Jin L, Mott KR, Kurylo J, BenMohamed L, Yukht A, Osorio N, Nesburn AB, Henderson G, Inman M, Jones C, Wechsler SL.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155148

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A Null Mutation in the Gene Encoding the Herpes Simplex Virus Type 1 UL37 Polypeptide Abrogates Virus Maturation. by Desai P, Sexton GL, McCaffery JM, Person S.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114600

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A Null Mutation in the UL36 Gene of Herpes Simplex Virus Type 1 Results in Accumulation of Unenveloped DNA-Filled Capsids in the Cytoplasm of Infected Cells. by Desai PJ.; 2000 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112442

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A Protective Role of Locally Administered Immunostimulatory CpG Oligodeoxynucleotide in a Mouse Model of Genital Herpes Infection. by Harandi AM, Eriksson K, Holmgren J.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140825

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A Protein Encoded by the Herpes Simplex Virus (HSV) Type 1 2-Kilobase LatencyAssociated Transcript Is Phosphorylated, Localized to the Nucleus, and Overcomes the Repression of Expression from Exogenous Promoters When Inserted into the Quiescent HSV Genome. by Thomas SK, Lilley CE, Latchman DS, Coffin RS.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136061

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A Virus with a Mutation in the ICP4-Binding Site in the L/ST Promoter of Herpes Simplex Virus Type 1, but Not a Virus with a Mutation in Open Reading Frame P, Exhibits Cell-Type-Specific Expression of [gamma]134.5 Transcripts and LatencyAssociated Transcripts. by Lee LY, Schaffer PA.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109655

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Accumulation of Herpes Simplex Virus Type 1 Early and Leaky-Late Proteins Correlates with Apoptosis Prevention in Infected Human HEp-2 Cells. by Aubert M, Rice SA, Blaho JA.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113998

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Accumulation of Viral Transcripts and DNA during Establishment of Latency by Herpes Simplex Virus. by Kramer MF, Chen SH, Knipe DM, Coen DM.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124594

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Activation of cJUN N-Terminal Kinase by Herpes Simplex Virus Type 1 Enhances Viral Replication. by McLean TI, Bachenheimer SL.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112860

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Activation of Interferon Response Factor-3 in Human Cells Infected with Herpes Simplex Virus Type 1 or Human Cytomegalovirus. by Preston CM, Harman AN, Nicholl MJ.; 2001 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114459

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Acyclovir Cream for Treatment of Herpes Simplex Labialis: Results of Two Randomized, Double-Blind, Vehicle-Controlled, Multicenter Clinical Trials. by Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127288

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Alpha and Gamma Interferons Inhibit Herpes Simplex Virus Type 1 Infection and Spread in Epidermal Cells after Axonal Transmission. by Mikloska Z, Cunningham AL.; 2001 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114768

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Alpha/Beta Interferon and Gamma Interferon Synergize To Inhibit the Replication of Herpes Simplex Virus Type 1. by Sainz B Jr, Halford WP.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136787

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Alphaherpesvirus Proteins Related to Herpes Simplex Virus Type 1 ICP0 Affect Cellular Structures and Proteins. by Parkinson J, Everett RD.; 2000 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102039

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Altering the Expression Kinetics of VP5 Results in Altered Virulence and Pathogenesis of Herpes Simplex Virus Type 1 in Mice. by Tran RK, Lieu PT, Aguilar S, Wagner EK, Bloom DC.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153803

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Amplification of Reiterated Sequences of Herpes Simplex Virus Type 1 (HSV-1) Genome To Discriminate between Clinical HSV-1 Isolates. by Maertzdorf J, Remeijer L, Van Der Lelij A, Buitenwerf J, Niesters HG, Osterhaus AD, Verjans GM.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85683

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An avirulent ICP34.5 deletion mutant of herpes simplex virus type 1 is capable of in vivo spontaneous reactivation. by Perng GC, Thompson RL, Sawtell NM, Taylor WE, Slanina SM, Ghiasi H, Kaiwar R, Nesburn AB, Wechsler SL.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189003

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An Enhanced Packaging System for Helper-Dependent Herpes Simplex Virus Vectors. by Stavropoulos TA, Strathdee CA.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109935

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An Important Role for Major Histocompatibility Complex Class I-Restricted T Cells, and a Limited Role for Gamma Interferon, in Protection of Mice against Lethal Herpes Simplex Virus Infection. by Holterman AX, Rogers K, Edelmann K, Koelle DM, Corey L, Wilson CB.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104449

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An Intertypic Herpes Simplex Virus Helicase-Primase Complex Associated with a Defect in Neurovirulence Has Reduced Primase Activity. by Barrera I, Bloom D, Challberg M.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124597

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Analysis of conserved domains of UL41 of herpes simplex virus type 1 in virion host shutoff and pathogenesis. by Strelow LI, Leib DA.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190531

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Analysis of HCF, the Cellular Cofactor of VP16, in Herpes Simplex Virus-Infected Cells. by LaBoissiere S, O'Hare P.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111518

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Analysis of Individual Human Trigeminal Ganglia for Latent Herpes Simplex Virus Type 1 and Varicella-Zoster Virus Nucleic Acids Using Real-Time PCR. by Cohrs RJ, Randall J, Smith J, Gilden DH, Dabrowski C, van der Keyl H, Tal-Singer R.; 2000 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112425

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Analysis of Protein Expression from within the Region Encoding the 2.0-Kilobase Latency-Associated Transcript of Herpes Simplex Virus Type 1. by Lock M, Miller C, Fraser NW.; 2001 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114134

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Analysis of the 2-kilobase latency-associated transcript expressed in PC12 cells productively infected with herpes simplex virus type 1: evidence for a stable, nonlinear structure. by Rodahl E, Haarr L.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191235

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Analysis of the Phosphorylation Sites of Herpes Simplex Virus Type 1 Regulatory Protein ICP27. by Zhi Y, Sandri-Goldin RM.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104088

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Anterograde Transport of Herpes Simplex Virus Proteins in Axons of Peripheral Human Fetal Neurons: an Immunoelectron Microscopy Study. by Holland DJ, Miranda-Saksena M, Boadle RA, Armati P, Cunningham AL.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112870

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Anterograde Transport of Herpes Simplex Virus Type 1 in Cultured, Dissociated Human and Rat Dorsal Root Ganglion Neurons. by Miranda-Saksena M, Armati P, Boadle RA, Holland DJ, Cunningham AL.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111661

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Antiviral Activity of a Selective Ribonucleotide Reductase Inhibitor against Acyclovir-Resistant Herpes Simplex Virus Type 1 In Vivo. by Duan J, Liuzzi M, Paris W, Lambert M, Lawetz C, Moss N, Jaramillo J, Gauthier J, Deziel R, Cordingley MG.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105657

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Antiviral effect of oryzacystatin, a proteinase inhibitor in rice, against herpes simplex virus type 1 in vitro and in vivo. by Aoki H, Akaike T, Abe K, Kuroda M, Arai S, Okamura R, Negi A, Maeda H.; 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162640

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Application of Competitive PCR to Cerebrospinal Fluid Samples from Patients with Herpes Simplex Encephalitis. by Domingues RB, Lakeman FD, Mayo MS, Whitley RJ.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105021

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Application of the Intracellular Gamma Interferon Assay To Recalculate the Potency of CD8 + T-Cell Responses to Herpes Simplex Virus. by Kumaraguru U, Rouse BT.; 2000 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112059

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Assembly and Organization of Glycoproteins B, C, D, and H in Herpes Simplex Virus Type 1 Particles Lacking Individual Glycoproteins: No Evidence for the Formation of a Complex of These Molecules. by Rodger G, Boname J, Bell S, Minson T.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113967

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Assembly of Infectious Herpes Simplex Virus Type 1 Virions in the Absence of FullLength VP22. by Pomeranz LE, Blaho JA.; 2000 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102043

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Assembly of the Herpes Simplex Virus Capsid: Preformed Triplexes Bind to the Nascent Capsid. by Spencer JV, Newcomb WW, Thomsen DR, Homa FL, Brown JC.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109620

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Assembly of the Herpes Simplex Virus Procapsid from Purified Components and Identification of Small Complexes Containing the Major Capsid and Scaffolding Proteins. by Newcomb WW, Homa FL, Thomsen DR, Trus BL, Cheng N, Steven A, Booy F, Brown JC.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104203

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Association of herpes simplex virus regulatory protein ICP22 with transcriptional complexes containing EAP, ICP4, RNA polymerase II, and viral DNA requires

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posttranslational modification by the U(L)13 proteinkinase. by Leopardi R, Ward PL, Ogle WO, Roizman B.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191165 •

ATP Depletion Blocks Herpes Simplex Virus DNA Packaging and Capsid Maturation. by Dasgupta A, Wilson DW.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104443

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ATP-Dependent Localization of the Herpes Simplex Virus Capsid Protein VP26 to Sites of Procapsid Maturation. by Chi JH, Wilson DW.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111482

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Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation in Mice. by Sundaresan P, Hunter WD, Martuza RL, Rabkin SD.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111891

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Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation of Intracerebral Injection in Nonhuman Primates. by Hunter WD, Martuza RL, Feigenbaum F, Todo T, Mineta T, Yazaki T, Toda M, Newsome JT, Platenberg RC, Manz HJ, Rabkin SD.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112710

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Axonal Transport and Sorting of Herpes Simplex Virus Components in a Mature Mouse Visual System. by LaVail JH, Tauscher AN, Aghaian E, Harrabi O, Sidhu SS.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155024

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B7 Costimulation Plays an Important Role in Protection from Herpes Simplex Virus Type 2-Mediated Pathology. by Thebeau LG, Morrison LA.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153796

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BAC-VAC, a novel generation of (DNA) vaccines: A bacterial artificial chromosome (BAC) containing a replication-competent, packaging-defective virus genome induces protective immunity against herpes simplex virus 1. by Suter M, Lew AM, Grob P, Adema GJ, Ackermann M, Shortman K, Fraefel C.; 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23055

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B-myb Promoter Retargeting of Herpes Simplex Virus [gamma]34.5 Gene-Mediated Virulence toward Tumor and Cycling Cells. by Chung RY, Saeki Y, Chiocca EA.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104282

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Calcium Phosphate Nanoparticles Induce Mucosal Immunity and Protection against Herpes Simplex Virus Type 2. by He Q, Mitchell A, Morcol T, Bell SJ.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120054

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Capsid Structure of Kaposi's Sarcoma-Associated Herpesvirus, a Gammaherpesvirus, Compared to Those of an Alphaherpesvirus, Herpes Simplex Virus Type 1, and a Betaherpesvirus, Cytomegalovirus. by Trus BL, Heymann JB, Nealon K, Cheng N, Newcomb WW, Brown JC, Kedes DH, Steven AC.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115914

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CD4 T-Cell Responses to Herpes Simplex Virus Type 2 Major Capsid Protein VP5: Comparison with Responses to Tegument and Envelope Glycoproteins. by Koelle DM, Schomogyi M, McClurkan C, Reymond SN, Chen HB.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113250

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cdc2 Cyclin-Dependent Kinase Binds and Phosphorylates Herpes Simplex Virus 1 UL42 DNA Synthesis Processivity Factor. by Advani SJ, Weichselbaum RR, Roizman B.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114607

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Cell-to-Cell Spread of Wild-Type Herpes Simplex Virus Type 1, but Not of Syncytial Strains, Is Mediated by the Immunoglobulin-Like Receptors That Mediate Virion Entry, Nectin1 (PRR1/HveC/HIgR) and Nectin2 (PRR2/HveB). by Cocchi F, Menotti L, Dubreuil P, Lopez M, Campadelli-Fiume G.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111902

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Cellular Transcription Factors Enhance Herpes Simplex Virus Type 1 oriS-Dependent DNA Replication. by Nguyen-Huynh AT, Schaffer PA.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109584

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Characterization of a Nerve Growth Factor-Inducible Cellular Activity That Enhances Herpes Simplex Virus Type 1 Gene Expression and Replication of an ICP0 Null Mutant in Cells of Neural Lineage. by Jordan R, Pepe J, Schaffer PA.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110163

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Characterization of a Type-Common Human Recombinant Monoclonal Antibody to Herpes Simplex Virus with High Therapeutic Potential. by De Logu A, Williamson RA, Rozenshteyn R, Ramiro-Ibanez F, Simpson CD, Burton DR, Paolo Sanna P.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105301

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Characterization of Herpes Simplex Virus-Containing Organelles by Subcellular Fractionation: Role for Organelle Acidification in Assembly of Infectious Particles. by Harley CA, Dasgupta A, Wilson DW.; 2001 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114030

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Characterization of Herpes Simplex Viruses Selected in Culture for Resistance to Penciclovir or Acyclovir. by Sarisky RT, Quail MR, Clark PE, Nguyen TT, Halsey WS, Wittrock RJ, Bartus JO, Van Horn MM, Sathe GM, Van Horn S, Kelly MD, Bacon TH, Leary JJ.; 2001 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114085

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Chimeric Nectin1-Poliovirus Receptor Molecules Identify a Nectin1 Region Functional in Herpes Simplex Virus Entry. by Cocchi F, Lopez M, Dubreuil P, Campadelli Fiume G, Menotti L.; 2001 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115042

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cis-acting elements involved in transcriptional regulation of the herpes simplex virus type 1 latency-associated promoter 1 (LAP1) in vitro and in vivo. by Soares K, Hwang DY, Ramakrishnan R, Schmidt MC, Fink DJ, Glorioso JC.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190496

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Civamide (cis-Capsaicin) for Treatment of Primary or Recurrent Experimental Genital Herpes. by Bourne N, Bernstein DI, Stanberry LR.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89543

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Cleavage in and around the DR1 Element of the a Sequence of Herpes Simplex Virus Type 1 Relevant to the Excision of DNA Fragments with Length Corresponding to One and Two Units of the a Sequence. by Umene K.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114302

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Clinical utility of a nested nucleic acid amplification format in comparison to viral culture for the diagnosis of mucosal herpes simplex infection in a genitourinary medicine setting. by Coyle PV, O'Neill HJ, McCaughey C, Wyatt DE, McBride MO.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=57742

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Colocalization of the Herpes Simplex Virus 1 UL4 Protein with Infected Cell Protein 22 in Small, Dense Nuclear Structures Formed prior to Onset of DNA Synthesis. by Jahedi S, Markovitz NS, Filatov F, Roizman B.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112558

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Comparative Evaluation of Colorimetric Microtiter Plate Systems for Detection of Herpes Simplex Virus in Cerebrospinal Fluid. by Tang YW, Rys PN, Rutledge BJ, Mitchell PS, Smith TF, Persing DH.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105189

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Comparative evaluation of microplate enzyme-linked immunosorbent assay versus plaque reduction assay for antiviral susceptibility testing of herpes simplex virus isolates. by Safrin S, Palacios E, Leahy BJ.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163250

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Comparative Performance of Herpes Simplex Virus Type 2-Specific Serologic Assays from Meridian Diagnostics and MRL Diagnostics. by Ribes JA, Hayes M, Smith A, Winters JL, Baker DJ.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88422

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Comparison of a direct antigen enzyme immunoassay, Herpchek, with cell culture for detection of herpes simplex virus from clinical specimens. by Verano L, Michalski FJ.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228171

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Comparison of a Monoclonal Antibody-Blocking Enzyme-Linked Immunoassay and a Strip Immunoblot Assay for Identifying Type-Specific Herpes Simplex Virus Type 2 Serological Responses. by Van Doornum GJ, Slomka MJ, Buimer M, Groen J, Van den Hoek JA, Cairo I, Vyse A, Brown DW.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95927

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Comparison of Adjuvant Efficacy of Herpes Simplex Virus Type 1 Recombinant Viruses Expressing TH1 and TH2 Cytokine Genes. by Osorio Y, Ghiasi H.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154018

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Comparison of Chemicon SimulFluor Direct Fluorescent Antibody Staining with Cell Culture and Shell Vial Direct Immunoperoxidase Staining for Detection of Herpes Simplex Virus and with Cytospin Direct Immunofluorescence Staining for Detection of Varicella-Zoster Virus. by Chan EL, Brandt K, Horsman GB.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96170

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Comparison of efficacies of famciclovir and valaciclovir against herpes simplex virus type 1 in a murine immunosuppression model. by Field HJ, Tewari D, Sutton D, Thackray AM.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162693

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Comparison of Polymorphism of Thymidine Kinase Gene and Restriction Fragment Length Polymorphism of Genomic DNA in Herpes Simplex Virus Type 1. by Nagamine M, Suzutani T, Saijo M, Hayashi K, Azuma M.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87019

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Comparison of Two Enzyme-Linked Immunosorbent Assays and One Rapid Immunoblot Assay for Detection of Herpes Simplex Virus Type 2-Specific Antibodies in Serum. by Groen J, Van Dijk G, Niesters HG, Van Der Meijden WI, Osterhaus AD.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104643

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Comparison of Washing and Swabbing Procedures for Collecting Genital Fluids To Assess Cervicovaginal Shedding of Herpes Simplex Virus Type 2 DNA. by NdjoyiMbiguino A, Ozouaki F, Legoff J, Mbopi-Keou FX, Si-Mohamed A, Onas IN, Avoune E, Belec L.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156498

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Complement Depletion Facilitates the Infection of Multiple Brain Tumors by an Intravascular, Replication-Conditional Herpes Simplex Virus Mutant. by Ikeda K, Wakimoto H, Ichikawa T, Jhung S, Hochberg FH, Louis DN, Chiocca EA.; 2000 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111999

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Confirmation of Low-Titer, Herpes Simplex Virus-Positive Specimen Results by the Enzyme-Linked Virus-Inducible System (ELVIS) Using PCR and Repeat Testing. by Patel N, Kauffmann L, Baniewicz G, Forman M, Evans M, Scholl D.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85862

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Conservation of Type-Specific B-Cell Epitopes of Glycoprotein G in Clinical Herpes Simplex Virus Type 2 Isolates. by Liljeqvist JA, Svennerholm B, Bergstrom T.; 2000 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87630

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Construction, Phenotypic Analysis, and Immunogenicity of a UL5/UL29 Double Deletion Mutant of Herpes Simplex Virus 2. by Da Costa X, Kramer MF, Zhu J, Brockman MA, Knipe DM.; 2000 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112327

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Cryopreserved Cell Monolayers for Rapid Detection of Herpes Simplex Virus and Influenza Virus. by Huang YT, Yan H, Sun Y, Jollick, Jr. JA, Baird H.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139648

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Cytokine-Mediated Survival from Lethal Herpes Simplex Virus Infection: Role of Programmed Neuronal Death. by Geiger KD, Gurushanthaiah D, Howes EL, Lewandowski GA, Reed JC, Bloom FE, Sarvetnick NE.; 1995 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42176

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Cytoplasmic Domain of Herpes Simplex Virus gE Causes Accumulation in the transGolgi Network, a Site of Virus Envelopment and Sorting of Virions to Cell Junctions. by McMillan TN, Johnson DC.; 2001 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115139

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Dendrimers, a New Class of Candidate Topical Microbicides with Activity against Herpes Simplex Virus Infection. by Bourne N, Stanberry LR, Kern ER, Holan G, Matthews B, Bernstein DI.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90087

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Detection and Direct Typing of Herpes Simplex Virus in Perianal Ulcers of Patients with AIDS by PCR. by do Nascimento MC, Sumita LM, de Souza VA, Pannuti CS.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104644

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Detection of a transforming fragment of herpes simplex virus type 2 in clinical specimens by PCR. The Canadian Women's HIV Study Group. by Guibinga GH, Coutlee F, Kessous A, Hankins C, Lapointe N, Richer G, Tousignant J.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229089

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Detection of Herpes Simplex Virus DNA by Real-Time PCR. by Kessler HH, Muhlbauer G, Rinner B, Stelzl E, Berger A, Dorr HW, Santner B, Marth E, Rabenau H.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86985

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Detection of Herpes Simplex Virus DNA in Genital and Dermal Specimens by LightCycler PCR after Extraction using the IsoQuick, MagNA Pure, and BioRobot 9604 Methods. by Espy MJ, Rys PN, Wold AD, Uhl JR, Sloan LM, Jenkins GD, Ilstrup DM, Cockerill FR III, Patel R, Rosenblatt JE, Smith TF.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88116

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Detection of herpes simplex virus type 1 latency-associated transcript expression in trigeminal ganglia by in situ reverse transcriptase PCR. by Ramakrishnan R, Poliani PL, Levine M, Glorioso JC, Fink DJ.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190691

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Detection of Herpes Simplex Virus Type 2-Specific Immunoglobulin G Antibodies in African Sera by Using Recombinant gG2, Western Blotting, and gG2 Inhibition. by Hogrefe W, Su X, Song J, Ashley R, Kong L.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130895

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Detection of JC Virus in Cerebrospinal Fluid (CSF) Samples from Patients with Progressive Multifocal Leukoencephalopathy but Not in CSF Samples from Patients with Herpes Simplex Encephalitis, Enteroviral Meningitis, or Multiple Sclerosis. by Bogdanovic G, Priftakis P, Hammarin AL, Soderstrom M, Samuelson A, LewensohnFuchs I, Dalianis T.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104707

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Detection of viral DNA to evaluate outcome of antiviral treatment of patients with recurrent genital herpes. by Diaz-Mitoma F, Ruben M, Sacks S, MacPherson P, Caissie G.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228865

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Development and Optimization of Herpes Simplex Virus Vectors for Multiple LongTerm Gene Delivery to the Peripheral Nervous System. by Palmer JA, Branston RH, Lilley CE, Robinson MJ, Groutsi F, Smith J, Latchman DS, Coffin RS.; 2000 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112048

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Development of a High-Throughput Quantitative Assay for Detecting Herpes Simplex Virus DNA in Clinical Samples. by Ryncarz AJ, Goddard J, Wald A, Huang ML, Roizman B, Corey L.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84990

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Diagnosis of Herpes Simplex Virus Infections in the Clinical Laboratory by LightCycler PCR. by Espy MJ, Uhl JR, Mitchell PS, Thorvilson JN, Svien KA, Wold AD, Smith TF.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86206

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Dichotomy of Glycoprotein G Gene in Herpes Simplex Virus Type 1 Isolates. by Rekabdar E, Tunback P, Liljeqvist JA, Lindh M, Bergstrom T.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130675

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Difference in Incidence of Spontaneous Mutations between Herpes Simplex Virus Types 1 and 2. by Sarisky RT, Nguyen TT, Duffy KE, Wittrock RJ, Leary JJ.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89907

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Differentiation of primary from nonprimary genital herpes infections by a herpes simplex virus-specific immunoglobulin G avidity assay. by Hashido M, Inouye S, Kawana T.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229837

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Dimethyl sulfoxide blocks herpes simplex virus-1 productive infection in vitro acting at different stages with positive cooperativity. Application of micro-array analysis. by Aguilar JS, Roy D, Ghazal P, Wagner EK.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116584

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Disruption of Virion Host Shutoff Activity Improves the Immunogenicity and Protective Capacity of a Replication-Incompetent Herpes Simplex Virus Type 1 Vaccine Strain. by Geiss BJ, Smith TJ, Leib DA, Morrison LA.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113198

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Disseminated Herpes Simplex Virus and Varicella Zoster Virus Coinfection in a Patient Taking Thalidomide for Relapsed Multiple Myeloma. by Curley MJ, Hussein SA, Hassoun PM.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130681

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DNA Immunization against Herpes Simplex Virus: Enhanced Efficacy Using a Sindbis Virus-Based Vector. by Hariharan MJ, Driver DA, Townsend K, Brumm D, Polo JM, Belli BA, Catton DJ, Hsu D, Mittelstaedt D, McCormack JE, Karavodin L, Dubensky TW Jr, Chang SM, Banks TA.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124565

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DNA Vaccines Encoding Interleukin-8 and RANTES Enhance Antigen-Specific Th1Type CD4 + T-Cell-Mediated Protective Immunity against Herpes Simplex Virus Type 2 In Vivo. by Sin JI, Kim JJ, Pachuk C, Satishchandran C, Weiner DB.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113206

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Double-Blind, Randomized, Placebo-Controlled Study of Topical 5% Acyclovir-1% Hydrocortisone Cream (ME-609) for Treatment of UV Radiation-Induced Herpes Labialis. by Evans TG, Bernstein DI, Raborn GW, Harmenberg J, Kowalski J, Spruance SL.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127265

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Downstream regulatory elements increase acute and latent herpes simplex virus type 2 latency-associated transcript expression but do not influence recurrence phenotype or establishment of latency. by Yoshikawa T, Stanberry LR, Bourne N, Krause PR.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189975

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Effect of Famciclovir on Herpes Simplex Virus Type 1 Corneal Disease and Establishment of Latency in Rabbits. by Loutsch JM, Sainz B Jr, Marquart ME, Zheng X, Kesavan P, Higaki S, Hill JM, Tal-Singer R.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90598

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Effect of foscarnet cream on experimental UV radiation-induced herpes labialis. by Bernstein DI, Schleupner CJ, Evans TG, Blumberg DA, Bryson Y, Grafford K, Broberg P, Martin-Munley S, Spruance SL.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=164045

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Effects of Antiviral Usage on Transmission Dynamics of Herpes Simplex Virus Type 1 and on Antiviral Resistance: Predictions of Mathematical Models. by Lipsitch M, Bacon TH, Leary JJ, Antia R, Levin BR.; 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90157

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Effects of Herpes Simplex Virus on Structure and Function of Nectin-1/HveC. by Krummenacher C, Baribaud I, Sanzo JF, Cohen GH, Eisenberg RJ.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153823

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Effects of Mutations within the Herpes Simplex Virus Type 1 DNA Encapsidation Signal on Packaging Efficiency. by Hodge PD, Stow ND.; 2001 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114466

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Effects of Targeting Herpes Simplex Virus Type 1 gD to the Endoplasmic Reticulum and trans-Golgi Network. by Whiteley A, Bruun B, Minson T, Browne H.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112986

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Efficacies of Gel Formulations Containing Foscarnet, Alone or Combined with Sodium Lauryl Sulfate, against Establishment and Reactivation of Latent Herpes Simplex Virus Type 1. by Piret J, Lamontagne J, Desormeaux A, Bergeron MG.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90421

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Efficacies of Topical Formulations of Foscarnet and Acyclovir and of 5-Percent Acyclovir Ointment (Zovirax) in a Murine Model of Cutaneous Herpes Simplex Virus Type 1 Infection. by Piret J, Desormeaux A, Gourde P, Juhasz J, Bergeron MG.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89624

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Efficient Activation of Viral Genomes by Levels of Herpes Simplex Virus ICP0 Insufficient To Affect Cellular Gene Expression or Cell Survival. by Hobbs WE, Brough DE, Kovesdi I, DeLuca NA.; 2001 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114132

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Enhancer and Long-Term Expression Functions of Herpes Simplex Virus Type 1 Latency-Associated Promoter Are both Located in the Same Region. by Berthomme H, Thomas J, Texier P, Epstein A, Feldman LT.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114183

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Equine Herpesvirus 1 Gene 12 Can Substitute for vmw65 in the Growth of Herpes Simplex Virus (HSV) Type 1, Allowing the Generation of Optimized Cell Lines for the Propagation of HSV Vectors with Multiple Immediate-Early Gene Defects. by Thomas SK, Lilley CE, Latchman DS, Coffin RS.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104267

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Evaluation of a Novel, Anti-Herpes Simplex Virus Compound, Acyclovir Elaidate (P4010), in the Female Guinea Pig Model of Genital Herpes. by Jennings R, Smith TL, Myhren F, Phillips J, Sandvold ML.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89020

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Evaluation of a peptidomimetic ribonucleotide reductase inhibitor with a murine model of herpes simplex virus type 1 ocular disease. by Brandt CR, Spencer B, Imesch P, Garneau M, Deziel R.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163269

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Evaluation of a quantitative competitive PCR assay for measuring herpes simplex virus DNA content in genital tract secretions. by Hobson A, Wald A, Wright N, Corey L.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229624

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Evaluation of Confirmatory Strategies for Detection of Type-Specific Antibodies against Herpes Simplex Virus Type 2. by Eing BR, Lippelt L, Lorentzen EU, Hafezi W, Schlumberger W, Steinhagen K, Kuhn JE.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153348

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Evaluation of LightCycler PCR for Implementation of Laboratory Diagnosis of Herpes Simplex Virus Infections. by Espy MJ, Ross TK, Teo R, Svien KA, Wold AD, Uhl JR, Smith TF.; 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87205

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Evaluation of Three Glycoprotein G2-Based Enzyme Immunoassays for Detection of Antibodies to Herpes Simplex Virus Type 2 in Human Sera. by Eis-Hubinger AM, Daumer M, Matz B, Schneweis KE.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84740

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Evidence for a Bidirectional Element Located Downstream from the Herpes Simplex Virus Type 1 Latency-Associated Promoter That Increases Its Activity during Latency. by Berthomme H, Lokensgard J, Yang L, Margolis T, Feldman LT.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111871

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Evidence for Controlled Incorporation of Herpes Simplex Virus Type 1 UL26 Protease into Capsids. by Sheaffer AK, Newcomb WW, Brown JC, Gao M, Weller SK, Tenney DJ.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112201

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Evidence that Herpes Simplex Virus VP16 Is Required for Viral Egress Downstream of the Initial Envelopment Event. by Mossman KL, Sherburne R, Lavery C, Duncan J, Smiley JR.; 2000 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112134

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Evidence that two latency-associated transcripts of herpes simplex virus type 1 are nonlinear. by Wu TT, Su YH, Block TM, Taylor JM.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190616

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Examination of the Kinetics of Herpes Simplex Virus Glycoprotein D Binding to the Herpesvirus Entry Mediator, Using Surface Plasmon Resonance. by Willis SH, Rux AH, Peng C, Whitbeck JC, Nicola AV, Lou H, Hou W, Salvador L, Eisenberg RJ, Cohen GH.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110398

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Experimental investigation of herpes simplex virus latency. by Wagner EK, Bloom DC.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=172928

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Explant-Induced Reactivation of Herpes Simplex Virus Occurs in Neurons Expressing Nuclear cdk2 and cdk4. by Schang LM, Bantly A, Schaffer PA.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136347

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Expression of Herpes Simplex Virus ICP0 Inhibits the Induction of InterferonStimulated Genes by Viral Infection. by Eidson KM, Hobbs WE, Manning BJ, Carlson P, DeLuca NA.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153810

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Famciclovir and Valaciclovir Differ in the Prevention of Herpes Simplex Virus Type 1 Latency in Mice: a Quantitative Study. by Thackray AM, Field HJ.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105644

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Flow cytometric analysis of herpes simplex virus type 1 susceptibility to acyclovir, ganciclovir, and foscarnet. by Pavic I, Hartmann A, Zimmermann A, Michel D, Hampl W, Schleyer I, Mertens T.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=164189

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Fluorescent Tagging of Herpes Simplex Virus Tegument Protein VP13/14 in Virus Infection. by Donnelly M, Elliott G.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115880

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Frequency of Acyclovir-Resistant Herpes Simplex Virus in Clinical Specimens and Laboratory Isolates. by Shin YK, Cai GY, Weinberg A, Leary JJ, Levin MJ.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87849

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Function of Dynein and Dynactin in Herpes Simplex Virus Capsid Transport. by Dohner K, Wolfstein A, Prank U, Echeverri C, Dujardin D, Vallee R, Sodeik B.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117943

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Functional Anatomy of Herpes Simplex Virus 1 Overlapping Genes Encoding Infected-Cell Protein 22 and US1.5 Protein. by Ogle WO, Roizman B.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104212

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Functional Interaction between Fluorodeoxyuridine-Induced Cellular Alterations and Replication of a Ribonucleotide Reductase-Negative Herpes Simplex Virus. by Petrowsky H, Roberts GD, Kooby DA, Burt BM, Bennett JJ, Delman KA, Stanziale SF, Delohery TM, Tong WP, Federoff HJ, Fong Y.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114433

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Functional Region IV of Glycoprotein D from Herpes Simplex Virus Modulates Glycoprotein Binding to the Herpesvirus Entry Mediator. by Rux AH, Willis SH, Nicola AV, Hou W, Peng C, Lou H, Cohen GH, Eisenberg RJ.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109930

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Gamma Interferon (IFN-[gamma]) Receptor Null-Mutant Mice Are More Susceptible to Herpes Simplex Virus Type 1 Infection than IFN-[gamma] Ligand Null-Mutant Mice. by Cantin E, Tanamachi B, Openshaw H, Mann J, Clarke K.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112570

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Gamma Interferon Can Prevent Herpes Simplex Virus Type 1 Reactivation from Latency in Sensory Neurons. by Liu T, Khanna KM, Carriere BN, Hendricks RL.; 2001 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114697

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Gamma interferon expression during acute and latent nervous system infection by herpes simplex virus type 1. by Cantin EM, Hinton DR, Chen J, Openshaw H.; 1995 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189304

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Gender Influences Herpes Simplex Virus Type 1 Infection in Normal and Gamma Interferon-Mutant Mice. by Han X, Lundberg P, Tanamachi B, Openshaw H, Longmate J, Cantin E.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115935

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Gene Array Analysis Reveals Changes in Peripheral Nervous System Gene Expression following Stimuli That Result in Reactivation of Latent Herpes Simplex Virus Type 1: Induction of Transcription Factor Bcl-3. by Tsavachidou D, Podrzucki W, Seykora J, Berger SL.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114562

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Genetic Analysis of the Role of Herpes Simplex Virus Type 1 Glycoprotein K in Infectious Virus Production and Egress. by Foster TP, Kousoulas KG.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112865

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Genetic Studies Exposing the Splicing Events Involved in Herpes Simplex Virus Type 1 Latency-Associated Transcript Production during Lytic and Latent Infection. by Alvira MR, Goins WF, Cohen JB, Glorioso JC.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104164

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Genital herpes. by Oakeshott P, Hay P.; 2002 May 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104337

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Genital Herpes: Review of the Epidemic and Potential Use of Type-Specific Serology. by Ashley RL, Wald A.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88903

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Global Analysis of Herpes Simplex Virus Type 1 Transcription Using an Oligonucleotide-Based DNA Microarray. by Stingley SW, Ramirez JJ, Aguilar SA, Simmen K, Sandri-Goldin RM, Ghazal P, Wagner EK.; 2000 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102029

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Glycoprotein D or J Delivered in trans Blocks Apoptosis in SK-N-SH Cells Induced by a Herpes Simplex Virus 1 Mutant Lacking Intact Genes Expressing Both Glycoproteins. by Zhou G, Galvan V, Campadelli-Fiume G, Roizman B.; 2000 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112461

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Glycoprotein K Specified by Herpes Simplex Virus Type 1 Is Expressed on Virions as a Golgi Complex-Dependent Glycosylated Species and Functions in Virion Entry. by Foster TP, Rybachuk GV, Kousoulas KG.; 2001 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116139

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Granzyme A, a Noncytolytic Component of CD8 + Cell Granules, Restricts the Spread of Herpes Simplex Virus in the Peripheral Nervous Systems of Experimentally Infected Mice. by Pereira RA, Simon MM, Simmons A.; 2000 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111627

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Heparan Sulfate Proteoglycan Binding by Herpes Simplex Virus Type 1 Glycoproteins B and C, Which Differ in Their Contributions to Virus Attachment, Penetration, and Cell-to-Cell Spread. by Laquerre S, Argnani R, Anderson DB, Zucchini S, Manservigi R, Glorioso JC.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110418

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Herpes simplex virus 1 activates cdc2 to recruit topoisomerase II[alpha] for post-DNA synthesis expression of late genes. by Advani SJ, Weichselbaum RR, Roizman B.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153640

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Herpes Simplex Virus 1 Blocks Caspase-3-Independent and Caspase-Dependent Pathways to Cell Death. by Galvan V, Brandimarti R, Roizman B.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104085

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Herpes simplex virus 1 induces and blocks apoptosis at multiple steps during infection and protects cells from exogenous inducers in a cell-type-dependent manner. by Galvan V, Roizman B.; 1998 Mar 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19940

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Herpes Simplex Virus 1 Open Reading Frames O and P Are Not Necessary for Establishment of Latent Infection in Mice. by Randall G, Lagunoff M, Roizman B.; 2000 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102098

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Herpes Simplex Virus 1 Regulatory Protein ICP22 Interacts with a New Cell CycleRegulated Factor and Accumulates in a Cell Cycle-Dependent Fashion in Infected Cells. by Bruni R, Roizman B.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110262

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Herpes Simplex Virus DNA Cleavage and Packaging Proteins Associate with the Procapsid prior to Its Maturation. by Sheaffer AK, Newcomb WW, Gao M, Yu D, Weller SK, Brown JC, Tenney DJ.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113965

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Herpes Simplex Virus DNA Cleavage and Packaging: Association of Multiple Forms of UL15-Encoded Proteins with B Capsids Requires at Least the UL6, UL17, and UL28 Genes. by Salmon B, Baines JD.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109752

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Herpes Simplex Virus DNA Packaging without Measurable DNA Synthesis. by Church GA, Dasgupta A, Wilson DW.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109718

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Herpes Simplex Virus gD and Virions Accumulate in Endosomes by Mannose 6Phosphate-Dependent and -Independent Mechanisms. by Brunetti CR, Dingwell KS, Wale C, Graham FL, Johnson DC.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109812

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Herpes Simplex Virus gE/gI Sorts Nascent Virions to Epithelial Cell Junctions, Promoting Virus Spread. by Johnson DC, Webb M, Wisner TW, Brunetti C.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113978

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Herpes simplex virus gene expression in neurons: viral DNA synthesis is a critical regulatory event in the branch point between the lytic and latent pathways. by Nichol PF, Chang JY, Johnson EM Jr, Olivo PD.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190505

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Herpes Simplex Virus Genome Isomerization: Origins of Adjacent Long Segments in Concatemeric Viral DNA. by Slobedman B, Zhang X, Simmons A.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103895

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Herpes Simplex Virus Glycoprotein D Can Bind to Poliovirus Receptor-Related Protein 1 or Herpesvirus Entry Mediator, Two Structurally Unrelated Mediators of Virus Entry. by Krummenacher C, Nicola AV, Whitbeck JC, Lou H, Hou W, Lambris JD, Geraghty RJ, Spear PG, Cohen GH, Eisenberg RJ.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109927

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Herpes Simplex Virus ICP0 and ICP34.5 Counteract Distinct Interferon-Induced Barriers to Virus Replication. by Mossman KL, Smiley JR.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135894

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Herpes Simplex Virus ICP0 Mutants Are Hypersensitive to Interferon. by Mossman KL, Saffran HA, Smiley JR.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111685

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Herpes Simplex Virus ICP27 Induces Cytoplasmic Accumulation of Unspliced Polyadenylated [alpha]-Globin Pre-mRNA in Infected HeLa Cells. by Cheung P, Ellison KS, Verity R, Smiley JR.; 2000 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111785

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Herpes simplex virus ICP27 protein provides viral mRNAs with access to the cellular mRNA export pathway. by Koffa MD, Clements JB, Izaurralde E, Wadd S, Wilson SA, Mattaj IW, Kuersten S.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125682

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Herpes Simplex Virus IE63 (ICP27) Protein Interacts with Spliceosome-Associated Protein 145 and Inhibits Splicing prior to the First Catalytic Step. by Bryant HE, Wadd SE, Lamond AI, Silverstein SJ, Clements JB.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114182

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Herpes Simplex Virus Infected Cell Polypeptide 4 Preferentially Represses Sp1Activated Over Basal Transcription from Its Own Promoter. by Gu B, Rivera-Gonzalez R, Smith CA, DeLuca NA.; 1993 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47602

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Herpes Simplex Virus Infections of Women and Their Offspring: Implications for a Developed Society. by Whitley RJ.; 1994 Mar 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43386

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Herpes Simplex Virus Latency-Associated Transcript Encodes a Protein Which Greatly Enhances Virus Growth, Can Compensate for Deficiencies in ImmediateEarly Gene Expression, and Is Likely To Function during Reactivation from Virus Latency. by Thomas SK, Gough G, Latchman DS, R. S. , Coffin.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112746

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Herpes Simplex Virus Nucleocapsids Mature to Progeny Virions by an Envelopment [right arrow] Deenvelopment [right arrow] Reenvelopment Pathway. by Skepper JN, Whiteley A, Browne H, Minson A.; 2001 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114284

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Herpes Simplex Virus Processivity Factor UL42 Imparts Increased DNA-Binding Specificity to the Viral DNA Polymerase and Decreased Dissociation from Primer-

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Template without Reducing the Elongation Rate. by Weisshart K, Chow CS, Coen DM.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103808 •

Herpes Simplex Virus Selectively Induces Expression of the CC Chemokine RANTES/CCL5 in Macrophages through a Mechanism Dependent on PKR and ICP0. by Melchjorsen J, Pedersen FS, Mogensen SC, Paludan SR.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135968

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Herpes Simplex Virus Triggers and Then Disarms a Host Antiviral Response. by Mossman KL, Macgregor PF, Rozmus JJ, Goryachev AB, Edwards AM, Smiley JR.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113971

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Herpes Simplex Virus Type 1 2-Kilobase Latency-Associated Transcript Intron Associates with Ribosomal Proteins and Splicing Factors. by Ahmed M, Fraser NW.; 2001 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116102

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Herpes Simplex Virus Type 1 Blocks the Apoptotic Host Cell Defense Mechanisms That Target Bcl-2 and Manipulates Activation of p38 Mitogen-Activated Protein Kinase To Improve Viral Replication. by Zachos G, Koffa M, Preston CM, Clements JB, Conner J.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115896

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Herpes Simplex Virus Type 1 Cleavage and Packaging Proteins UL15 and UL28 Are Associated with B but Not C Capsids during Packaging. by Yu D, Weller SK.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109972

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Herpes Simplex Virus Type 1 Corneal Infection Results in Periocular Disease by Zosteriform Spread. by Summers BC, Margolis TP, Leib DA.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114911

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Herpes Simplex Virus Type 1 Entry into Host Cells: Reconstitution of Capsid Binding and Uncoating at the Nuclear Pore Complex In Vitro. by Ojala PM, Sodeik B, Ebersold MW, Kutay U, Helenius A.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85943

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Herpes Simplex Virus Type 1 Entry Is Inhibited by the Cobalt Chelate Complex CTC96. by Schwartz JA, Lium EK, Silverstein SJ.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114157

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Herpes Simplex Virus Type 1 Evades the Effects of Antibody and Complement In Vivo. by Lubinski JM, Jiang M, Hook L, Chang Y, Sarver C, Mastellos D, Lambris JD, Cohen GH, Eisenberg RJ, Friedman HM.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136467

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Herpes Simplex Virus Type 1 Gene UL14: Phenotype of a Null Mutant and Identification of the Encoded Protein. by Cunningham C, Davison AJ, MacLean AR, Taus NS, Baines JD.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111510

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Herpes Simplex Virus Type 1 Glycoprotein B Requires a Cysteine Residue at Position 633 for Folding, Processing, and Incorporation into Mature Infectious Virus Particles. by Laquerre S, Anderson DB, Argnani R, Glorioso JC.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110055

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Herpes Simplex Virus Type 1 Glycoprotein E Domains Involved in Virus Spread and Disease. by Saldanha CE, Lubinski J, Martin C, Nagashunmugam T, Wang L, van der Keyl H, Tal-Singer R, Friedman HM.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112186

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Herpes Simplex Virus Type 1 Glycoprotein gC Mediates Immune Evasion In Vivo. by Lubinski JM, Wang L, Soulika AM, Burger R, Wetsel RA, Colten H, Cohen GH, Eisenberg RJ, Lambris JD, Friedman HM.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110183

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Herpes Simplex Virus Type 1 ICP0 Protein Does Not Accumulate in the Nucleus of Primary Neurons in Culture. by Chen XP, Li J, Mata M, Goss J, Wolfe D, Glorioso JC, Fink DJ.; 2000 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102052

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Herpes Simplex Virus Type 1 ICP4 Promotes Transcription Preinitiation Complex Formation by Enhancing the Binding of TFIID to DNA. by Grondin B, DeLuca N.; 2000 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112430

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Herpes Simplex Virus Type 1 Immediate-Early Protein Vmw110 Induces the Proteasome-Dependent Degradation of the Catalytic Subunit of DNA-Dependent Protein Kinase. by Parkinson J, Lees-Miller SP, Everett RD.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103871

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Herpes Simplex Virus Type 1 Immediate-Early Protein Vmw110 Inhibits Progression of Cells through Mitosis and from G1 into S Phase of the Cell Cycle. by Lomonte P, Everett RD.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112980

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Herpes Simplex Virus Type 1 Latency-Associated Transcript Gene Promotes Neuronal Survival. by Thompson RL, Sawtell NM.; 2001 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114389

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Herpes Simplex Virus Type 1 Latency-Associated Transcripts Suppress Viral Replication and Reduce Immediate-Early Gene mRNA Levels in a Neuronal Cell Line. by Mador N, Goldenberg D, Cohen O, Panet A, Steiner I.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110070

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Herpes Simplex Virus Type 1 Origins of DNA Replication Play No Role in the Regulation of Flanking Promoters. by Summers BC, Leib DA.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136320

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Herpes Simplex Virus Type 1 Promoter Activity during Latency Establishment, Maintenance, and Reactivation in Primary Dorsal Root Neurons In Vitro. by Arthur JL, Scarpini CG, Connor V, Lachmann RH, Tolkovsky AM, Efstathiou S.; 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114879

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Herpes simplex virus type 1 protein IE63 affects the nuclear export of virus introncontaining transcripts. by Phelan A, Dunlop J, Clements JB.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190482

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Herpes Simplex Virus Type 1 Renders Infected Cells Resistant to Cytotoxic TLymphocyte-Induced Apoptosis. by Jerome KR, Tait JF, Koelle DM, Corey L.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109392

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Herpes Simplex Virus Type 1 Serum Neutralizing Antibody Titers Increase during Latency in Rabbits Latently Infected with Latency-Associated Transcript (LAT)-

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Positive but Not LAT-Negative Viruses. by Perng GC, Slanina SM, Yukht A, Ghiasi H, Nesburn AB, Wechsler SL.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113008 •

Herpes Simplex Virus Type 1 UL34 Gene Product Is Required for Viral Envelopment. by Roller RJ, Zhou Y, Schnetzer R, Ferguson J, DeSalvo D.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111520

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Herpes Simplex Virus Type 1 Vector-Mediated Expression of Nerve Growth Factor Protects Dorsal Root Ganglion Neurons from Peroxide Toxicity. by Goins WF, Lee KA, Cavalcoli JD, O'Malley ME, DeKosky ST, Fink DJ, Glorioso JC.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103859

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Herpes Simplex Virus Type 1-Specific Cytotoxic T-Lymphocyte Arming Occurs within Lymph Nodes Draining the Site of Cutaneous Infection. by Jones CM, Cose SC, Coles RM, Winterhalter AC, Brooks AG, Heath WR, Carbone FR.; 2000 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111723

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Herpes Simplex Virus Type 2 Glycoprotein G-Negative Clinical Isolates Are Generated by Single Frameshift Mutations. by Liljeqvist JA, Svennerholm B, Bergstrom T.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113027

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Herpes Simplex Virus Types 1 and 2 Differ in Their Interaction with Heparan Sulfate. by Trybala E, Liljeqvist JA, Svennerholm B, Bergstrom T.; 2000 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102109

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Herpes Simplex Virus Vectors Elicit Durable Immune Responses in the Presence of Preexisting Host Immunity. by Brockman MA, Knipe DM.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136066

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Herpes Simplex Virus Virion Host Shutoff (vhs) Activity Alters Periocular Disease in Mice. by Smith TJ, Ackland-Berglund CE, Leib DA.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111869

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Herpes Simplex Virus Virion Host Shutoff Protein Requires a Mammalian Factor for Efficient In Vitro Endoribonuclease Activity. by Lu P, Jones FE, Saffran HA, Smiley JR.; 2001 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114023

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Herpes Simplex Virus with Highly Reduced gD Levels Can Efficiently Enter and Spread between Human Keratinocytes. by Huber MT, Wisner TW, Hegde NR, Goldsmith KA, Rauch DA, Roller RJ, Krummenacher C, Eisenberg RJ, Cohen GH, Johnson DC.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114605

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Herpes simplex viruses: is a vaccine tenable? by Whitley RJ, Roizman B.; 2002 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151069

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Herpes Simplex Virus-Induced Keratitis: Evaluation of the Role of Molecular Mimicry in Lesion Pathogenesis. by Deshpande SP, Lee S, Zheng M, Song B, Knipe D, Kapp JA, Rouse BT.; 2001 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114101

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High frequency of CD8+ cytotoxic T-lymphocyte precursors specific for herpes simplex viruses in persons with genital herpes. by Posavad CM, Koelle DM, Corey L.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190896

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High-dose ocular infection with a herpes simplex virus type 1 ICP34.5 deletion mutant produces no corneal disease or neurovirulence yet results in wild-type levels of spontaneous reactivation. by Perng GC, Ghiasi H, Slanina SM, Nesburn AB, Wechsler SL.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190146

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Highly Reliable Heterologous System for Evaluating Resistance of Clinical Herpes Simplex Virus Isolates to Nucleoside Analogues. by Bestman-Smith J, Schmit I, Papadopoulou B, Boivin G.; 2001 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114104

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Human Corneal Cells and Other Fibroblasts Can Stimulate the Appearance of Herpes Simplex Virus from Quiescently Infected PC12 Cells. by Su YH, Meegalla RL, Chowhan R, Cubitt C, Oakes JE, Lausch RN, Fraser NW, Block TM.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104196

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Human Immunodeficiency Virus tat Gene Transfer to the Murine Central Nervous System Using a Replication-Defective Herpes Simplex Virus Vector Stimulates Transforming Growth Factor Beta 1 Gene Expression. by Rasty S, Thatikunta P, Gordon J, Khalili K, Amini S, Glorioso JC.; 1996 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39191

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Human Neuron-Committed Teratocarcinoma NT2 Cell Line Has Abnormal ND10 Structures and Is Poorly Infected by Herpes Simplex Virus Type 1. by Hsu WL, Everett RD.; 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114873

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Human Thymidine Kinase Can Functionally Replace Herpes Simplex Virus Type 1 Thymidine Kinase for Viral Replication in Mouse Sensory Ganglia and Reactivation from Latency upon Explant. by Chen SH, Cook WJ, Grove KL, Coen DM.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109874

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Humoral response to herpes simplex virus is complement-dependent. by Da Costa XJ, Brockman MA, Alicot E, Ma M, Fischer MB, Zhou X, Knipe DM, Carroll MC.; 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23060

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HveA (Herpesvirus Entry Mediator A), a Coreceptor for Herpes Simplex Virus Entry, also Participates in Virus-Induced Cell Fusion. by Terry-Allison T, Montgomery RI, Whitbeck JC, Xu R, Cohen GH, Eisenberg RJ, Spear PG.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110382

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ICP0 Is Required for Efficient Reactivation of Herpes Simplex Virus Type 1 from Neuronal Latency. by Halford WP, Schaffer PA.; 2001 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114117

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ICP0, ICP4, or VP16 Expressed from Adenovirus Vectors Induces Reactivation of Latent Herpes Simplex Virus Type 1 in Primary Cultures of Latently Infected Trigeminal Ganglion Cells. by Halford WP, Kemp CD, Isler JA, Davido DJ, Schaffer PA.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114330

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ICP22 and the UL13 Protein Kinase Are both Required for Herpes Simplex VirusInduced Modification of the Large Subunit of RNA Polymerase II. by Long MC, Leong V, Schaffer PA, Spencer CA, Rice SA.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112617

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Identification of a Region of the Herpes Simplex Virus Single-Stranded DNABinding Protein Involved in Cooperative Binding. by Dudas KC, Ruyechan WT.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109371

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Identification of an Export Control Sequence and a Requirement for the KH Domains in ICP27 from Herpes Simplex Virus Type 1. by Soliman TM, Silverstein SJ.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112281

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Identification of Crucial Hydrogen-Bonding Residues for the Interaction of Herpes Simplex Virus DNA Polymerase Subunits via Peptide Display, Mutational, and Calorimetric Approaches. by Bridges KG, Chow CS, Coen DM.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114902

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Identification of Herpes Simplex Virus Type 1 Latency-Associated Transcript Sequences That both Inhibit Apoptosis and Enhance the Spontaneous Reactivation Phenotype. by Jin L, Peng W, Perng GC, Brick DJ, Nesburn AB, Jones C, Wechsler SL.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155006

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Immature Monocyte-Derived Dendritic Cells Are Productively Infected with Herpes Simplex Virus Type 1. by Mikloska Z, Bosnjak L, Cunningham AL.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114311

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Immunization against genital herpes with a vaccine virus that has defects in productive and latent infection. by Da Costa XJ, Jones CA, Knipe DM.; 1999 Jun 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22033

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Immunization with a replication-deficient mutant of herpes simplex virus type 1 (HSV-1) induces a CD8+ cytotoxic T-lymphocyte response and confers a level of protection comparable to that of wild-type HSV-1. by Brehm MA, Bonneau RH, Knipe DM, Tevethia SS.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191500

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Immunization with a Single Major Histocompatibility Complex Class I-Restricted Cytotoxic T-Lymphocyte Recognition Epitope of Herpes Simplex Virus Type 2 Confers Protective Immunity. by Blaney JE Jr, Nobusawa E, Brehm MA, Bonneau RH, Mylin LM, Fu TM, Kawaoka Y, Tevethia SS.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110466

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Immunization with Chaperone-Peptide Complex Induces Low-Avidity Cytotoxic T Lymphocytes Providing Transient Protection against Herpes Simplex Virus Infection. by Kumaraguru U, Gierynska M, Norman S, Bruce BD, Rouse BT.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135705

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Immunization with DNA Vaccines Encoding Glycoprotein D or Glycoprotein B, Alone or in Combination, Induces Protective Immunity in Animal Models of Herpes Simplex Virus-2 Disease. by McClements WL, Armstrong ME, Keys RD, Liu MA.; 1996 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38071

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Immunization with recombinant varicella-zoster virus expressing herpes simplex virus type 2 glycoprotein D reduces the severity of genital herpes in guinea pigs. by Heineman TC, Connelly BL, Bourne N, Stanberry LR, Cohen J.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189763

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Immunoglobulin G is the main protective antibody in mouse vaginal secretions after vaginal immunization with attenuated herpes simplex virus type 2. by Parr EL, Parr MB.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192266

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Immunohistochemical Analysis of Primary Sensory Neurons Latently Infected with Herpes Simplex Virus Type 1. by Yang L, Voytek CC, Margolis TP.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111530

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In Vitro Processing of Herpes Simplex Virus Type 1 DNA Replication Intermediates by the Viral Alkaline Nuclease, UL12. by Goldstein JN, Weller SK.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110293

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In vivo epinephrine reactivation of ocular herpes simplex virus type 1 in the rabbit is correlated to a 370-base-pair region located between the promoter and the 5' end of the 2.0 kilobase latency-associated transcript. by Hill JM, Maggioncalda JB, Garza HH Jr, Su YH, Fraser NW, Block TM.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190787

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In Vivo Immune Evasion Mediated by the Herpes Simplex Virus Type 1 Immunoglobulin G Fc Receptor. by Nagashunmugam T, Lubinski J, Wang L, Goldstein LT, Weeks BS, Sundaresan P, Kang EH, Dubin G, Friedman HM.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110157

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In Vivo Modulation of Vaccine-Induced Immune Responses toward a Th1 Phenotype Increases Potency and Vaccine Effectiveness in a Herpes Simplex Virus Type 2 Mouse Model. by Sin JI, Kim JJ, Boyer JD, Ciccarelli RB, Higgins TJ, Weiner DB.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103857

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Induction and Prevention of Apoptosis in Human HEp-2 Cells by Herpes Simplex Virus Type 1. by Aubert M, O'Toole J, Blaho JA.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113091

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Induction of CD8 T-Cell-Specific Systemic and Mucosal Immunity against Herpes Simplex Virus with CpG-Peptide Complexes. by Gierynska M, Kumaraguru U, Eo SK, Lee S, Krieg A, Rouse BT.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136257

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Induction of mucosal immunity against herpes simplex virus by plasmid DNA immunization. by Kuklin N, Daheshia M, Karem K, Manickan E, Rouse BT.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191446

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Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection. by Liu T, Tang Q, Hendricks RL.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189813

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Inhibition by Interferon of Herpes Simplex Virus Type 1-Activated Transcription of tat-Defective Provirus. by Popik W, Pitha PM.; 1991 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52760

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Inhibition of Herpes Simplex Virus Replication by a 2-Amino Thiazole via Interactions with the Helicase Component of the UL5-UL8-UL52 Complex. by Spector FC, Liang L, Giordano H, Sivaraja M, Peterson MG.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109917

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Interaction between Herpes Simplex Virus Type 1 IE63 Protein and Cellular Protein p32. by Bryant HE, Matthews DA, Wadd S, Scott JE, Kean J, Graham S, Russell WC, Clements JB.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113237

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Interactions of Herpes Simplex Virus Type 1 with ND10 and Recruitment of PML to Replication Compartments. by Burkham J, Coen DM, Hwang CB, Weller SK.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114819

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Interference with Major Histocompatibility Complex Class II-Restricted Antigen Presentation in the Brain by Herpes Simplex Virus Type 1: A Possible Mechanism of Evasion of the Immune Response. by Lewandowski GA, Lo D, Bloom FE.; 1993 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46009

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Interleukin-12 (IL-12) and IL-18 Are Important in Innate Defense against Genital Herpes Simplex Virus Type 2 Infection in Mice but Are Not Required for the Development of Acquired Gamma Interferon-Mediated Protective Immunity. by Harandi AM, Svennerholm B, Holmgren J, Eriksson K.; 2001 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114395

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Interleukin-12- and Gamma Interferon-Dependent Innate Immunity Are Essential and Sufficient for Long-Term Survival of Passively Immunized Mice Infected with Herpes Simplex Virus Type 1. by Vollstedt S, Franchini M, Alber G, Ackermann M, Suter M.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114530

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Interleukin-18 Protects Mice against Acute Herpes Simplex Virus Type 1 Infection. by Fujioka N, Akazawa R, Ohashi K, Fujii M, Ikeda M, Kurimoto M.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104486

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Intracellular Cre-Mediated Deletion of the Unique Packaging Signal Carried by a Herpes Simplex Virus Type 1 Recombinant and Its Relationship to the CleavagePackaging Process. by Logvinoff C, Epstein AL.; 2000 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116351

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Intrastrain Variants of Herpes Simplex Virus Type 1 Isolated from a Neonate with Fatal Disseminated Infection Differ in the ICP34.5 Gene, Glycoprotein Processing, and Neuroinvasiveness. by Bower JR, Mao H, Durishin C, Rozenbom E, Detwiler M, Rempinski D, Karban TL, Rosenthal KS.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104162

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Intravenous Penciclovir for Treatment of Herpes Simplex Infections in Immunocompromised Patients: Results of a Multicenter, Acyclovir-Controlled Trial. by Lazarus HM, Belanger R, Candoni A, Aoun M, Jurewicz R, Marks L.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89132

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Involvement of Apolipoprotein E in the Hematogenous Route of Herpes Simplex Virus Type 1 to the Central Nervous System. by Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136918

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Isolation of Herpes Simplex Virus Procapsids from Cells Infected with a ProteaseDeficient Mutant Virus. by Newcomb WW, Trus BL, Cheng N, Steven AC, Sheaffer AK, Tenney DJ, Weller SK, Brown JC.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111641

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Isomerization of a Uniquely Designed Amplicon during Herpes Simplex VirusMediated Replication. by Wang H, Fu X, Zhang X.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114627

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Laboratory diagnosis of central nervous system infections with herpes simplex virus by PCR performed with cerebrospinal fluid specimens. by Mitchell PS, Espy MJ, Smith TF, Toal DR, Rys PN, Berbari EF, Osmon DR, Persing DH.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230078

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Lack of Interleukin-6 (IL-6) Enhances Susceptibility to Infection but Does Not Alter Latency or Reactivation of Herpes Simplex Virus Type 1 in IL-6 Knockout Mice. by LeBlanc RA, Pesnicak L, Cabral ES, Godleski M, Straus SE.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112831

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Limits in Reliability of Glycoprotein G-Based Type-Specific Serologic Assays for Herpes Simplex Virus Types 1 and 2. by Schmid DS, Brown DR, Nisenbaum R, Burke RL, Alexander D', Ashley R, Pellett PE, Reeves WC.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84313

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Live-Cell Analysis of a Green Fluorescent Protein-Tagged Herpes Simplex Virus Infection. by Elliott G, O'Hare P.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104190

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Local Periocular Vaccination Protects against Eye Disease More Effectively Than Systemic Vaccination following Primary Ocular Herpes Simplex Virus Infection in Rabbits. by Nesburn AB, Slanina S, Burke RL, Ghiasi H, Bahri S, Wechsler SL.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110076

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Localization of a Binding Site for Herpes Simplex Virus Glycoprotein D on Herpesvirus Entry Mediator C by Using Antireceptor Monoclonal Antibodies. by Krummenacher C, Baribaud I, Ponce de Leon M, Whitbeck JC, Lou H, Cohen GH, Eisenberg RJ.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113165

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Localization of a Passively Transferred Human Recombinant Monoclonal Antibody to Herpes Simplex Virus Glycoprotein D to Infected Nerve Fibers and Sensory Neurons In Vivo. by Sanna PP, Deerinck TJ, Ellisman MH.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112904

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Localization of the gD-Binding Region of the Human Herpes Simplex Virus Receptor, HveA. by Whitbeck JC, Connolly SA, Willis SH, Hou W, Krummenacher C, Ponce de Leon M, Lou H, Baribaud I, Eisenberg RJ, Cohen GH.; 2001 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113910

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Longitudinal study of genital infection by herpes simplex virus type 1 in western Scotland over 15 years. by Scoular A, Norrie J, Gillespie G, Mir N, Carman WF.; 2002 Jun 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115212

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Long-Term Transgene Expression in Mice Infected with a Herpes Simplex Virus Type 1 Mutant Severely Impaired for Immediate-Early Gene Expression. by Marshall KR, Lachmann RH, Efstathiou S, Rinaldi A, Preston CM.; 2000 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111616

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Mandelic Acid Condensation Polymer: Novel Candidate Microbicide for Prevention of Human Immunodeficiency Virus and Herpes Simplex Virus Entry. by Herold BC, Scordi-Bello I, Cheshenko N, Marcellino D, Dzuzelewski M, Francois F, Morin R, Casullo VM, Anderson RA, Chany II C, Waller DP, Zaneveld LJ, Klotman ME.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136750

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Mapping of Genes Involved in Murine Herpes Simplex Virus Keratitis: Identification of Genes and Their Modifiers. by Norose K, Yano A, Zhang XM, Blankenhorn E, Heber-Katz E.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136007

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Mapping of Herpes Simplex Virus 1 Genes with Mutations which Overcome Host Restrictions to Infection. by Brandimarti R, Huang T, Roizman B, Campadelli-Fiume G.; 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44004

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Mechanism of Reduced T-Cell Effector Functions and Class-Switched Antibody Responses to Herpes Simplex Virus Type 2 in the Absence of B7 Costimulation. by Thebeau LG, Morrison LA.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141105

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Mechanisms of herpes simplex virus type 1 reactivation. by Halford WP, Gebhardt BM, Carr DJ.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190459

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Microtubule Reorganization during Herpes Simplex Virus Type 1 Infection Facilitates the Nuclear Localization of VP22, a Major Virion Tegument Protein. by Kotsakis A, Pomeranz LE, Blouin A, Blaho JA.; 2001 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115115

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Modified FGF4 Signal Peptide Inhibits Entry of Herpes Simplex Virus Type 1. by Bultmann H, Busse JS, Brandt CR.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115887

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Modified VP22 Localizes to the Cell Nucleus during Synchronized Herpes Simplex Virus Type 1 Infection. by Pomeranz LE, Blaho JA.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112762

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Modulation of Immunity against Herpes Simplex Virus Infection via Mucosal Genetic Transfer of Plasmid DNA Encoding Chemokines. by Eo SK, Lee S, Chun S, Rouse BT.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113952

86

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Molecular Approaches To Detecting Herpes Simplex Virus and Enteroviruses in the Central Nervous System. by Smalling TW, Sefers SE, Li H, Tang YW.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120559

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Molecular Diagnosis of Herpes Simplex Virus Infections in the Central Nervous System. by Tang YW, Mitchell PS, Espy MJ, Smith TF, Persing DH.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85100

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Monoclonal Antibodies to Distinct Sites on Herpes Simplex Virus (HSV) Glycoprotein D Block HSV Binding to HVEM. by Nicola AV, Ponce de Leon M, Xu R, Hou W, Whitbeck JC, Krummenacher C, Montgomery RI, Spear PG, Eisenberg RJ, Cohen GH.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109580

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mRNA Degradation by the Virion Host Shutoff (Vhs) Protein of Herpes Simplex Virus: Genetic and Biochemical Evidence that Vhs Is a Nuclease. by Everly, Jr. DN, Feng P, Mian IS, Read GS.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136990

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Mucosal Immunity to Herpes Simplex Virus Type 2 Infection in the Mouse Vagina Is Impaired by In Vivo Depletion of T Lymphocytes. by Parr MB, Parr EL.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109710

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Multiple Immediate-Early Gene-Deficient Herpes Simplex Virus Vectors Allowing Efficient Gene Delivery to Neurons in Culture and Widespread Gene Delivery to the Central Nervous System In Vivo. by Lilley CE, Groutsi F, Han Z, Palmer JA, Anderson PN, Latchman DS, Coffin RS.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114179

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Mutations in Herpes Simplex Virus Glycoprotein D Distinguish Entry of Free Virus from Cell-Cell Spread. by Rauch DA, Rodriguez N, Roller RJ.; 2000 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112422

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Mutations in the 5' end of the herpes simplex virus type 2 latency-associated transcript (LAT) promoter affect LAT expression in vivo but not the rate of spontaneous reactivation of genital herpes. by Wang K, Pesnicak L, Straus SE.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192147

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Nectin2[alpha] (PRR2[alpha] or HveB) and Nectin2[delta] Are Low-Efficiency Mediators for Entry of Herpes Simplex Virus Mutants Carrying the Leu25Pro Substitution in Glycoprotein D. by Lopez M, Cocchi F, Menotti L, Avitabile E, Dubreuil P, Campadelli-Fiume G.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111461

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Neither LAT nor Open Reading Frame P Mutations Increase Expression of Spliced or Intron-Containing ICP0 Transcripts in Mouse Ganglia Latently Infected with Herpes Simplex Virus. by Chen SH, Lee LY, Garber DA, Schaffer PA, Knipe DM, Coen DM.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136172

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Neurons Differentially Activate the Herpes Simplex Virus Type 1 Immediate-Early Gene ICP0 and ICP27 Promoters in Transgenic Mice. by Loiacono CM, Myers R, Mitchell WJ.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153807

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Neutralizing Antibodies Inhibit Axonal Spread of Herpes Simplex Virus Type 1 to Epidermal Cells In Vitro. by Mikloska Z, Sanna PP, Cunningham AL.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112655

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Neutrophil-mediated suppression of virus replication after herpes simplex virus type 1 infection of the murine cornea. by Tumpey TM, Chen SH, Oakes JE, Lausch RN.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189893

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Neutrophils Aid in Protection of the Vaginal Mucosae of Immune Mice against Challenge with Herpes Simplex Virus Type 2. by Milligan GN.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112717

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Noninvasive Bioluminescence Imaging of Herpes Simplex Virus Type 1 Infection and Therapy in Living Mice. by Luker GD, Bardill JP, Prior JL, Pica CM, PiwnicaWorms D, Leib DA.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136903

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Novel Approach for Specific Detection of Herpes Simplex Virus Type 1 and 2 Antibodies and Immunoglobulin G and M Antibodies. by Ohana B, Lipson M, Vered N, Srugo I, Ahdut M, Morag A.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95983

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Novel Class of Thiourea Compounds That Inhibit Herpes Simplex Virus Type 1 DNA Cleavage and Encapsidation: Resistance Maps to the UL6 Gene. by van Zeijl M, Fairhurst J, Jones TR, Vernon SK, Morin J, LaRocque J, Feld B, O'Hara B, Bloom JD, Johann SV.; 2000 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102102

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Novel, Soluble Isoform of the Herpes Simplex Virus (HSV) Receptor Nectin1 (or PRR1-HIgR-HveC) Modulates Positively and Negatively Susceptibility to HSV Infection. by Lopez M, Cocchi F, Avitabile E, Leclerc A, Adelaide J, Campadelli-Fiume G, Dubreuil P.; 2001 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114282

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NP-1, a Rabbit [alpha]-Defensin, Prevents the Entry and Intercellular Spread of Herpes Simplex Virus Type 2. by Sinha S, Cheshenko N, Lehrer RI, Herold BC.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151743

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Nuclear Localization and Shuttling of Herpes Simplex Virus Tegument Protein VP13/14. by Donnelly M, Elliott G.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115879

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Nuclear sites of herpes simplex virus type 1 DNA replication and transcription colocalize at early times postinfection and are largely distinct from RNA processing factors. by Phelan A, Dunlop J, Patel AH, Stow ND, Clements JB.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191164

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Optimized Viral Dose and Transient Immunosuppression Enable Herpes Simplex Virus ICP0-Null Mutants To Establish Wild-Type Levels of Latency In Vivo. by Halford WP, Schaffer PA.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112092

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Oral Bioavailability and In Vivo Efficacy of the Helicase-Primase Inhibitor BILS 45 BS against Acyclovir-Resistant Herpes Simplex Virus Type 1. by Duan J, Liuzzi M,

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Paris W, Liard F, Browne A, Dansereau N, Simoneau B, Faucher AM, Cordingley MG.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155846 •

Oral inoculation with herpes simplex virus type 1 infects enteric neuron and mucosal nerve fibers within the gastrointestinal tract in mice. by Gesser RM, Koo SC.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190294

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Origin Binding Protein-Containing Protein-DNA Complex Formation at Herpes Simplex Virus Type 1 oriS: Role in oriS-Dependent DNA Replication. by Isler JA, Schaffer PA.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114407

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Overexpression of Interleukin-2 by a Recombinant Herpes Simplex Virus Type 1 Attenuates Pathogenicity and Enhances Antiviral Immunity. by Ghiasi H, Osorio Y, Perng GC, Nesburn AB, Wechsler SL.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136420

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Overexpression of the herpes simplex virus type 1 immediate-early regulatory protein, ICP27, is responsible for the aberrant localization of ICP0 and mutant forms of ICP4 in ICP4 mutant virus-infected cells. by Zhu Z, DeLuca NA, Schaffer PA.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190492

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Packaging of Genomic and Amplicon DNA by the Herpes Simplex Virus Type 1 UL25-Null Mutant KUL25NS. by Stow ND.; 2001 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114657

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Packaging-Competent Capsids of a Herpes Simplex Virus Temperature-Sensitive Mutant Have Properties Similar to Those of In Vitro-Assembled Procapsids. by Rixon FJ, McNab D.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112631

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Pathogenesis of Herpes Simplex Virus Type 1-Induced Corneal Inflammation in Perforin-Deficient Mice. by Chang E, Galle L, Maggs D, Estes DM, Mitchell WJ.; 2000 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112466

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Pathogenesis of Herpes Simplex Virus Type 2 Virion Host Shutoff (vhs) Mutants. by Smith TJ, Morrison LA, Leib DA.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153813

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Pathogenesis of Herpes Simplex Virus-Induced Ocular Immunoinflammatory Lesions in B-Cell-Deficient Mice. by Deshpande SP, Zheng M, Daheshia M, Rouse BT.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111859

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Penciclovir Susceptibilities of Herpes Simplex Virus Isolates from Patients Using Penciclovir Cream for Treatment of Recurrent Herpes Labialis. by Sarisky RT, Bacon T, Boon R, Locke L, Nguyen TT, Leary J, Esser K, Saltzman R.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127441

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Performance of Two Commercial Glycoprotein G-Based Enzyme Immunoassays for Detecting Antibodies to Herpes Simplex Viruses 1 and 2 in Children and Young Adolescents. by Leach CT, Ashley RL, Baillargeon J, Jenson HB.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120053

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Persistence and Expression of the Herpes Simplex Virus Genome in the Absence of Immediate-Early Proteins. by Samaniego LA, Neiderhiser L, DeLuca NA.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109808

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Persistence of Herpes Simplex Virus Type 1 DNA in Chronic Conjunctival and Eyelid Lesions of Mice. by Maggs DJ, Chang E, Nasisse MP, Mitchell WJ.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110335

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Persistence of Infectious Herpes Simplex Virus Type 2 in the Nervous System in Mice after Antiviral Chemotherapy. by Thackray AM, Field HJ.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89634

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Perturbation of Cell Cycle Progression and Cellular Gene Expression as a Function of Herpes Simplex Virus ICP0. by Hobbs WE II, DeLuca NA.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112842

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Phosphorylation of Structural Components Promotes Dissociation of the Herpes Simplex Virus Type 1 Tegument. by Morrison EE, Wang YF, Meredith DM.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109932

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Phosphorylation of the Herpes Simplex Virus Type 1 Origin Binding Protein. by Isler JA, Schaffer PA.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113959

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Phosphorylation of Transcription Factor Sp1 during Herpes Simplex Virus Type 1 Infection. by Kim DB, DeLuca NA.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136260

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Picornavirus Internal Ribosome Entry Site Elements Target RNA Cleavage Events Induced by the Herpes Simplex Virus Virion Host Shutoff Protein. by Elgadi MM, Smiley JR.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112956

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Plasma versus Serum for Detection of Herpes Simplex Virus Type 2-Specific Immunoglobulin G Antibodies with a Glycoprotein G2-Based Enzyme Immunoassay. by Cherpes TL, Meyn LA, Hillier SL.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156559

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Pocket Protein p130/Rb2 Is Required for Efficient Herpes Simplex Virus Type 1 Gene Expression and Viral Replication. by Ehmann GL, Burnett HA, Bachenheimer SL.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114444

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Posttranslational Processing of Infected Cell Proteins 0 and 4 of Herpes Simplex Virus 1 Is Sequential and Reflects the Subcellular Compartment in Which the Proteins Localize. by Advani SJ, Hagglund R, Weichselbaum RR, Roizman B.; 2001 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115034

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Potent In Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293. by Betz UA, Fischer R, Kleymann G, Hendrix M, RubsamenWaigmann H.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127257

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Potential Role for Luman, the Cellular Homologue of Herpes Simplex Virus VP16 ([alpha] Gene trans-Inducing Factor), in Herpesvirus Latency. by Lu R, Misra V.; 2000 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111614

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Processing of [alpha]-Globin and ICP0 mRNA in Cells Infected with Herpes Simplex Virus Type 1 ICP27 Mutants. by Ellison KS, Rice SA, Verity R, Smiley JR.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112251

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Progesterone Increases Susceptibility and Decreases Immune Responses to Genital Herpes Infection. by Kaushic C, Ashkar AA, Reid LA, Rosenthal KL.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152159

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Protective antibody therapy is associated with reduced chemokine transcripts in herpes simplex virus type 1 corneal infection. by Su YH, Yan XT, Oakes JE, Lausch RN.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189943

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Protective Mucosal Immunity to Ocular Herpes Simplex Virus Type 1 Infection in Mice by Using Escherichia coli Heat-Labile Enterotoxin B Subunit as an Adjuvant. by Richards CM, Aman AT, Hirst TR, Hill TJ, Williams NA.; 2001 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114075

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Protective T-Cell-Based Immunity Induced in Neonatal Mice by a Single Replicative Cycle of Herpes Simplex Virus. by Franchini M, Abril C, Schwerdel C, Ruedl C, Ackermann M, Suter M.; 2001 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113900

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Proteolytic Cleavage of the Amino Terminus of the UL15 Gene Product of Herpes Simplex Virus Type 1 Is Coupled with Maturation of Viral DNA into Unit-Length Genomes. by Salmon B, Nalwanga D, Fan Y, Baines JD.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112851

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PrPc Expression Influences the Establishment of Herpes Simplex Virus Type 1 Latency. by Thackray AM, Bujdoso R.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153799

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Pseudotyping of Glycoprotein D-Deficient Herpes Simplex Virus Type 1 with Vesicular Stomatitis Virus Glycoprotein G Enables Mutant Virus Attachment and Entry. by Anderson DB, Laquerre S, Goins WF, Cohen JB, Glorioso JC.; 2000 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111736

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Quantitation of herpes simplex virus type 1 DNA and latency-associated transcripts in rabbit trigeminal ganglia demonstrates a stable reservoir of viral nucleic acids during latency. by Hill JM, Gebhardt BM, Wen R, Bouterie AM, Thompson HW, O'Callaghan RJ, Halford WP, Kaufman HE.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190176

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Quantitation of Latent Varicella-Zoster Virus and Herpes Simplex Virus Genomes in Human Trigeminal Ganglia. by Pevenstein SR, Williams RK, McChesney D, Mont EK, Smialek JE, Straus SE.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113107

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Quantitative Analysis of Herpes Simplex Virus Reactivation In Vivo Demonstrates that Reactivation in the Nervous System Is Not Inhibited at Early Times Postinoculation. by Sawtell NM.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150616

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Rapid Detection and Typing of Herpes Simplex Virus DNA in Clinical Specimens by the Hybrid Capture II Signal Amplification Probe Test. by Michalski FJ.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104646

Studies

91

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Rapid detection and typing of herpes simplex virus DNA in clinical specimens by the hybrid capture II signal amplification probe test. by Cullen AP, Long CD, Lorincz AT.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229953

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Rapid Detection of Herpes Simplex Virus and Varicella-Zoster Virus Infections by Real-Time PCR. by Weidmann M, Meyer-Konig U, Hufert FT.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153887

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Rapid Phenotypic Characterization Method for Herpes Simplex Virus and VaricellaZoster Virus Thymidine Kinases To Screen for Acyclovir-Resistant Viral Infection. by Suzutani T, Saijo M, Nagamine M, Ogasawara M, Azuma M.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86603

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Rapid Screening Tests for Determining In Vitro Susceptibility of Herpes Simplex Virus Clinical Isolates. by de la Iglesia P, Melon S, Lopez B, Rodriguez M, Blanco MI, Mellado P, de Ona M.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105060

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Ras-GAP Binding and Phosphorylation by Herpes Simplex Virus Type 2 RR1 PK (ICP10) and Activation of the Ras/MEK/MAPK Mitogenic Pathway Are Required for Timely Onset of Virus Growth. by Smith CC, Nelson J, Aurelian L, Gober M, Goswami BB.; 2000 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110916

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Reactivation of thymidine kinase-defective herpes simplex virus is enhanced by nucleoside. by Tenser RB, Gaydos A, Hay KA.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189942

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Recognition of Herpes Simplex Virus Type 2 Tegument Proteins by CD4 T Cells Infiltrating Human Genital Herpes Lesions. by Koelle DM, Frank JM, Johnson ML, Kwok WW.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109983

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Recombinant Herpes Simplex Virus Type 1 Engineered for Targeted Binding to Erythropoietin Receptor-Bearing Cells. by Laquerre S, Anderson DB, Stolz DB, Glorioso JC.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110478

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Recombinant Herpes Simplex Virus Type 1 Expressing Murine Interleukin-4 Is Less Virulent than Wild-Type Virus in Mice. by Ghiasi H, Osorio Y, Perng GC, Nesburn AB, Wechsler SL.; 2001 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114471

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Recovery of an Unusual Fusogenic Herpes Simplex Virus Type 2 Strain from a Clinical Specimen. by Johnson FB.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130920

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Region of Herpes Simplex Virus Type 1 Latency-Associated Transcript Sufficient for Wild-Type Spontaneous Reactivation Promotes Cell Survival in Tissue Culture. by Inman M, Perng GC, Henderson G, Ghiasi H, Nesburn AB, Wechsler SL, Jones C.; 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114855

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Herpes Simplex

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Regional Distribution of Antibodies to Herpes Simplex Virus Type 1 (HSV-1) and HSV-2 in Men and Women in Ontario, Canada. by Howard M, Sellors JW, Jang D, Robinson NJ, Fearon M, Kaczorowski J, Chernesky M.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149555

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Regions of the Herpes Simplex Virus Type 1 Latency-Associated Transcript That Protect Cells from Apoptosis In Vitro and Protect Neuronal Cells In Vivo. by Ahmed M, Lock M, Miller CG, Fraser NW.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136840

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Regulation of herpes simplex virus [gamma]134.5 expression and oncolysis of diffuse liver metastases by Myb34.5. by Nakamura H, Kasuya H, Mullen JT, Yoon SS, Pawlik TM, Chandrasekhar S, Donahue JM, Chiocca EA, Chung RY, Tanabe KK.; 2002 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150923

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Replication Fidelity of the supF Gene Integrated in the Thymidine Kinase Locus of Herpes Simplex Virus Type 1. by Hwang YT, Liu BY, Hwang CB.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136086

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Replication of Herpes Simplex Virus Type 1 within Trigeminal Ganglia Is Required for High Frequency but Not High Viral Genome Copy Number Latency. by Thompson RL, Sawtell NM.; 2000 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111617

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Requirement for Cellular Cyclin-Dependent Kinases in Herpes Simplex Virus Replication and Transcription. by Schang LM, Phillips J, Schaffer PA.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110224

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Requirement of Interaction of Nectin-1[alpha]/HveC with Afadin for Efficient CellCell Spread of Herpes Simplex Virus Type 1. by Sakisaka T, Taniguchi T, Nakanishi H, Takahashi K, Miyahara M, Ikeda W, Yokoyama S, Peng YF, Yamanishi K, Takai Y.; 2001 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114228

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Requirements for the Induction of Interleukin-6 by Herpes Simplex Virus-Infected Leukocytes. by Paludan SR.; 2001 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115044

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Requirements for the Nuclear-Cytoplasmic Translocation of Infected-Cell Protein 0 of Herpes Simplex Virus 1. by Lopez P, Van Sant C, Roizman B.; 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114874

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RNA Polymerase II Holoenzyme Modifications Accompany Transcription Reprogramming in Herpes Simplex Virus Type 1-Infected Cells. by Jenkins HL, Spencer CA.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114559

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Role for Gamma Interferon in Control of Herpes Simplex Virus Type 1 Reactivation. by Cantin E, Tanamachi B, Openshaw H.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104106

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Role of CD28/CD80-86 and CD40/CD154 Costimulatory Interactions in Host Defense to Primary Herpes Simplex Virus Infection. by Edelmann KH, Wilson CB.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113957

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Role of Cyclin D3 in the Biology of Herpes Simplex Virus 1 ICP0. by Van Sant C, Lopez P, Advani SJ, Roizman B.; 2001 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115135

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93

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Role of histamine in natural killer cell-dependent protection against herpes simplex virus type 2 infection in mice. by Hellstrand K, Asea A, Hermodsson S.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170145

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Role of matrix metalloproteinase-9 in angiogenesis caused by ocular infection with herpes simplex virus. by Lee S, Zheng M, Kim B, Rouse BT.; 2002 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150797

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Role of the UL25 Gene Product in Packaging DNA into the Herpes Simplex Virus Capsid: Location of UL25 Product in the Capsid and Demonstration that It Binds DNA. by Ogasawara M, Suzutani T, Yoshida I, Azuma M.; 2001 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114049

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Role of the virion host shutoff (vhs) of herpes simplex virus type 1 in latency and pathogenesis. by Strelow LI, Leib DA.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189589

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Roles of different T-cell subsets in control of herpes simplex virus infection determined by using T-cell-deficient mouse-models. by Manickan E, Rouse BT.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189778

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Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins. by Schang LM, Rosenberg A, Schaffer PA.; 2000 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111691

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Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD8 + cytotoxic T lymphocyte responses. by Posavad CM, Koelle DM, Shaughnessy MF, Corey L.; 1997 Sep 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23355

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Simultaneous PCR detection of Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus types 1 and 2 from genital ulcers. by Orle KA, Gates CA, Martin DH, Body BA, Weiss JB.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228728

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Site-Directed Mutagenesis of the Virion Host Shutoff Gene (UL41) of Herpes Simplex Virus (HSV): Analysis of Functional Differences between HSV Type 1 (HSV-1) and HSV-2 Alleles. by Everly DN Jr, Read GS.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112944

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Small Dense Nuclear Bodies Are the Site of Localization of Herpes Simplex Virus 1 UL3 and UL4 Proteins and of ICP22 Only When the Latter Protein Is Present. by Markovitz NS, Roizman B.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111565

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Social stress and the reactivation of latent herpes simplex virus type 1. by Padgett DA, Sheridan JF, Dorne J, Berntson GG, Candelora J, Glaser R.; 1998 Jun 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22787

94

Herpes Simplex

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Sodium Lauryl Sulfate Increases the Efficacy of a Topical Formulation of Foscarnet against Herpes Simplex Virus Type 1 Cutaneous Lesions in Mice. by Piret J, Desormeaux A, Cormier H, Lamontagne J, Gourde P, Juhasz J, Bergeron MG.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90056

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Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice. by Feldman LT, Ellison AR, Voytek CC, Yang L, Krause P, Margolis TP.; 2002 Jan 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117416

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Structural and Antigenic Analysis of a Truncated Form of the Herpes Simplex Virus Glycoprotein gH-gL Complex. by Peng T, Ponce de Leon M, Novotny MJ, Jiang H, Lambris JD, Dubin G, Spear PG, Cohen GH, Eisenberg RJ.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110415

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Surveillance for Antiviral-Agent-Resistant Herpes Simplex Virus in the General Population with Recurrent Herpes Labialis. by Bacon TH, Boon RJ, Schultz M, HodgesSavola C.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127455

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Survey of Resistance of Herpes Simplex Virus to Acyclovir in Northwest England. by Christophers J, Clayton J, Craske J, Ward R, Collins P, Trowbridge M, Darby G.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105557

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Tegument-Specific, Virus-Reactive CD4 T Cells Localize to the Cornea in Herpes Simplex Virus Interstitial Keratitis in Humans. by Koelle DM, Reymond SN, Chen H, Kwok WW, McClurkan C, Gyaltsong T, Petersdorf EW, Rotkis W, Talley AR, Harrison DA.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113172

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Temporal Regulation of Herpes Simplex Virus Type 2 VP22 Expression and Phosphorylation. by Geiss BJ, Tavis JE, Metzger LM, Leib DA, Morrison LA.; 2001 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114653

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The 2.2-Kilobase Latency-Associated Transcript of Herpes Simplex Virus Type 2 Does Not Modulate Viral Replication, Reactivation, or Establishment of Latency in Transgenic Mice. by Wang K, Pesnicak L, Guancial E, Krause PR, Straus SE.; 2001 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115061

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The 60-Residue C-Terminal Region of the Single-Stranded DNA Binding Protein of Herpes Simplex Virus Type 1 Is Required for Cooperative DNA Binding. by Mapelli M, Muhleisen M, Persico G, van der Zandt H, Tucker PA.; 2000 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102075

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The Ability of Herpes Simplex Virus Type 1 Immediate-Early Protein Vmw110 To Bind to a Ubiquitin-Specific Protease Contributes to Its Roles in the Activation of Gene Expression and Stimulation of Virus Replication. by Everett RD, Meredith M, Orr A.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103848

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The abundant latency-associated transcripts of herpes simplex virus type 1 are bound to polyribosomes in cultured neuronal cells and during latent infection in mouse trigeminal ganglia. by Goldenberg D, Mador N, Ball MJ, Panet A, Steiner I.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191416

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95

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The Antiviral Efficacy of the Murine Alpha-1 Interferon Transgene against Ocular Herpes Simplex Virus Type 1 Requires the Presence of CD4 +, [alpha]/[beta] T-Cell Receptor-Positive T Lymphocytes with the Capacity To Produce Gamma Interferon. by Carr DJ, Noisakran S.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136437

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The Conserved Carboxyl-Terminal Half of Herpes Simplex Virus Type 1 Regulatory Protein ICP27 Is Dispensable for Viral Growth in the Presence of Compensatory Mutations. by Bunnell SM, Rice SA.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112256

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The Cytotoxic T-Cell Response to Herpes Simplex Virus Type 1 Infection of C57BL/6 Mice Is Almost Entirely Directed against a Single Immunodominant Determinant. by Wallace ME, Keating R, Heath WR, Carbone FR.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104289

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The Disappearance of Cyclins A and B and the Increase in Activity of the G2/M-Phase Cellular Kinase cdc2 in Herpes Simplex Virus 1-Infected Cells Require Expression of the [alpha]22/US1.5 and UL13 Viral Genes. by Advani SJ, Brandimarti R, Weichselbaum RR, Roizman B.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111507

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The Domains of Glycoprotein D Required To Block Apoptosis Depend on Whether Glycoprotein D Is Present in the Virions Carrying Herpes Simplex Virus 1 Genome Lacking the Gene Encoding the Glycoprotein. by Zhou G, Roizman B.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114332

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The Early Expression of Glycoprotein B from Herpes Simplex Virus Can Be Detected by Antigen-Specific CD8 + T Cells. by Mueller SN, Jones CM, Chen W, Kawaoka Y, Castrucci MR, Heath WR, Carbone FR.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141123

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The Ectodomain of a Novel Member of the Immunoglobulin Subfamily Related to the Poliovirus Receptor Has the Attributes of a Bona Fide Receptor for Herpes Simplex Virus Types 1 and 2 in Human Cells. by Cocchi F, Menotti L, Mirandola P, Lopez M, Campadelli-Fiume G.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110516

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The essential protein encoded by the UL31 gene of herpes simplex virus 1 depends for its stability on the presence of UL34 protein. by Ye GJ, Roizman B.; 2000 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27138

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The estimated economic burden of genital herpes in the United States. An analysis using two costing approaches. by Szucs TD, Berger K, Fisman DN, Harbarth S.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35281

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The First Immunoglobulin-Like Domain of HveC Is Sufficient To Bind Herpes Simplex Virus gD with Full Affinity, While the Third Domain Is Involved in Oligomerization of HveC. by Krummenacher C, Rux AH, Whitbeck JC, Ponce-de-Leon M, Lou H, Baribaud I, Hou W, Zou C, Geraghty RJ, Spear PG, Eisenberg RJ, Cohen GH.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112829

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The Genome Sequence of Herpes Simplex Virus Type 2. by Dolan A, Jamieson FE, Cunningham C, Barnett BC, McGeoch DJ.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109494

96

Herpes Simplex

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The gH-gL Complex of Herpes Simplex Virus (HSV) Stimulates Neutralizing Antibody and Protects Mice against HSV Type 1 Challenge. by Peng T, Ponce-de-Leon M, Jiang H, Dubin G, Lubinski JM, Eisenberg RJ, Cohen GH.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109350

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The Herpes Simplex Virus gE-gI Complex Facilitates Cell-to-Cell Spread and Binds to Components of Cell Junctions. by Dingwell KS, Johnson DC.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110310

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The Herpes Simplex Virus Type 1 Cleavage/Packaging Protein, UL32, Is Involved in Efficient Localization of Capsids to Replication Compartments. by Lamberti C, Weller SK.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109547

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The Herpes Simplex Virus Type 1 Regulatory Protein ICP27 Is Required for the Prevention of Apoptosis in Infected Human Cells. by Aubert M, Blaho JA.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104038

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The Herpes Simplex Virus Type 1 UL17 Gene Encodes Virion Tegument Proteins That Are Required for Cleavage and Packaging of Viral DNA. by Salmon B, Cunningham C, Davison AJ, Harris WJ, Baines JD.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109600

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The Herpes Simplex Virus Type 1 US11 Protein Interacts with Protein Kinase R in Infected Cells and Requires a 30-Amino-Acid Sequence Adjacent to a Kinase Substrate Domain. by Cassady KA, Gross M.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135940

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The Herpes Simplex Virus US11 Protein Effectively Compensates for the [gamma]134.5 Gene if Present before Activation of Protein Kinase R by Precluding Its Phosphorylation and That of the [alpha] Subunit of Eukaryotic Translation Initiation Factor 2. by Cassady KA, Gross M, Roizman B.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110273

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The Herpes Simplex Virus vhs Protein Induces Endoribonucleolytic Cleavage of Target RNAs in Cell Extracts. by Elgadi MM, Hayes CE, Smiley JR.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104239

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The High Mobility Group Protein 1 Is a Coactivator of Herpes Simplex Virus ICP4 In Vitro. by Carrozza MJ, DeLuca N.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109883

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The Latency-Associated Transcript Gene Enhances Establishment of Herpes Simplex Virus Type 1 Latency in Rabbits. by Perng GC, Slanina SM, Yukht A, Ghiasi H, Nesburn AB, Wechsler SL.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111666

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The Latent Herpes Simplex Virus Type 1 Genome Copy Number in Individual Neurons Is Virus Strain Specific and Correlates with Reactivation. by Sawtell NM, Poon DK, Tansky CS, Thompson RL.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110155

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The Major Neutralizing Antigenic Site on Herpes Simplex Virus Glycoprotein D Overlaps a Receptor-Binding Domain. by Whitbeck JC, Muggeridge MI, Rux AH, Hou W, Krummenacher C, Lou H, van Geelen A, Eisenberg RJ, Cohen GH.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113037

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97

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The NH2 Terminus of the Herpes Simplex Virus Type 1 Regulatory Protein ICP0 Contains a Promoter-Specific Transcription Activation Domain. by Lium EK, Panagiotidis CA, Wen X, Silverstein SJ.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110090

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The PK Domain of the Large Subunit of Herpes Simplex Virus Type 2 Ribonucleotide Reductase (ICP10) Is Required for Immediate-Early Gene Expression and Virus Growth. by Smith CC, Peng T, Kulka M, Aurelian L.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110331

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The Polyserine Tract of Herpes Simplex Virus ICP4 Is Required for Normal Viral Gene Expression and Growth in Murine Trigeminal Ganglia. by Bates PA, DeLuca NA.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109933

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The Probability of In Vivo Reactivation of Herpes Simplex Virus Type 1 Increases with the Number of Latently Infected Neurons in the Ganglia. by Sawtell NM.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109900

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The Product of the Herpes Simplex Virus Type 1 UL25 Gene Is Required for Encapsidation but Not for Cleavage of Replicated Viral DNA. by McNab AR, Desai P, Person S, Roof LL, Thomsen DR, Newcomb WW, Brown JC, Homa FL.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124578

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The Quantity of Latent Viral DNA Correlates with the Relative Rates at Which Herpes Simplex Virus Types 1 and 2 Cause Recurrent Genital Herpes Outbreaks. by Lekstrom-Himes JA, Pesnicak L, Straus SE.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109720

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The range and distribution of murine central nervous system cells infected with the gamma(1)34.5- mutant of herpes simplex virus 1. by Markovitz NS, Baunoch D, Roizman B.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191798

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The region of the herpes simplex virus type 1 LAT gene that is colinear with the ICP34.5 gene is not involved in spontaneous reactivation. by Perng GC, Chokephaibulkit K, Thompson RL, Sawtell NM, Slanina SM, Ghiasi H, Nesburn AB, Wechsler SL.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189815

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The role of cdc2 in the expression of herpes simplex virus genes. by Advani SJ, Weichselbaum RR, Roizman B.; 2000 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27137

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The Role of Herpes Simplex Virus ICP27 in the Regulation of UL24 Gene Expression by Differential Polyadenylation. by Hann LE, Cook WJ, Uprichard SL, Knipe DM, Coen DM.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110073

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The spontaneous reactivation function of the herpes simplex virus type 1 LAT gene resides completely within the first 1.5 kilobases of the 8.3-kilobase primary transcript. by Perng GC, Ghiasi H, Slanina SM, Nesburn AB, Wechsler SL.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189902

98

Herpes Simplex

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The Spread of Herpes Simplex Virus Type 1 from Trigeminal Neurons to the Murine Cornea: an Immunoelectron Microscopy Study. by Ohara PT, Chin MS, LaVail JH.; 2000 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112000

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The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections. by Heise MT, Virgin HW 4th.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=188658

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The Transgenic ICP4 Promoter Is Activated in Schwann Cells in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus Type 1. by Taus NS, Mitchell WJ.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114614

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The transneuronal spread phenotype of herpes simplex virus type 1 infection of the mouse hind footpad. by Engel JP, Madigan TC, Peterson GM.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191353

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The UL3 Protein of Herpes Simplex Virus 1 Is Translated Predominantly from the Second In-Frame Methionine Codon and Is Subject to at Least Two Posttranslational Modifications. by Markovitz NS, Filatov F, Roizman B.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112816

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The UL6 Gene Product Forms the Portal for Entry of DNA into the Herpes Simplex Virus Capsid. by Newcomb WW, Juhas RM, Thomsen DR, Homa FL, Burch AD, Weller SK, Brown JC.; 2001 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114672

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The US3 Protein Kinase Blocks Apoptosis Induced by the d120 Mutant of Herpes Simplex Virus 1 at a Premitochondrial Stage. by Munger J, Chee AV, Roizman B.; 2001 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114261

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The vhs1 Mutant Form of Herpes Simplex Virus Virion Host Shutoff Protein Retains Significant Internal Ribosome Entry Site-Directed RNA Cleavage Activity. by Lu P, Saffran HA, Smiley JR.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114006

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Therapeutic Immunization with a Virion Host Shutoff-Defective, ReplicationIncompetent Herpes Simplex Virus Type 1 Strain Limits Recurrent Herpetic Ocular Infection. by Keadle TL, Morrison LA, Morris JL, Pepose JS, Stuart PM.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136075

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Three Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutants with Distinct and Asymmetric Effects on Virulence in Mice Compared with Rabbits. by Perng GC, Esmaili D, Slanina SM, Yukht A, Ghiasi H, Osorio N, Mott KR, Maguen B, Jin L, Nesburn AB, Wechsler SL.; 2001 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114470

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Time-Resolved Fluorometry PCR Assay for Rapid Detection of Herpes Simplex Virus in Cerebrospinal Fluid. by Hukkanen V, Rehn T, Kajander R, Sjoroos M, Waris M.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87359

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Tracking the Spread of a lacZ-Tagged Herpes Simplex Virus Type 1 between the Eye and the Nervous System of the Mouse: Comparison of Primary and Recurrent Infection. by Shimeld C, Efstathiou S, Hill T.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114931

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Transcription of Herpes Simplex Virus Immediate-Early and Early Genes Is Inhibited by Roscovitine, an Inhibitor Specific for Cellular Cyclin-Dependent Kinases. by Schang LM, Rosenberg A, Schaffer PA.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104461

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Translational Compensation of a Frameshift Mutation Affecting Herpes Simplex Virus Thymidine Kinase Is Sufficient To Permit Reactivation from Latency. by Griffiths A, Chen SH, Horsburgh BC, Coen DM.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152167

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Truncation of the C-Terminal Acidic Transcriptional Activation Domain of Herpes Simplex Virus VP16 Renders Expression of the Immediate-Early Genes Almost Entirely Dependent on ICP0. by Mossman KL, Smiley JR.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113019

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Typing of Clinical Herpes Simplex Virus Type 1 and Type 2 Isolates with Monoclonal Antibodies. by Liljeqvist JA, Svennerholm B, Bergstrom T.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85325

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UL27.5 Is a Novel [gamma]2 Gene Antisense to the Herpes Simplex Virus 1 Gene Encoding Glycoprotein B. by Chang YE, Menotti L, Filatov F, Campadelli-Fiume G, Roizman B.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110411

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UL31 and UL34 Proteins of Herpes Simplex Virus Type 1 Form a Complex That Accumulates at the Nuclear Rim and Is Required for Envelopment of Nucleocapsids. by Reynolds AE, Ryckman BJ, Baines JD, Zhou Y, Liang L, Roller RJ.; 2001 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115125

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Use of Differential Display Reverse Transcription-PCR To Reveal Cellular Changes during Stimuli That Result in Herpes Simplex Virus Type 1 Reactivation from Latency: Upregulation of Immediate-Early Cellular Response Genes TIS7, Interferon, and Interferon Regulatory Factor-1. by Tal-Singer R, Podrzucki W, Lasner TM, Skokotas A, Leary JJ, Fraser NW, Berger SL.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124603

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Use of Immunostimulatory Sequence-Containing Oligonucleotides as Topical Therapy for Genital Herpes Simplex Virus Type 2 Infection. by Pyles RB, Higgins D, Chalk C, Zalar A, Eiden J, Brown C, Van Nest G, Stanberry LR.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136753

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Vaccine-Induced Serum Immunoglobin Contributes to Protection from Herpes Simplex Virus Type 2 Genital Infection in the Presence of Immune T Cells. by Morrison LA, Zhu L, Thebeau LG.; 2001 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114025

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Vaginal formulations of carrageenan protect mice from herpes simplex virus infection. by Zacharopoulos VR, Phillips DM.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170551

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Variability of the Glycoprotein G Gene in Clinical Isolates of Herpes Simplex Virus Type 1. by Rekabdar E, Tunback P, Liljeqvist JA, Bergstrom T.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95783

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Viral replication is required for induction of ocular immunopathology by herpes simplex virus. by Babu JS, Thomas J, Kanangat S, Morrison LA, Knipe DM, Rouse BT.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189793

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Virus-Cell Interactions Regulating Induction of Tumor Necrosis Factor Alpha Production in Macrophages Infected with Herpes Simplex Virus. by Paludan SR, Mogensen SC.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114591

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Visualization of Tegument-Capsid Interactions and DNA in Intact Herpes Simplex Virus Type 1 Virions. by Zhou ZH, Chen DH, Jakana J, Rixon FJ, Chiu W.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104084

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Zinc Salts Inactivate Clinical Isolates of Herpes Simplex Virus In Vitro. by Arens M, Travis S.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86580

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with herpes simplex, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “herpes simplex” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for herpes simplex (hyperlinks lead to article summaries): •

A double-blind, randomized, placebo-controlled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery. Author(s): Watts DH, Brown ZA, Money D, Selke S, Huang ML, Sacks SL, Corey L. Source: American Journal of Obstetrics and Gynecology. 2003 March; 188(3): 836-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634667&dopt=Abstract

6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A modification of the epidermal scarification model of herpes simplex virus infection to achieve a reproducible and uniform progression of disease. Author(s): Goel N, Docherty JJ, Fu MM, Zimmerman DH, Rosenthal KS. Source: Journal of Virological Methods. 2002 December; 106(2): 153-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393145&dopt=Abstract

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A prospective study of genital herpes simplex virus type 2 infection in human immunodeficiency virus type 1 (HIV-1)-seropositive women: correlations with CD4 cell count and plasma HIV-1 RNA level. Author(s): Wright PW, Hoesley CJ, Squires KE, Croom-Rivers A, Weiss HL, Gnann JW Jr. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 January 15; 36(2): 207-11. Epub 2003 Jan 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522754&dopt=Abstract

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A strict-late viral promoter is a strong tumor-specific promoter in the context of an oncolytic herpes simplex virus. Author(s): Fu X, Meng F, Tao L, Jin A, Zhang X. Source: Gene Therapy. 2003 August; 10(17): 1458-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900760&dopt=Abstract

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Activation of latent Lyme borreliosis concurrent with a herpes simplex virus type 1 infection. Author(s): Gylfe A, Wahlgren M, Fahlen L, Bergstrom S. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(12): 922-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587627&dopt=Abstract

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Activation of the human endogenous retrovirus W long terminal repeat by herpes simplex virus type 1 immediate early protein 1. Author(s): Lee WJ, Kwun HJ, Kim HS, Jang KL. Source: Molecules and Cells. 2003 February 28; 15(1): 75-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12661764&dopt=Abstract

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Acute cerebellitis caused by herpes simplex virus type 1. Author(s): Ciardi M, Giacchetti G, Fedele CG, Tenorio A, Brandi A, Libertone R, Ajassa C, Borgese L, Delia S. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 February 1; 36(3): E50-4. Epub 2003 January 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12539091&dopt=Abstract

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Adrenal insufficiency combined with gastric cardia ulcer due to herpes simplex virus type 1 infection. Author(s): Su CC, Lu JJ, Perng CL, Chen CS, Lee CC. Source: J Formos Med Assoc. 2002 October; 101(10): 719-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517048&dopt=Abstract

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Adults with atopic dermatitis and herpes simplex and topical therapy with tacrolimus: what kind of prevention? Author(s): Lubbe J, Sanchez-Politta S, Tschanz C, Saurat JH. Source: Archives of Dermatology. 2003 May; 139(5): 670-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756112&dopt=Abstract

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Amino acid changes within conserved region III of the herpes simplex virus and human cytomegalovirus DNA polymerases confer resistance to 4-oxodihydroquinolines, a novel class of herpesvirus antiviral agents. Author(s): Thomsen DR, Oien NL, Hopkins TA, Knechtel ML, Brideau RJ, Wathen MW, Homa FL. Source: Journal of Virology. 2003 February; 77(3): 1868-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525621&dopt=Abstract

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Amino acid substitutions in the effector domain of the gamma(1)34.5 protein of herpes simplex virus 1 have differential effects on viral response to interferon-alpha. Author(s): Cerveny M, Hessefort S, Yang K, Cheng G, Gross M, He B. Source: Virology. 2003 March 15; 307(2): 290-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667799&dopt=Abstract

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An uncommon case of disseminated neonatal herpes simplex infection presenting with pneumonia and pleural effusions. Author(s): Langlet C, Gaugler C, Castaing M, Astruc D, Falkenrodt A, Neuville A, Messer J. Source: European Journal of Pediatrics. 2003 July; 162(7-8): 532-3. Epub 2003 May 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12733067&dopt=Abstract

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Analysis of the herpes simplex virus type 1 UL6 gene in patients with stromal keratitis. Author(s): Ellison AR, Yang L, Cevallos AV, Margolis TP. Source: Virology. 2003 May 25; 310(1): 24-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788627&dopt=Abstract

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Analysis of the role of the membrane-spanning and cytoplasmic tail domains of herpes simplex virus type 1 glycoprotein D in membrane fusion. Author(s): Browne H, Bruun B, Whiteley A, Minson T. Source: The Journal of General Virology. 2003 May; 84(Pt 5): 1085-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692272&dopt=Abstract

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Antiviral activity of Spirulina maxima against herpes simplex virus type 2. Author(s): Hernandez-Corona A, Nieves I, Meckes M, Chamorro G, Barron BL. Source: Antiviral Research. 2002 December; 56(3): 279-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406511&dopt=Abstract

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Antiviral therapy in children with varicella zoster virus and herpes simplex virus infections. Author(s): Enright AM, Prober C. Source: Herpes : the Journal of the Ihmf. 2003 August; 10(2): 32-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14577952&dopt=Abstract

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Are latent, immediate-early genes of herpes simplex virus-1 essential in causing trigeminal neuralgia? Author(s): Ecker AD, Smith JE. Source: Medical Hypotheses. 2002 November; 59(5): 603-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12376087&dopt=Abstract

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Association between acquisition of herpes simplex virus type 2 in women and bacterial vaginosis. Author(s): Cherpes TL, Meyn LA, Krohn MA, Lurie JG, Hillier SL. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 August 1; 37(3): 319-25. Epub 2003 July 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884154&dopt=Abstract

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Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Author(s): Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Ruslanova I, Yolken RH. Source: Archives of General Psychiatry. 2003 May; 60(5): 466-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742867&dopt=Abstract

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Association of the herpes simplex virus type 1 Us11 gene product with the cellular kinesin light-chain-related protein PAT1 results in the redistribution of both polypeptides. Author(s): Benboudjema L, Mulvey M, Gao Y, Pimplikar SW, Mohr I. Source: Journal of Virology. 2003 September; 77(17): 9192-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915535&dopt=Abstract

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B7 costimulation plays an important role in protection from herpes simplex virus type 2-mediated pathology. Author(s): Thebeau LG, Morrison LA. Source: Journal of Virology. 2002 March; 76(5): 2563-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836436&dopt=Abstract

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Baseline IgG antibody titers to Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, and cytomegalovirus and the risk for cardiovascular disease in women. Author(s): Ridker PM, Hennekens CH, Buring JE, Kundsin R, Shih J. Source: Annals of Internal Medicine. 1999 October 19; 131(8): 573-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10523217&dopt=Abstract

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Bcl-2 blocks a caspase-dependent pathway of apoptosis activated by herpes simplex virus 1 infection in HEp-2 cells. Author(s): Galvan V, Brandimarti R, Munger J, Roizman B. Source: Journal of Virology. 2000 February; 74(4): 1931-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10644366&dopt=Abstract

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BCL-2 transduction, using a herpes simplex virus amplicon, protects hippocampal neurons from transient global ischemia. Author(s): Antonawich FJ, Federoff HJ, Davis JN. Source: Experimental Neurology. 1999 March; 156(1): 130-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10192784&dopt=Abstract

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Bilateral acute retinal necrosis and herpes simplex type 2 encephalitis in a neonate. Author(s): Kychenthal A, Coombes A, Greenwood J, Pavesio C, Aylward GW. Source: The British Journal of Ophthalmology. 2001 May; 85(5): 629-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11351976&dopt=Abstract

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Bilateral necrotizing herpetic retinopathy three years after herpes simplex encephalitis following pulse corticosteroid treatment. Author(s): Verma L, Venkatesh P, Satpal G, Rathore K, Tewari HK. Source: Retina (Philadelphia, Pa.). 1999; 19(5): 464-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10546950&dopt=Abstract

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Binding partners for the UL11 tegument protein of herpes simplex virus type 1. Author(s): Loomis JS, Courtney RJ, Wills JW. Source: Journal of Virology. 2003 November; 77(21): 11417-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557627&dopt=Abstract

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Biological purging of breast cancer cells using an attenuated replication-competent herpes simplex virus in human hematopoietic stem cell transplantation. Author(s): Wu A, Mazumder A, Martuza RL, Liu X, Thein M, Meehan KR, Rabkin SD. Source: Cancer Research. 2001 April 1; 61(7): 3009-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11306480&dopt=Abstract

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Biosynthetic ganciclovir triphosphate: its isolation and characterization from ganciclovir-treated herpes simplex thymidine kinase-transduced murine cells. Author(s): Agbaria R, Candotti F, Kelley JA, Hao Z, Johns DG, Cooney DA, Blaese RM, Ford H Jr. Source: Biochemical and Biophysical Research Communications. 2001 November 30; 289(2): 525-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11716505&dopt=Abstract

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B-myb promoter retargeting of herpes simplex virus gamma34.5 gene-mediated virulence toward tumor and cycling cells. Author(s): Chung RY, Saeki Y, Chiocca EA. Source: Journal of Virology. 1999 September; 73(9): 7556-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10438845&dopt=Abstract

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Bone marrow transplantation in a child with Wiskott-Aldrich syndrome latently infected with acyclovir-resistant (ACV(r)) herpes simplex virus type 1: emergence of foscarnet-resistant virus originating from the ACV(r) virus. Author(s): Saijo M, Yasuda Y, Yabe H, Kato S, Suzutani T, De Clercq E, Niikura M, Maeda A, Kurane I, Morikawa S. Source: Journal of Medical Virology. 2002 September; 68(1): 99-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210436&dopt=Abstract

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Brain stem encephalitis caused by primary herpes simplex 2 infection in a young woman. Author(s): Tang JW, Coward LJ, Davies NW, Geretti AM, Howard RS, Hirsch NP, Ward KN. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 September; 74(9): 1323-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933947&dopt=Abstract

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Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Author(s): Mesnil M, Yamasaki H. Source: Cancer Research. 2000 August 1; 60(15): 3989-99. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10945596&dopt=Abstract

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Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes. Author(s): Walling HW, Swarthout JT, Culver KW. Source: Cancer Gene Therapy. 2000 February; 7(2): 187-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10770626&dopt=Abstract

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Cell culture replication of herpes simplex virus and, or human cytomegalovirus is inhibited by 3,7-dialkoxylated, 1-hydroxyacridone derivatives. Author(s): Lowden CT, Bastow KF. Source: Antiviral Research. 2003 August; 59(3): 143-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12927304&dopt=Abstract

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Cell response to herpes simplex virus type 1 infection mediated by biphasic calciumphosphate ceramics: in vitro approach. Author(s): Varadinova TL, Zlateva KT, Dyulgerova EI. Source: Journal of Biomedical Materials Research. 2001 November; 57(2): 232-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11484186&dopt=Abstract

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Cellular expression of gH confers resistance to herpes simplex virus type-1 entry. Author(s): Scanlan PM, Tiwari V, Bommireddy S, Shukla D. Source: Virology. 2003 July 20; 312(1): 14-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12890617&dopt=Abstract

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Cesarean delivery and risk of herpes simplex virus infection. Author(s): Cohan D. Source: Jama : the Journal of the American Medical Association. 2003 May 7; 289(17): 2208; Author Reply 2208-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734124&dopt=Abstract

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Cesarean delivery and risk of herpes simplex virus infection. Author(s): Rouse DJ, Stringer JS. Source: Jama : the Journal of the American Medical Association. 2003 May 7; 289(17): 2208; Author Reply 2208-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734123&dopt=Abstract

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Characterization of a neurovirulent aciclovir-resistant variant of herpes simplex virus. Author(s): Grey F, Sowa M, Collins P, Fenton RJ, Harris W, Snowden W, Efstathiou S, Darby G. Source: The Journal of General Virology. 2003 June; 84(Pt 6): 1403-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771407&dopt=Abstract

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Chimeric Dr fimbriae with a herpes simplex virus type 1 epitope as a model for a recombinant vaccine. Author(s): Zalewska B, Piatek R, Konopa G, Nowicki B, Nowicki S, Kur J. Source: Infection and Immunity. 2003 October; 71(10): 5505-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500468&dopt=Abstract

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Chimeric nectin1-poliovirus receptor molecules identify a nectin1 region functional in herpes simplex virus entry. Author(s): Cocchi F, Lopez M, Dubreuil P, Campadelli Fiume G, Menotti L. Source: Journal of Virology. 2001 September; 75(17): 7987-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11483743&dopt=Abstract

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Chlamydia trachomatis, herpes simplex virus 2, and human T-cell lymphotrophic virus type 1 are not associated with grade of cervical neoplasia in Jamaican colposcopy patients. Author(s): Castle PE, Escoffery C, Schachter J, Rattray C, Schiffman M, Moncada J, Sugai K, Brown C, Cranston B, Hanchard B, Palefsky JM, Burk RD, Hutchinson ML, Strickler HD. Source: Sexually Transmitted Diseases. 2003 July; 30(7): 575-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838087&dopt=Abstract

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Clinical aspects of recurrent oral herpes simplex virus infection. Author(s): Glick M. Source: Compend Contin Educ Dent. 2002 July; 23(7 Suppl 2): 4-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789980&dopt=Abstract

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Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebo-controlled trial. Author(s): Sacks SL, Thisted RA, Jones TM, Barbarash RA, Mikolich DJ, Ruoff GE, Jorizzo JL, Gunnill LB, Katz DH, Khalil MH, Morrow PR, Yakatan GJ, Pope LE, Berg JE; Docosanol 10% Cream Study Group. Source: Journal of the American Academy of Dermatology. 2001 August; 45(2): 222-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11464183&dopt=Abstract

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Clinical spectrum and laboratory characteristics associated with detection of herpes simplex virus DNA in cerebrospinal fluid. Author(s): O'Sullivan CE, Aksamit AJ, Harrington JR, Harmsen WS, Mitchell PS, Patel R. Source: Mayo Clinic Proceedings. 2003 November; 78(11): 1347-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14601693&dopt=Abstract

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Clinical utility of oral valacyclovir compared with oral acyclovir for the prevention of herpes simplex virus mucositis following autologous bone marrow transplantation or stem cell rescue therapy. Author(s): Eisen D, Essell J, Broun ER, Sigmund D, DeVoe M. Source: Bone Marrow Transplantation. 2003 January; 31(1): 51-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621507&dopt=Abstract

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Close association of predominant genotype of herpes simplex virus type 1 with eczema herpeticum analyzed using restriction fragment length polymorphism of polymerase chain reaction. Author(s): Yoshida M, Umene K. Source: Journal of Virological Methods. 2003 April; 109(1): 11-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668262&dopt=Abstract

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Comparison of a monoclonal antibody-blocking enzyme-linked immunoassay and a strip immunoblot assay for identifying type-specific herpes simplex virus type 2 serological responses. Author(s): Van Doornum GJ, Slomka MJ, Buimer M, Groen J, Van den Hoek JA, Cairo I, Vyse A, Brown DW. Source: Clinical and Diagnostic Laboratory Immunology. 2000 July; 7(4): 641-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10882665&dopt=Abstract

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Comparison of polymorphism of thymidine kinase gene and restriction fragment length polymorphism of genomic DNA in herpes simplex virus type 1. Author(s): Nagamine M, Suzutani T, Saijo M, Hayashi K, Azuma M. Source: Journal of Clinical Microbiology. 2000 July; 38(7): 2750-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10878078&dopt=Abstract

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Comparison of washing and swabbing procedures for collecting genital fluids to assess cervicovaginal shedding of herpes simplex virus type 2 DNA. Author(s): Ndjoyi-Mbiguino A, Ozouaki F, Legoff J, Mbopi-Keou FX, Si-Mohamed A, Onas IN, Avoune E, Belec L. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2662-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791898&dopt=Abstract

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Construction of multiply disabled herpes simplex viral vectors for gene delivery to the nervous system. Author(s): Lilley CE, Coffin RS. Source: Methods in Molecular Medicine. 2003; 76: 33-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526157&dopt=Abstract

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C-terminal region of herpes simplex virus ICP8 protein needed for intranuclear localization. Author(s): Taylor TJ, Knipe DM. Source: Virology. 2003 May 10; 309(2): 219-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758170&dopt=Abstract

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Cytologic, colposcopic, and virologic detection of cervical herpes simplex virus. Author(s): Elnashar AM, Aboelea A, Tantawy TA. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2003 April; 81(1): 69-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676402&dopt=Abstract

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Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation: potential of vhs- HSV vectors for dendritic cell-mediated immunotherapy. Author(s): Samady L, Costigliola E, MacCormac L, McGrath Y, Cleverley S, Lilley CE, Smith J, Latchman DS, Chain B, Coffin RS. Source: Journal of Virology. 2003 March; 77(6): 3768-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610151&dopt=Abstract

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Detection of cutaneous herpes simplex virus infections by immunofluorescence vs. PCR. Author(s): Bezold G, Lange M, Gethoffer K, Gall H, Peter RU. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2003 July; 17(4): 430-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12834453&dopt=Abstract

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Detection of Herpes simplex virus DNA by real-time PCR. Author(s): Kessler HH, Muhlbauer G, Rinner B, Stelzl E, Berger A, Dorr HW, Santner B, Marth E, Rabenau H. Source: Journal of Clinical Microbiology. 2000 July; 38(7): 2638-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10878056&dopt=Abstract

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Detection of herpes simplex virus DNA in dried blood spots making a retrospective diagnosis possible. Author(s): Ilona LF, Pia O, Marianne F, Gunilla M. Source: Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. 2003 January; 26(1): 39-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589833&dopt=Abstract

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Detection of herpes simplex virus, cytomegalovirus, and Epstein-Barr virus in the semen of men attending an infertility clinic. Author(s): Kapranos N, Petrakou E, Anastasiadou C, Kotronias D. Source: Fertility and Sterility. 2003 June; 79 Suppl 3: 1566-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801561&dopt=Abstract

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Determination of minimum herpes simplex virus type 1 components necessary to localize transcriptionally active DNA to ND10. Author(s): Tang Q, Li L, Ishov AM, Revol V, Epstein AL, Maul GG. Source: Journal of Virology. 2003 May; 77(10): 5821-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12719575&dopt=Abstract

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Diagnosis and management of recurrent herpes simplex induced by fixed prosthodontic tissue management: a clinical report. Author(s): Williamson RT. Source: The Journal of Prosthetic Dentistry. 1999 July; 82(1): 1-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10384159&dopt=Abstract

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Diagnosis and management of recurrent herpes simplex infections. Author(s): Siegel MA. Source: The Journal of the American Dental Association. 2002 September; 133(9): 1245-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356256&dopt=Abstract

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Differences in the N termini of herpes simplex virus type 1 and 2 gDs that influence functional interactions with the human entry receptor Nectin-2 and an entry receptor expressed in Chinese hamster ovary cells. Author(s): Zago A, Spear PG. Source: Journal of Virology. 2003 September; 77(17): 9695-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915581&dopt=Abstract

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Differential mutation patterns in thymidine kinase and DNA polymerase genes of herpes simplex virus type 1 clones passaged in the presence of acyclovir or penciclovir. Author(s): Suzutani T, Ishioka K, De Clercq E, Ishibashi K, Kaneko H, Kira T, Hashimoto K, Ogasawara M, Ohtani K, Wakamiya N, Saijo M. Source: Antimicrobial Agents and Chemotherapy. 2003 May; 47(5): 1707-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12709344&dopt=Abstract

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Diffuse white matter lesions in a case of herpes simplex encephalitis. Author(s): Ueda N, Miyasaki H, Kuroiwa Y. Source: Journal of Neurology. 2003 July; 250(7): 867-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883931&dopt=Abstract

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Diffusion-weighted MR imaging findings in a patient with herpes simplex encephalitis. Author(s): Heiner L, Demaerel P. Source: European Journal of Radiology. 2003 March; 45(3): 195-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12595103&dopt=Abstract

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Disabled infectious single cycle herpes simplex virus (DISC-HSV) is a candidate vector system for gene delivery/expression of GM-CSF in human prostate cancer therapy. Author(s): Parkinson RJ, Mian S, Bishop MC, Gray T, Li G, McArdle SE, Ali S, Rees RC. Source: The Prostate. 2003 June 15; 56(1): 65-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746848&dopt=Abstract

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Disseminated cutaneous herpes simplex virus type-1 with interstitial pneumonia as a first presentation of AIDS. Author(s): Umar SH, Kanth A. Source: Journal of the National Medical Association. 1999 August; 91(8): 471-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12656437&dopt=Abstract

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Disseminated herpes simplex after total skin electron beam radiotherapy for mycosis fungoides. Author(s): Smith BD, Son CB, Wilson LD. Source: Journal of the Royal Society of Medicine. 2003 October; 96(10): 500-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519729&dopt=Abstract

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Divergence of reiterated sequences in a series of genital isolates of herpes simplex virus type 1 from individual patients. Author(s): Umene K, Kawana T. Source: The Journal of General Virology. 2003 April; 84(Pt 4): 917-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12655092&dopt=Abstract

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Do we need antivirals for genital herpes simplex virus and human papillomavirus infection? Author(s): Gross G. Source: International Journal of Antimicrobial Agents. 1999 June; 12(1): 1-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10389641&dopt=Abstract

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Drug resistance patterns of recombinant herpes simplex virus DNA polymerase mutants generated with a set of overlapping cosmids and plasmids. Author(s): Bestman-Smith J, Boivin G. Source: Journal of Virology. 2003 July; 77(14): 7820-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829822&dopt=Abstract

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Dynamics of transgene expression in human glioblastoma cells mediated by herpes simplex virus/adeno-associated virus amplicon vectors. Author(s): Lam P, Hui KM, Wang Y, Allen PD, Louis DN, Yuan CJ, Breakefield XO. Source: Human Gene Therapy. 2002 December 10; 13(18): 2147-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12542846&dopt=Abstract

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Dysregulated expression of IFN-gamma and IL-10 and impaired IFN-gammamediated responses at different disease stages in patients with genital herpes simplex virus-2 infection. Author(s): Singh R, Kumar A, Creery WD, Ruben M, Giulivi A, Diaz-Mitoma F. Source: Clinical and Experimental Immunology. 2003 July; 133(1): 97-107. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823283&dopt=Abstract

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Ectopic expression of herpes simplex virus-thymidine kinase gene in human nonsmall cell lung cancer cells conferred caspase-activated apoptosis sensitized by ganciclovir. Author(s): Chiu CC, Kang YL, Yang TH, Huang CH, Fang K. Source: International Journal of Cancer. Journal International Du Cancer. 2002 December 1; 102(4): 328-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12402300&dopt=Abstract

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Effect of Ca2+-dependent cell death on the release of herpes simplex virus. Author(s): Yura Y, Matsumoto R, Sumi T, Kusaka J. Source: Archives of Virology. 2003 February; 148(2): 221-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556989&dopt=Abstract

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Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. Author(s): Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Source: Jama : the Journal of the American Medical Association. 2003 January 8; 289(2): 203-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517231&dopt=Abstract

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Effective treatment of herpes simplex labialis with penciclovir cream: combined results of two trials. Author(s): Raborn GW, Martel AY, Lassonde M, Lewis MA, Boon R, Spruance SL; Worldwide Topical Penciclovir Collaborative Study Group. Source: The Journal of the American Dental Association. 2002 March; 133(3): 303-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11934185&dopt=Abstract

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Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells. Author(s): Wakimoto H, Johnson PR, Knipe DM, Chiocca EA. Source: Gene Therapy. 2003 June; 10(11): 983-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756419&dopt=Abstract

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Efficiency of reconstitution of immunoglobulin g from blood specimens dried on filter paper and utility in herpes simplex virus type-specific serology screening. Author(s): Hogrefe WR, Ernst C, Su X. Source: Clinical and Diagnostic Laboratory Immunology. 2002 November; 9(6): 1338-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12414771&dopt=Abstract

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Elimination of the truncated message from the herpes simplex virus thymidine kinase suicide gene. Author(s): Chalmers D, Ferrand C, Apperley JF, Melo JV, Ebeling S, Newton I, Duperrier A, Hagenbeek A, Garrett E, Tiberghien P, Garin M. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2001 August; 4(2): 146-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11482986&dopt=Abstract

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Emergence of herpes simplex type 1 as the main cause of recurrent genital ulcerative disease in women in Northern Ireland. Author(s): Coyle PV, O'Neill HJ, Wyatt DE, McCaughey C, Quah S, McBride MO. Source: Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. 2003 May; 27(1): 22-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727525&dopt=Abstract

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Engineered herpes simplex virus 1 is dependent on IL13Ralpha 2 receptor for cell entry and independent of glycoprotein D receptor interaction. Author(s): Zhou G, Ye GJ, Debinski W, Roizman B. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 November 12; 99(23): 15124-9. Epub 2002 Nov 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417744&dopt=Abstract

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Entry of herpes simplex virus type 1 into primary sensory neurons in vitro is mediated by Nectin-1/HveC. Author(s): Richart SM, Simpson SA, Krummenacher C, Whitbeck JC, Pizer LI, Cohen GH, Eisenberg RJ, Wilcox CL. Source: Journal of Virology. 2003 March; 77(5): 3307-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584355&dopt=Abstract

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Epidemiology of herpes simplex virus types 1 and 2 in Germany: what has changed? Author(s): Buxbaum S, Geers M, Gross G, Schofer H, Rabenau HF, Doerr HW. Source: Medical Microbiology and Immunology. 2003 August; 192(3): 177-81. Epub 2003 May 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761673&dopt=Abstract

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Erythema multiforme secondary to herpes simplex infection: a case report. Author(s): Ayangco L, Sheridan PJ, Rogers RS. Source: J Periodontol. 2001 July; 72(7): 953-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11495145&dopt=Abstract

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Estimating the costs and benefits of screening monogamous, heterosexual couples for unrecognised infection with herpes simplex virus type 2. Author(s): Fisman DN, Hook EW 3rd, Goldie SJ. Source: Sexually Transmitted Infections. 2003 February; 79(1): 45-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12576614&dopt=Abstract

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Evidence against a simple tethering model for enhancement of herpes simplex virus DNA polymerase processivity by accessory protein UL42. Author(s): Chaudhuri M, Parris DS. Source: Journal of Virology. 2002 October; 76(20): 10270-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239303&dopt=Abstract

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Excretion of herpes simplex virus type 2 glycoprotein D into the culture medium. Author(s): Murata T, Goshima F, Takakuwa H, Nishiyama Y. Source: The Journal of General Virology. 2002 November; 83(Pt 11): 2791-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388815&dopt=Abstract

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Experimental use of natural interferon alpha by peroral administration in patients affected by recidivant herpes simplex. Author(s): Pisani M, Bozzi M. Source: Clin Ter. 2000; 151(1 Suppl 1): 19-22. English, Italian. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10876962&dopt=Abstract

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Exploitation of the Herpes simplex virus translocating protein VP22 to carry influenza virus proteins into cells for studies of apoptosis: direct confirmation that neuraminidase induces apoptosis and indications that other proteins may have a role. Author(s): Morris SJ, Smith H, Sweet C. Source: Archives of Virology. 2002 May; 147(5): 961-79. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12021867&dopt=Abstract

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Exploiting virus stealth technology for xenotransplantation: reduced human T cell responses to porcine cells expressing herpes simplex virus ICP47. Author(s): Crew MD, Phanavanh B. Source: Xenotransplantation. 2003 January; 10(1): 50-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535225&dopt=Abstract

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Expression of human immunodeficiency virus type 1 gp120 from herpes simplex virus type 1-derived amplicons results in potent, specific, and durable cellular and humoral immune responses. Author(s): Hocknell PK, Wiley RD, Wang X, Evans TG, Bowers WJ, Hanke T, Federoff HJ, Dewhurst S. Source: Journal of Virology. 2002 June; 76(11): 5565-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11991985&dopt=Abstract

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Extramammary Paget's disease with superimposed herpes simplex virus infection: immunohistochemical comparison with cases of the two respective diseases. Author(s): Yamamoto O, Yasuda H. Source: The British Journal of Dermatology. 2003 June; 148(6): 1258-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828759&dopt=Abstract

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Facial herpes simplex: autoinoculation by an intubation mask. Author(s): Martineau MR, Chapman MS. Source: The Journal of Trauma. 2002 August; 53(2): 389-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12169957&dopt=Abstract

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Failure to genotype herpes simplex virus by real-time PCR assay and melting curve analysis due to sequence variation within probe binding sites. Author(s): Anderson TP, Werno AM, Beynon KA, Murdoch DR. Source: Journal of Clinical Microbiology. 2003 May; 41(5): 2135-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734260&dopt=Abstract

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Famiciclovir therapy (famvir) for herpes simplex and herpes zoster infections. Author(s): Tyring S. Source: Skin Therapy Letter. 2001 November; 6(12): 1-2, 5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11753535&dopt=Abstract

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Familial herpes simplex encephalitis. Author(s): Jackson AC, Melanson M, Rossiter JP. Source: Annals of Neurology. 2002 March; 51(3): 406-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11891839&dopt=Abstract

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Fatal disseminated herpes simplex virus infection in a previously healthy pregnant woman. A case report. Author(s): Frederick DM, Bland D, Gollin Y. Source: J Reprod Med. 2002 July; 47(7): 591-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12170540&dopt=Abstract

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Fatal herpes simplex virus hepatitis complicating chemotherapy with weekly docetaxel. Author(s): Hofer S, Hunziker S, Tornillo L, Ludwig CU. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 February; 14(2): 340. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562665&dopt=Abstract

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Fate of the inner nuclear membrane protein lamin B receptor and nuclear lamins in herpes simplex virus type 1 infection. Author(s): Scott ES, O'Hare P. Source: Journal of Virology. 2001 September; 75(18): 8818-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11507226&dopt=Abstract

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Fetal demise due to herpes simplex virus: an illustrated case report. Author(s): Barefoot KH, Little GA, Ornvold KT. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2002 January; 22(1): 86-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11840250&dopt=Abstract

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Findings in a patient with herpes simplex viral meningitis associated with acute retinal necrosis syndrome. Author(s): Tada Y, Negoro K, Morimatsu M, Makino H, Nishida T. Source: Ajnr. American Journal of Neuroradiology. 2001 August; 22(7): 1300-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11498417&dopt=Abstract

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Five cases of fulminant hepatitis due to herpes simplex virus in adults. Author(s): Pinna AD, Rakela J, Demetris AJ, Fung JJ. Source: Digestive Diseases and Sciences. 2002 April; 47(4): 750-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11991604&dopt=Abstract

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Florid CD4+, CD56+ T-cell infiltrate associated with Herpes simplex infection simulating nasal NK-/T-cell lymphoma. Author(s): Taddesse-Heath L, Feldman JI, Fahle GA, Fischer SH, Sorbara L, Raffeld M, Jaffe ES. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 2003 February; 16(2): 166-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591970&dopt=Abstract

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Frequency of herpes simplex virus in Syria based on type-specific serological assay. Author(s): Ibrahim AI, Kouwatli KM, Obeid MT. Source: Saudi Med J. 2000 April; 21(4): 355-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11533818&dopt=Abstract

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Frequency of herpes simplex virus, cytomegalovirus and human papillomavirus DNA in semen. Author(s): Aynaud O, Poveda JD, Huynh B, Guillemotonia A, Barrasso R. Source: International Journal of Std & Aids. 2002 August; 13(8): 547-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12194737&dopt=Abstract

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Friendly fire: redirecting herpes simplex virus-1 for therapeutic applications. Author(s): Advani SJ, Weichselbaum RR, Whitley RJ, Roizman B. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2002 September; 8(9): 551-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427216&dopt=Abstract

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Frontal impairment and confabulation after herpes simplex encephalitis: A case report. Author(s): Del Grosso Destreri N, Farina E, Calabrese E, Pinardi G, Imbornone E, Mariani C. Source: Archives of Physical Medicine and Rehabilitation. 2002 March; 83(3): 423-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11887126&dopt=Abstract

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Fulminant course of herpes simplex virus reactivation in an apparently immunocompetent woman. Author(s): Tischendorf JJ, Grosse V, Flik J, Verhagen W, Manns MP, Trautwein C. Source: International Journal of Infectious Diseases : Ijid : Official Publication of the International Society for Infectious Diseases. 2003 June; 7(2): 160-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839720&dopt=Abstract

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Fulminant hepatic failure due to herpes simplex after hysteroscopy. Author(s): Price TM, Harris JB. Source: Obstetrics and Gynecology. 2001 November; 98(5 Pt 2): 954-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11704219&dopt=Abstract

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Fulminant hepatic failure from herpes simplex in pregnancy. Author(s): Nagappan R, Parkin G, Simpson I, Sievert W. Source: The Medical Journal of Australia. 2002 June 17; 176(12): 595-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12064959&dopt=Abstract

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Function of dynein and dynactin in herpes simplex virus capsid transport. Author(s): Dohner K, Wolfstein A, Prank U, Echeverri C, Dujardin D, Vallee R, Sodeik B. Source: Molecular Biology of the Cell. 2002 August; 13(8): 2795-809. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12181347&dopt=Abstract

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Functional characterization of the HveA homolog specified by African green monkey kidney cells with a herpes simplex virus expressing the green fluorescence protein. Author(s): Foster TP, Chouljenko VN, Kousoulas KG. Source: Virology. 1999 June 5; 258(2): 365-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10366573&dopt=Abstract

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Ganciclovir and penciclovir, but not acyclovir, induce apoptosis in herpes simplex virus thymidine kinase-transformed baby hamster kidney cells. Author(s): Shaw MM, Gurr WK, Watts PA, Littler E, Field HJ. Source: Antivir Chem Chemother. 2001 May; 12(3): 175-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959326&dopt=Abstract

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Gene delivery using herpes simplex virus vectors. Author(s): Burton EA, Fink DJ, Glorioso JC. Source: Dna and Cell Biology. 2002 December; 21(12): 915-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573050&dopt=Abstract

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Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors. Author(s): Yenari MA, Dumas TC, Sapolsky RM, Steinberg GK. Source: Neurological Research. 2001 July; 23(5): 543-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11474812&dopt=Abstract

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Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors. Author(s): Yenari MA, Dumas TC, Sapolsky RM, Steinberg GK. Source: Annals of the New York Academy of Sciences. 2001 June; 939: 340-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11462790&dopt=Abstract

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Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase. Author(s): Barzon L, Bonaguro R, Castagliuolo I, Chilosi M, Franchin E, Del Vecchio C, Giaretta I, Boscaro M, Palu G. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 January; 148(1): 73-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534360&dopt=Abstract

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Gene therapy with herpes simplex virus vectors: progress and prospects for clinical neuroscience. Author(s): Latchman DS. Source: The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry. 2001 December; 7(6): 528-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11765130&dopt=Abstract

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General and specific alterations in programming of global viral gene expression during infection by VP16 activation-deficient mutants of herpes simplex virus type 1. Author(s): Yang WC, Devi-Rao GV, Ghazal P, Wagner EK, Triezenberg SJ. Source: Journal of Virology. 2002 December; 76(24): 12758-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438601&dopt=Abstract

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Generation of fusion genes carrying drug resistance, green fluorescent protein, and herpes simplex virus thymidine kinase genes in a single cistron. Author(s): Oh SC, Nam SY, Kwon HC, Kim CM, Seo JS, Seong RH, Jang YJ, Chung YH, Chung HY. Source: Molecules and Cells. 2001 April 30; 11(2): 192-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11355700&dopt=Abstract

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Genetic characterization of thymidine kinase from acyclovir-resistant and susceptible herpes simplex virus type 1 isolated from bone marrow transplant recipients. Author(s): Morfin F, Souillet G, Bilger K, Ooka T, Aymard M, Thouvenot D. Source: The Journal of Infectious Diseases. 2000 July; 182(1): 290-3. Epub 2000 June 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10882609&dopt=Abstract

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Genetically engineered herpes simplex viral vectors in the treatment of brain tumors: a review. Author(s): Aghi M, Chiocca EA. Source: Cancer Investigation. 2003 April; 21(2): 278-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12743992&dopt=Abstract

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Genetically engineered human herpes simplex virus in the treatment of brain tumours. Author(s): Markert JM, Parker JN, Gillespie GY, Whitley RJ. Source: Herpes : the Journal of the Ihmf. 2001 March; 8(1): 17-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11867012&dopt=Abstract

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Genital herpes simplex infections: some therapeutic dilemmas. Author(s): Mills J, Mindel A. Source: Sexually Transmitted Diseases. 2003 March; 30(3): 232-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616142&dopt=Abstract

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Genital herpes simplex virus infection in the adolescent: special considerations for management. Author(s): Stanberry LR, Rosenthal SL. Source: Paediatric Drugs. 2002; 4(5): 291-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11994034&dopt=Abstract

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Genital herpes simplex virus type 1 infection: new fields for an old acquaintance? Author(s): Lippelt L, Braun RW, Kuhn JE. Source: Intervirology. 2002; 45(1): 2-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11937764&dopt=Abstract

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Genital shedding of herpes simplex virus among men. Author(s): Wald A, Zeh J, Selke S, Warren T, Ashley R, Corey L. Source: The Journal of Infectious Diseases. 2002 October 15; 186 Suppl 1: S34-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353185&dopt=Abstract

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Genital shedding of herpes simplex virus-2 DNA and HIV-1 RNA and proviral DNA in HIV-1- and herpes simplex virus-2-coinfected African women. Author(s): Mbopi-Keou FX, Legoff J, Gresenguet G, Si-Mohamed A, Matta M, Mayaud P, Andreoletti L, Malkin JE, Weiss H, Brown D, Belec L. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2003 June 1; 33(2): 121-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794542&dopt=Abstract

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Genotyping of herpes simplex virus type 1 strains isolated from ocular materials of patients with herpetic keratitis. Author(s): Umene K, Inoue T, Inoue Y, Shimomura Y. Source: Journal of Medical Virology. 2003 September; 71(1): 75-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858412&dopt=Abstract

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Glycoprotein B from strain 17 of herpes simplex virus type I contains an invariant chain homologous sequence that binds to MHC class II molecules. Author(s): Sievers E, Neumann J, Raftery M, SchOnrich G, Eis-Hubinger AM, Koch N. Source: Immunology. 2002 September; 107(1): 129-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12225371&dopt=Abstract

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Glycosaminoglycan-binding ability is a feature of wild-type strains of herpes simplex virus type 1. Author(s): Trybala E, Roth A, Johansson M, Liljeqvist JA, Rekabdar E, Larm O, Bergstrom T. Source: Virology. 2002 October 25; 302(2): 413-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12441085&dopt=Abstract

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Graft failure in human donor corneas due to transmission of herpes simplex virus. Author(s): Biswas S, Suresh P, Bonshek RE, Corbitt G, Tullo AB, Ridgway AE. Source: The British Journal of Ophthalmology. 2000 July; 84(7): 701-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10873977&dopt=Abstract

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Herpes simplex encephalitis and radiotherapy. Author(s): Riel-Romero RM, Baumann RJ. Source: Pediatric Neurology. 2003 July; 29(1): 69-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679127&dopt=Abstract

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Herpes simplex encephalitis. Author(s): Hu Z, Yang Q, Bo X, Li J. Source: Lancet. 2003 July 26; 362(9380): 280. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892957&dopt=Abstract

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Herpes simplex encephalitis. A study of seven patients and their immunological response prior to routine acyclovir treatment. Author(s): Bell JB, Davies RA, Thompson EJ. Source: The Journal of Infection. 2003 August; 47(2): 161-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860151&dopt=Abstract

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Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions. Author(s): Burt RK, Drobyski WR, Seregina T, Traynor A, Oyama Y, Keever-Taylor C, Stefka J, Kuzel TM, Brush M, Rodriquez J, Burns W, Tennant L, Link C. Source: Experimental Hematology. 2003 October; 31(10): 903-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14550806&dopt=Abstract

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Herpes simplex type-1 virus infection. Author(s): Huber MA. Source: Quintessence Int. 2003 June; 34(6): 453-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859090&dopt=Abstract

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Herpes simplex virus and Meniere's disease. Author(s): Vrabec JT. Source: The Laryngoscope. 2003 September; 113(9): 1431-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12972911&dopt=Abstract

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Herpes simplex virus causing superficial wound infection in total hip arthroplasty. Author(s): Alexander P, Wismer D. Source: The Journal of Arthroplasty. 2003 June; 18(4): 516-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820099&dopt=Abstract

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Herpes simplex virus DNA in corneal transplants: prospective study of 38 recipients. Author(s): Robert PY, Adenis JP, Denis F, Alain S, Ranger-Rogez S. Source: Journal of Medical Virology. 2003 September; 71(1): 69-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858411&dopt=Abstract

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Herpes simplex virus glycoproteins gD and gE/gI serve essential but redundant functions during acquisition of the virion envelope in the cytoplasm. Author(s): Farnsworth A, Goldsmith K, Johnson DC. Source: Journal of Virology. 2003 August; 77(15): 8481-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857917&dopt=Abstract

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Herpes simplex virus infections of the central nervous system. Author(s): Kimberlin DW. Source: Seminars in Pediatric Infectious Diseases. 2003 April; 14(2): 83-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881795&dopt=Abstract

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Herpes simplex virus triggers activation of calcium-signaling pathways. Author(s): Cheshenko N, Del Rosario B, Woda C, Marcellino D, Satlin LM, Herold BC. Source: The Journal of Cell Biology. 2003 October 27; 163(2): 283-93. Epub 2003 Oct 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14568989&dopt=Abstract

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Herpes simplex virus type 1 exhibits a tropism for basal entry in polarized epithelial cells. Author(s): Schelhaas M, Jansen M, Haase I, Knebel-Morsdorf D. Source: The Journal of General Virology. 2003 September; 84(Pt 9): 2473-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917468&dopt=Abstract

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Herpes simplex virus type 1 glycoprotein B sorting in hippocampal neurons. Author(s): Potel C, Kaelin K, Danglot L, Triller A, Vannier C, Rozenberg F. Source: The Journal of General Virology. 2003 October; 84(Pt 10): 2613-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679595&dopt=Abstract

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Herpes simplex virus type 1 targets the MHC class II processing pathway for immune evasion. Author(s): Neumann J, Eis-Hubinger AM, Koch N. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 September 15; 171(6): 307583. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12960333&dopt=Abstract

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Herpes simplex virus type 1 tegument protein VP22 interacts with TAF-I proteins and inhibits nucleosome assembly but not regulation of histone acetylation by INHAT. Author(s): van Leeuwen H, Okuwaki M, Hong R, Chakravarti D, Nagata K, O'Hare P. Source: The Journal of General Virology. 2003 September; 84(Pt 9): 2501-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917472&dopt=Abstract

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Herpes simplex virus type 2 as a cause of severe meningitis in immunocompromised adults. Author(s): Mommeja-Marin H, Lafaurie M, Scieux C, Galicier L, Oksenhendler E, Molina JM. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 December 1; 37(11): 1527-33. Epub 2003 November 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14614676&dopt=Abstract

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Herpes simplex virus type 2 seropositivity in a sexually transmitted disease clinic in Israel. Author(s): Feldman PA, Steinberg J, Madeb R, Bar G, Nativ O, Tal J, Srugo I. Source: Isr Med Assoc J. 2003 September; 5(9): 626-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14509150&dopt=Abstract

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Herpes simplex virus vectors for Parkinson's disease. Author(s): Latchman DS. Source: Int Rev Neurobiol. 2003; 55: 223-41. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968539&dopt=Abstract

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Herpes simplex virus-associated sepsis in a previously infected immunocompetent adult. Author(s): Zahariadis G, Jerome KR, Corey L. Source: Annals of Internal Medicine. 2003 July 15; 139(2): 153-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859170&dopt=Abstract

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Hypertrophic herpes simplex virus in HIV patients. Author(s): Fangman WL, Rao CH, Myers SA. Source: J Drugs Dermatol. 2003 April; 2(2): 198-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852374&dopt=Abstract

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Identification of a novel human sand family protein in human fibroblasts induced by herpes simplex virus 1 binding. Author(s): Dong S, Dong C, Liu L, Che Y, Sun M, Hu F, Li J, Li Q. Source: Acta Virol. 2003; 47(1): 27-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828340&dopt=Abstract

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Identification of herpes simplex virus DNA and lack of human herpesvirus-8 DNA in mycosis fungoides. Author(s): Erkek E, Senturk N, Dincer I, Olut AI, Kocagoz T, Bukulmez G, Sahin S. Source: Acta Dermato-Venereologica. 2002; 82(3): 214-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353718&dopt=Abstract

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Identification of herpes simplex virus type 1 latency-associated transcript sequences that both inhibit apoptosis and enhance the spontaneous reactivation phenotype. Author(s): Jin L, Peng W, Perng GC, Brick DJ, Nesburn AB, Jones C, Wechsler SL. Source: Journal of Virology. 2003 June; 77(11): 6556-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12743314&dopt=Abstract

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Identification, localization, and regulation of expression of the UL24 protein of herpes simplex virus type 1. Author(s): Pearson A, Coen DM. Source: Journal of Virology. 2002 November; 76(21): 10821-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368325&dopt=Abstract

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Imaging of the varicella zoster virion in the viral highways: comparison with herpes simplex viruses 1 and 2, cytomegalovirus, pseudorabies virus, and human herpes viruses 6 and 7. Author(s): Padilla JA, Nii S, Grose C. Source: Journal of Medical Virology. 2003; 70 Suppl 1: S103-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627497&dopt=Abstract

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Impact of process conditions on the centrifugal recovery of a disabled herpes simplex virus. Author(s): Lotfian P, Levy MS, Coffin RS, Fearn T, Ayazi-Shamlou P. Source: Biotechnology Progress. 2003 January-February; 19(1): 209-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573027&dopt=Abstract

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In vitro antiviral activity of Phyllanthus orbicularis extracts against herpes simplex virus type 1. Author(s): Fernandez Romero JA, Del Barrio Alonso G, Romeu Alvarez B, Gutierrez Y, Valdes VS, Parra F. Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 980-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680841&dopt=Abstract

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In vitro thymidine kinase/ganciclovir-based suicide gene therapy using replication defective herpes simplex virus-1 against leukemic B-cell malignancies (MCL, HCL, BCLL). Author(s): Misumi M, Suzuki T, Moriuchi S, Glorioso JC, Bessho M. Source: Leukemia Research. 2003 August; 27(8): 695-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801527&dopt=Abstract

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Inactivated parapoxvirus ovis (Orf virus) has antiviral activity against hepatitis B virus and herpes simplex virus. Author(s): Weber O, Siegling A, Friebe A, Limmer A, Schlapp T, Knolle P, Mercer A, Schaller H, Volk HD. Source: The Journal of General Virology. 2003 July; 84(Pt 7): 1843-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810878&dopt=Abstract

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Incidence and prevalence of herpes simplex virus type 2 infection in persons seeking repeat HIV counseling and testing. Author(s): Turner KR, McFarland W, Kellogg TA, Wong E, Page-Shafer K, Louie B, Dilley J, Kent CK, Klausner J. Source: Sexually Transmitted Diseases. 2003 April; 30(4): 331-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12671554&dopt=Abstract

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Inflammatory optic neuropathy as the presenting feature of herpes simplex acute retinal necrosis. Author(s): Francis PJ, Jackson H, Stanford MR, Graham EM. Source: The British Journal of Ophthalmology. 2003 April; 87(4): 512-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12642331&dopt=Abstract

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Inhibition of herpes simplex virus 1 gene expression by designer zinc-finger transcription factors. Author(s): Papworth M, Moore M, Isalan M, Minczuk M, Choo Y, Klug A. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 February 18; 100(4): 1621-6. Epub 2003 Feb 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574501&dopt=Abstract

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Inhibition of PACT-mediated activation of PKR by the herpes simplex virus type 1 Us11 protein. Author(s): Peters GA, Khoo D, Mohr I, Sen GC. Source: Journal of Virology. 2002 November; 76(21): 11054-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368348&dopt=Abstract

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Interventions for herpes simplex virus epithelial keratitis. Author(s): Wilhelmus KR. Source: Cochrane Database Syst Rev. 2003; (3): Cd002898. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917935&dopt=Abstract

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Intracellular localization of Herpes simplex virus type 1 thymidine kinase fused to different fluorescent proteins depends on choice of fluorescent tag. Author(s): Soling A, Simm A, Rainov N. Source: Febs Letters. 2002 September 11; 527(1-3): 153-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220652&dopt=Abstract

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Intracranial hemorrhage in herpes simplex encephalitis: an unusual presentation. Author(s): Erdem G, Vanderford PA, Bart RD. Source: Pediatric Neurology. 2002 September; 27(3): 221-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393133&dopt=Abstract

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Intrauterine herpes simplex infection. Author(s): Vasileiadis GT, Roukema HW, Romano W, Walton JC, Gagnon R. Source: American Journal of Perinatology. 2003 February; 20(2): 55-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660908&dopt=Abstract

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Involvement of apolipoprotein E in the hematogenous route of herpes simplex virus type 1 to the central nervous system. Author(s): Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F. Source: Journal of Virology. 2002 December; 76(23): 12394-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12414984&dopt=Abstract

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Ionizing radiation improves survival in mice bearing intracranial high-grade gliomas injected with genetically modified herpes simplex virus. Author(s): Bradley JD, Kataoka Y, Advani S, Chung SM, Arani RB, Gillespie GY, Whitley RJ, Markert JM, Roizman B, Weichselbaum RR. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1999 June; 5(6): 1517-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10389941&dopt=Abstract

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Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase. Author(s): Stanziale SF, Petrowsky H, Joe JK, Roberts GD, Zager JS, Gusani NJ, BenPorat L, Gonen M, Fong Y. Source: Surgery. 2002 August; 132(2): 353-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12219034&dopt=Abstract

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Kinetic analysis of glycoprotein C of herpes simplex virus types 1 and 2 binding to heparin, heparan sulfate, and complement component C3b. Author(s): Rux AH, Lou H, Lambris JD, Friedman HM, Eisenberg RJ, Cohen GH. Source: Virology. 2002 March 15; 294(2): 324-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12009874&dopt=Abstract

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Kinetics and crystal structure of the wild-type and the engineered Y101F mutant of Herpes simplex virus type 1 thymidine kinase interacting with (North)methanocarba-thymidine. Author(s): Prota A, Vogt J, Pilger B, Perozzo R, Wurth C, Marquez VE, Russ P, Schulz GE, Folkers G, Scapozza L. Source: Biochemistry. 2000 August 8; 39(31): 9597-603. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10924157&dopt=Abstract

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La Crosse encephalitis presenting like herpes simplex encephalitis in an immunocompromised adult. Author(s): Wurtz R, Paleologos N. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2000 October; 31(4): 1113-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11049801&dopt=Abstract

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LaCrosse viral encephalitis mimics herpes simplex viral encephalitis. Author(s): Sokol DK, Kleiman MB, Garg BP. Source: Pediatric Neurology. 2001 November; 25(5): 413-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11744319&dopt=Abstract

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Lactoferrin and lactoferricin inhibit Herpes simplex 1 and 2 infection and exhibit synergy when combined with acyclovir. Author(s): Andersen JH, Jenssen H, Gutteberg TJ. Source: Antiviral Research. 2003 May; 58(3): 209-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767468&dopt=Abstract

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Large-scale comparison of experimental adjuvants with herpes simplex virus vaccine reveals a correlation of protection with IgG2a and IgG2b responses. Author(s): Simms JR, Jennings R, Richardson VJ, Heath AW. Source: Journal of Medical Virology. 2002 September; 68(1): 82-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210434&dopt=Abstract

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Late recurrence of herpes simplex virus meningoencephalitis in two infants. Author(s): Mandyla H, Anagnostakis D, Koutsovitis P, Siahanidou T, Youroukos S. Source: European Journal of Pediatrics. 2001 December; 160(12): 732-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11795682&dopt=Abstract

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Latent herpes simplex virus infection of sensory neurons alters neuronal gene expression. Author(s): Kramer MF, Cook WJ, Roth FP, Zhu J, Holman H, Knipe DM, Coen DM. Source: Journal of Virology. 2003 September; 77(17): 9533-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915567&dopt=Abstract

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Latent herpes simplex virus-1 infection in SCID mice transferred with immune CD4+T cells: a new model for latency. Author(s): Minagawa H, Yanagi Y. Source: Archives of Virology. 2000; 145(11): 2259-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11205116&dopt=Abstract

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Latent multiple infections by herpes simplex virus type 1. Author(s): Fujita H. Source: Kurume Med J. 2000; 47(2): 159-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10948654&dopt=Abstract

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Limits of early diagnosis of herpes simplex encephalitis in children: a retrospective study of 38 cases. Author(s): De Tiege X, Heron B, Lebon P, Ponsot G, Rozenberg F. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 May 15; 36(10): 1335-9. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746782&dopt=Abstract

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Liver failure caused by herpes simplex virus thymidine kinase plus ganciclovir therapy is associated with mitochondrial dysfunction and mitochondrial DNA depletion. Author(s): Herraiz M, Beraza N, Solano A, Sangro B, Montoya J, Qian C, Prieto J, Bustos M. Source: Human Gene Therapy. 2003 March 20; 14(5): 463-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691611&dopt=Abstract

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Local delivery of CpG oligodeoxynucleotides induces rapid changes in the genital mucosa and inhibits replication, but not entry, of herpes simplex virus type 2. Author(s): Ashkar AA, Bauer S, Mitchell WJ, Vieira J, Rosenthal KL. Source: Journal of Virology. 2003 August; 77(16): 8948-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885911&dopt=Abstract

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Localization of a binding site for herpes simplex virus glycoprotein D on herpesvirus entry mediator C by using antireceptor monoclonal antibodies. Author(s): Krummenacher C, Baribaud I, Ponce de Leon M, Whitbeck JC, Lou H, Cohen GH, Eisenberg RJ. Source: Journal of Virology. 2000 December; 74(23): 10863-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11069980&dopt=Abstract

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Localization of the gD-binding region of the human herpes simplex virus receptor, HveA. Author(s): Whitbeck JC, Connolly SA, Willis SH, Hou W, Krummenacher C, Ponce de Leon M, Lou H, Baribaud I, Eisenberg RJ, Cohen GH. Source: Journal of Virology. 2001 January; 75(1): 171-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11119586&dopt=Abstract

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Localized herpes simplex lymphadenitis mimicking large-cell (Richter's) transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma. Author(s): Joseph L, Scott MA, Schichman SA, Zent CS. Source: American Journal of Hematology. 2001 December; 68(4): 287-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11754420&dopt=Abstract

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Long term persistence of herpes simplex virus-specific CD8+ CTL in persons with frequently recurring genital herpes. Author(s): Posavad CM, Huang ML, Barcy S, Koelle DM, Corey L. Source: Journal of Immunology (Baltimore, Md. : 1950). 2000 July 15; 165(2): 1146-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10878394&dopt=Abstract

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Longitudinal reliability of focus glycoprotein G-based type-specific enzyme immunoassays for detection of herpes simplex virus types 1 and 2 in women. Author(s): Cherpes TL, Ashley RL, Meyn LA, Hillier SL. Source: Journal of Clinical Microbiology. 2003 February; 41(2): 671-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574265&dopt=Abstract

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Longitudinal study of genital infection by herpes simplex virus type 1 in Western Scotland over 15 years. Author(s): Scoular A, Norrie J, Gillespie G, Mir N, Carman WF. Source: Bmj (Clinical Research Ed.). 2002 June 8; 324(7350): 1366-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052804&dopt=Abstract

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Long-term prophylactic antiviral therapy for recurrent herpes simplex: the controversy goes on. Author(s): Wolf R, Wolf D, Orion E, Matz H. Source: Clinics in Dermatology. 2003 March-April; 21(2): 164-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12706334&dopt=Abstract

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Lower interleukin-2 and higher serum tumor necrosis factor-a levels are associated with perimenstrual, recurrent, facial Herpes simplex infection in young women. Author(s): Mysliwska J, Trzonkowski P, Bryl E, Lukaszuk K, Mysliwski A. Source: Eur Cytokine Netw. 2000 September; 11(3): 397-406. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11022124&dopt=Abstract

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Luman, the cellular counterpart of herpes simplex virus VP16, is processed by regulated intramembrane proteolysis. Author(s): Raggo C, Rapin N, Stirling J, Gobeil P, Smith-Windsor E, O'Hare P, Misra V. Source: Molecular and Cellular Biology. 2002 August; 22(16): 5639-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12138176&dopt=Abstract

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Management of acute ulcerative and necrotising herpes simplex and zoster keratitis with amniotic membrane transplantation. Author(s): Heiligenhaus A, Li H, Hernandez Galindo EE, Koch JM, Steuhl KP, Meller D. Source: The British Journal of Ophthalmology. 2003 October; 87(10): 1215-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507749&dopt=Abstract

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Management of acyclovir-resistant herpes simplex virus. Author(s): Chilukuri S, Rosen T. Source: Dermatologic Clinics. 2003 April; 21(2): 311-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757254&dopt=Abstract

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Mandelic acid condensation polymer: novel candidate microbicide for prevention of human immunodeficiency virus and herpes simplex virus entry. Author(s): Herold BC, Scordi-Bello I, Cheshenko N, Marcellino D, Dzuzelewski M, Francois F, Morin R, Casullo VM, Anderson RA, Chany C 2nd, Waller DP, Zaneveld LJ, Klotman ME. Source: Journal of Virology. 2002 November; 76(22): 11236-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388683&dopt=Abstract

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Maternal Herpes simplex virus type 2 encephalitis following Cesarean section. Author(s): Godet C, Beby-Defaux A, Agius G, Pourrat O, Robert R. Source: The Journal of Infection. 2003 August; 47(2): 174-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860155&dopt=Abstract

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Membrane association of VP22, a herpes simplex virus type 1 tegument protein. Author(s): Brignati MJ, Loomis JS, Wills JW, Courtney RJ. Source: Journal of Virology. 2003 April; 77(8): 4888-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12663795&dopt=Abstract

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Molecular approaches to detecting herpes simplex virus and enteroviruses in the central nervous system. Author(s): Smalling TW, Sefers SE, Li H, Tang YW. Source: Journal of Clinical Microbiology. 2002 July; 40(7): 2317-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12089241&dopt=Abstract

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Molecular basis of the interactions between herpes simplex viruses and HIV-1. Author(s): Palu G, Benetti L, Calistri A. Source: Herpes : the Journal of the Ihmf. 2001 July; 8(2): 50-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11867019&dopt=Abstract

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Molecular diagnosis of herpes simplex virus infections in the central nervous system. Author(s): Tang YW, Mitchell PS, Espy MJ, Smith TF, Persing DH. Source: Journal of Clinical Microbiology. 1999 July; 37(7): 2127-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10364574&dopt=Abstract

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Morphologic, immunohistochemical, immunologic, ultrastructural, and time-related study of herpes simplex virus type 1-infected cultured human fibroblasts. Author(s): Jensen HL, Norrild B. Source: Applied Immunohistochemistry & Molecular Morphology : Aimm / Official Publication of the Society for Applied Immunohistochemistry. 2002 March; 10(1): 71-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893041&dopt=Abstract

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Multiplex polymerase chain reaction for detection of herpes simplex virus type 1, type 2, cytomegalovirus, and varicella-zoster virus in ocular viral infections. Author(s): Zhang Y, Kimura T, Fujiki K, Sakuma H, Murakami A, Kanai A. Source: Japanese Journal of Ophthalmology. 2003 May-June; 47(3): 260-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782161&dopt=Abstract

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Mutant herpes simplex virus-mediated suppression of retinoblastoma. Author(s): Kogishi J, Miyatake S, Hangai M, Akimoto M, Okazaki K, Honda Y. Source: Current Eye Research. 1999 May; 18(5): 321-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10372992&dopt=Abstract

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Mutation of the protein tyrosine kinase consensus site in the herpes simplex virus 1 alpha22 gene alters ICP22 posttranslational modification. Author(s): O'Toole JM, Aubert M, Kotsakis A, Blaho JA. Source: Virology. 2003 January 5; 305(1): 153-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504549&dopt=Abstract

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Mutation spectra of herpes simplex virus type 1 thymidine kinase mutants. Author(s): Lu Q, Hwang YT, Hwang CB. Source: Journal of Virology. 2002 June; 76(11): 5822-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11992012&dopt=Abstract

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Mutations in the N termini of herpes simplex virus type 1 and 2 gDs alter functional interactions with the entry/fusion receptors HVEM, nectin-2, and 3-O-sulfated heparan sulfate but not with nectin-1. Author(s): Yoon M, Zago A, Shukla D, Spear PG. Source: Journal of Virology. 2003 September; 77(17): 9221-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915538&dopt=Abstract

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Natural history of genital herpes simplex virus type 1 infection. Author(s): Engelberg R, Carrell D, Krantz E, Corey L, Wald A. Source: Sexually Transmitted Diseases. 2003 February; 30(2): 174-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12567178&dopt=Abstract

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Natural history of neonatal herpes simplex virus infections in the acyclovir era. Author(s): Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Soong SJ, Kiell J, Lakeman FD, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Source: Pediatrics. 2001 August; 108(2): 223-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11483781&dopt=Abstract

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Need for diagnostic screening of Herpes simplex virus in patients with nongonococcal urethritis. Author(s): Madeb R, Nativ O, Benilevi D, Feldman PA, Halachmi S, Srugo I. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2000 June; 30(6): 982-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10880323&dopt=Abstract

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Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum. Author(s): Malm G, Forsgren M. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 1999 July; 81(1): F24-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10375358&dopt=Abstract

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Neonatal herpes simplex: pulmonary and intracranial findings. Author(s): Carey BE. Source: Neonatal Netw. 2002 September-October; 21(6): 63-7. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12240514&dopt=Abstract

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Neonatal liver transplantation for fulminant hepatitis caused by herpes simplex virus type 2. Author(s): Lee WS, Kelly DA, Tanner MS, Ramani P, de Ville de Goyet J, McKiernan PJ. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 August; 35(2): 220-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12187302&dopt=Abstract

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NF-kappaB is required for apoptosis prevention during herpes simplex virus type 1 infection. Author(s): Goodkin ML, Ting AT, Blaho JA. Source: Journal of Virology. 2003 July; 77(13): 7261-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805425&dopt=Abstract

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Nodular perianal herpes simplex with prominent plasma cell infiltration. Author(s): Gubinelli E, Cocuroccia B, Lazzarotto T, Girolomoni G. Source: Sexually Transmitted Diseases. 2003 February; 30(2): 157-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12567175&dopt=Abstract

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Novel agents and strategies to treat herpes simplex virus infections. Author(s): Kleymann G. Source: Expert Opinion on Investigational Drugs. 2003 February; 12(2): 165-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556212&dopt=Abstract

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Novel mutations in the thymidine kinase and DNA polymerase genes of acyclovir and foscarnet resistant herpes simplex viruses infecting an immunocompromised patient. Author(s): Chibo D, Mijch A, Doherty R, Birch C. Source: Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. 2002 August; 25(2): 165-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12367650&dopt=Abstract

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Oct-1 is posttranslationally modified and exhibits reduced capacity to bind cognate sites at late times after infection with herpes simplex virus 1. Author(s): Advani SJ, Durand LO, Weichselbaum RR, Roizman B. Source: Journal of Virology. 2003 November; 77(22): 11927-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14581529&dopt=Abstract

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Oncolytic herpes simplex virus for tumor therapy. Author(s): Hu JC, Coffin RS. Source: Int Rev Neurobiol. 2003; 55: 165-84. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968536&dopt=Abstract

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Oncolytic herpes simplex virus vectors for cancer virotherapy. Author(s): Varghese S, Rabkin SD. Source: Cancer Gene Therapy. 2002 December; 9(12): 967-78. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522436&dopt=Abstract

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Oncolytic viral therapy for human ovarian cancer using a novel replication-competent herpes simplex virus type I mutant in a mouse model. Author(s): Nawa A, Nozawa N, Goshima F, Nagasaka T, Kikkawa F, Niwa Y, Nakanishi T, Kuzuya K, Nishiyama Y. Source: Gynecologic Oncology. 2003 October; 91(1): 81-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14529666&dopt=Abstract

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Oncolytic virus therapy using genetically engineered herpes simplex viruses. Author(s): Todo T. Source: Hum Cell. 2002 September; 15(3): 151-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12703545&dopt=Abstract

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One in the eye for herpes simplex virus. Author(s): Wood I. Source: Trends in Pharmacological Sciences. 2002 August; 23(8): 355-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12377572&dopt=Abstract

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Optimisation of herpes simplex virus-based vectors for delivery to human peripheral blood mononuclear cells. Author(s): Papageorgiou K, Isenberg DA, Latchman DS. Source: Journal of Immunological Methods. 2002 December 15; 270(2): 235-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379328&dopt=Abstract

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Oral mucosal herpes simplex ulceration in an HIV-seropositive man. Author(s): Phelan JA, Kerpel SM, Freedman PD. Source: Aids Read. 1999 January-February; 9(1): 35-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728881&dopt=Abstract

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Oral valacyclovir versus intravenous acyclovir in preventing herpes simplex virus infections in autologous stem cell transplant recipients. Author(s): Liesveld JL, Abboud CN, Ifthikharuddin JJ, Lancet JE, Wedow LA, Oliva J, Stamm CG, Nichols D. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2002; 8(12): 662-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12523578&dopt=Abstract

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Overproduction of gamma interferon in B/Jas inbred rabbits with herpes simplex virus encephalitis. Author(s): Yuasa T, Isono T, Tooyama I, Seto A. Source: Microbiology and Immunology. 1999; 43(4): 365-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10385203&dopt=Abstract

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Pathologic quiz case: multiple foci of necrosis in the liver in a patient with T-cell lymphoma. Herpes simplex virus hepatitis. Author(s): Tan G, Frankel WL, Suster S. Source: Archives of Pathology & Laboratory Medicine. 2003 August; 127(8): 1049-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873187&dopt=Abstract

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Phenotypic and genotypic methods for the detection of herpes simplex virus serotypes. Author(s): Madhavan HN, Priya K, Bagyalakshmi R. Source: Journal of Virological Methods. 2003 March; 108(1): 97-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12565159&dopt=Abstract

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PML residue lysine 160 is required for the degradation of PML induced by herpes simplex virus type 1 regulatory protein ICP0. Author(s): Boutell C, Orr A, Everett RD. Source: Journal of Virology. 2003 August; 77(16): 8686-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885887&dopt=Abstract

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Postinfectious autoimmune-mediated encephalitis eight months after herpes simplex encephalitis. Author(s): Joos AA, Ziyeh S, Rauer S, Keller E, Huzly D, Lucking CH. Source: European Neurology. 2003; 50(1): 54-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824714&dopt=Abstract

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Potentiated gene delivery to tumors using herpes simplex virus/Epstein-Barr virus/RV tribrid amplicon vectors. Author(s): Hampl JA, Camp SM, Mydlarz WK, Hampl M, Ichikawa T, Chiocca EA, Louis DN, Sena-Esteves M, Breakefield XO. Source: Human Gene Therapy. 2003 May 1; 14(7): 611-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804144&dopt=Abstract

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Prevalence of herpes simplex virus antibodies in childhood and adolescence: a crosssectional study. Author(s): Tunback P, Bergstrom T, Andersson AS, Nordin P, Krantz I, Lowhagen GB. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(8): 498-502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14514152&dopt=Abstract

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Prevention of herpes simplex virus eye disease: a cost-effectiveness analysis. Author(s): Lairson DR, Begley CE, Reynolds TF, Wilhelmus KR. Source: Archives of Ophthalmology. 2003 January; 121(1): 108-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12523894&dopt=Abstract

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Problems in the use of herpes simplex virus as a vector. Author(s): Feldman LT. Source: Int Rev Neurobiol. 2003; 55: 99-109. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968532&dopt=Abstract

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Protection by herpes simplex virus glycoprotein D against Fas-mediated apoptosis: role of nuclear factor kappaB. Author(s): Medici MA, Sciortino MT, Perri D, Amici C, Avitabile E, Ciotti M, Balestrieri E, De Smaele E, Franzoso G, Mastino A. Source: The Journal of Biological Chemistry. 2003 September 19; 278(38): 36059-67. Epub 2003 July 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12844494&dopt=Abstract

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Psychosocial impact of serological diagnosis of herpes simplex virus type 2: a qualitative assessment. Author(s): Melville J, Sniffen S, Crosby R, Salazar L, Whittington W, Dithmer-Schreck D, DiClemente R, Wald A. Source: Sexually Transmitted Infections. 2003 August; 79(4): 280-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12902574&dopt=Abstract

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Quantitation of herpes simplex DNA in blood during aciclovir therapy with competitive PCR ELISA. Author(s): Bezold G, Gottlober P, Leiter U, Kerscher M, Krahn G, Peter RU. Source: Dermatology (Basel, Switzerland). 2000; 201(4): 296-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11146337&dopt=Abstract

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Quantitation of latent varicella-zoster virus and herpes simplex virus genomes in human trigeminal ganglia. Author(s): Pevenstein SR, Williams RK, McChesney D, Mont EK, Smialek JE, Straus SE. Source: Journal of Virology. 1999 December; 73(12): 10514-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10559370&dopt=Abstract

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Quantitation of viral load in neonatal herpes simplex virus infection and comparison between type 1 and type 2. Author(s): Kimura H, Ito Y, Futamura M, Ando Y, Yabuta Y, Hoshino Y, Nishiyama Y, Morishima T. Source: Journal of Medical Virology. 2002 July; 67(3): 349-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12116026&dopt=Abstract

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Reactivation of herpes simplex keratitis during TL01 phototherapy for psoriasis. Author(s): Wong GA, Kaye SB, Parslew R. Source: Clinical and Experimental Dermatology. 2003 July; 28(4): 453-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823318&dopt=Abstract

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Recent progress in herpes simplex virus immunobiology and vaccine research. Author(s): Koelle DM, Corey L. Source: Clinical Microbiology Reviews. 2003 January; 16(1): 96-113. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525427&dopt=Abstract

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Recurrent dermatomal vesicular skin lesions: a clue to diagnosis of herpes simplex virus 2 meningitis. Author(s): Gonzales N, Tyler KL, Gilden DH. Source: Archives of Neurology. 2003 June; 60(6): 868-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810492&dopt=Abstract

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Recurrent herpes simplex labialis: selected therapeutic options. Author(s): Raborn GW, Grace MG. Source: Journal (Canadian Dental Association). 2003 September; 69(8): 498-503. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954137&dopt=Abstract

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Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. Author(s): Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 February; 74(2): 2624. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531966&dopt=Abstract

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Replication and interaction of herpes simplex virus and human papillomavirus in differentiating host epithelial tissue. Author(s): Meyers C, Andreansky SS, Courtney RJ. Source: Virology. 2003 October 10; 315(1): 43-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14592758&dopt=Abstract

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Replication-initiator protein (UL9) of the herpes simplex virus 1 binds NFB42 and is degraded via the ubiquitin-proteasome pathway. Author(s): Eom CY, Lehman IR. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 August 19; 100(17): 9803-7. Epub 2003 Aug 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904574&dopt=Abstract

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Resolution of psychiatric symptoms secondary to herpes simplex encephalitis. Author(s): Gaber TA, Eshiett M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 August; 74(8): 1164; Author Reply 1164. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876271&dopt=Abstract

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Risk factors for infection with herpes simplex virus type 2: role of smoking, douching, uncircumcised males, and vaginal flora. Author(s): Cherpes TL, Meyn LA, Krohn MA, Hillier SL. Source: Sexually Transmitted Diseases. 2003 May; 30(5): 405-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916131&dopt=Abstract

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RNAs extracted from herpes simplex virus 1 virions: apparent selectivity of viral but not cellular RNAs packaged in virions. Author(s): Sciortino MT, Suzuki M, Taddeo B, Roizman B. Source: Journal of Virology. 2001 September; 75(17): 8105-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11483756&dopt=Abstract

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Schizophreniform disorder with cerebrospinal fluid PCR positivity for herpes simplex virus type 1. Author(s): Chiveri L, Sciacco M, Prelle A. Source: European Neurology. 2003; 50(3): 182-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530627&dopt=Abstract

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Secreted portion of glycoprotein g of herpes simplex virus type 2 is a novel antigen for type-discriminating serology. Author(s): Gorander S, Svennerholm B, Liljeqvist JA. Source: Journal of Clinical Microbiology. 2003 August; 41(8): 3681-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904375&dopt=Abstract

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Seroprevalence and correlates of herpes simplex virus type 2 among urban Tanzanian women. Author(s): Msuya SE, Mbizvo E, Hussain A, Sam NE, Jeansson S, Stray-Pedersen B. Source: Sexually Transmitted Diseases. 2003 July; 30(7): 588-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838089&dopt=Abstract

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Sero-prevalence of Herpes simplex virus type 2 (HSV-2) in Rakai district, Uganda. Author(s): Emonyi IW, Gray RH, Zenilman J, Schmidt K, Wawer MJ, Sewankambo KN, Serwadda D, Kiwanuka N, Nalugoda F. Source: East Afr Med J. 2000 August; 77(8): 428-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12862067&dopt=Abstract

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Sexual and demographic risk factors for herpes simplex virus type 2 according to schooling level among Mexican youths. Author(s): Abraham CD, Conde-Glez CJ, Cruz-Valdez A, Sanchez-Zamorano L, Hernandez-Marquez C, Lazcano-Ponce E. Source: Sexually Transmitted Diseases. 2003 July; 30(7): 549-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838082&dopt=Abstract

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Socio-demographic characteristics and sex practices related to herpes simplex virus type 2 infection in Mexican and Central American female sex workers. Author(s): Uribe-Salas F, Conde-Glez CJ, Juarez-Figueroa L, Hernandez-Castellanos A. Source: Epidemiology and Infection. 2003 October; 131(2): 859-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14596526&dopt=Abstract

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Specific association of glycoprotein B with lipid rafts during herpes simplex virus entry. Author(s): Bender FC, Whitbeck JC, Ponce de Leon M, Lou H, Eisenberg RJ, Cohen GH. Source: Journal of Virology. 2003 September; 77(17): 9542-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915568&dopt=Abstract

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Structure-based mutagenesis of herpes simplex virus glycoprotein D defines three critical regions at the gD-HveA/HVEM binding interface. Author(s): Connolly SA, Landsburg DJ, Carfi A, Wiley DC, Cohen GH, Eisenberg RJ. Source: Journal of Virology. 2003 July; 77(14): 8127-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829851&dopt=Abstract

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Suppression of human papillomavirus gene expression in vitro and in vivo by herpes simplex virus type 2 infection. Author(s): Fang L, Ward MG, Welsh PA, Budgeon LR, Neely EB, Howett MK. Source: Virology. 2003 September 15; 314(1): 147-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517068&dopt=Abstract

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Sweet's syndrome associated with Mycobacterium chelonae and herpes simplex virus infections: a case report. Author(s): Theng TS, Chan YC, Leow YH, Tan SH. Source: Ann Acad Med Singapore. 2003 May; 32(3): 411-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854387&dopt=Abstract

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Tetracycline-regulated gene expression in replication-incompetent herpes simplex virus vectors. Author(s): Schmeisser F, Donohue M, Weir JP. Source: Human Gene Therapy. 2002 December 10; 13(18): 2113-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12542843&dopt=Abstract

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The degradation of promyelocytic leukemia and Sp100 proteins by herpes simplex virus 1 is mediated by the ubiquitin-conjugating enzyme UbcH5a. Author(s): Gu H, Roizman B. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 July 22; 100(15): 8963-8. Epub 2003 Jul 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12855769&dopt=Abstract

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The dual role of CD8+ T lymphocytes in the development of stress-induced herpes simplex encephalitis. Author(s): Anglen CS, Truckenmiller ME, Schell TD, Bonneau RH. Source: Journal of Neuroimmunology. 2003 July; 140(1-2): 13-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12864968&dopt=Abstract

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The gene that encodes the herpes simplex virus type 1 latency-associated transcript influences the accumulation of transcripts (Bcl-x(L) and Bcl-x(S)) that encode apoptotic regulatory proteins. Author(s): Peng W, Henderson G, Perng GC, Nesburn AB, Wechsler SL, Jones C. Source: Journal of Virology. 2003 October; 77(19): 10714-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970460&dopt=Abstract

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The herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 interacts with and Ubiquitinates p53. Author(s): Boutell C, Everett RD. Source: The Journal of Biological Chemistry. 2003 September 19; 278(38): 36596-602. Epub 2003 July 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12855695&dopt=Abstract

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The interaction between dendritic cells and herpes simplex virus-1. Author(s): Kobelt D, Lechmann M, Steinkasserer A. Source: Curr Top Microbiol Immunol. 2003; 276: 145-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797447&dopt=Abstract

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The prevalence of Herpes simplex virus type-2 infection in blood donors in Harare, Zimbabwe. Author(s): Gwanzura L, Chigonda TG, Mvere D, De Villiers DM, Siziya S, Mason PR. Source: Cent Afr J Med. 2002 March-April; 48(3-4): 38-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12971156&dopt=Abstract

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The R1 subunit of herpes simplex virus ribonucleotide reductase has chaperone-like activity similar to Hsp27. Author(s): Chabaud S, Lambert H, Sasseville AM, Lavoie H, Guilbault C, Massie B, Landry J, Langelier Y. Source: Febs Letters. 2003 June 19; 545(2-3): 213-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804778&dopt=Abstract

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The replication-competent oncolytic herpes simplex mutant virus NV1066 is effective in the treatment of esophageal cancer. Author(s): Stiles BM, Bhargava A, Adusumilli PS, Stanziale SF, Kim TH, Rusch VW, Fong Y. Source: Surgery. 2003 August; 134(2): 357-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12947341&dopt=Abstract

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Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. Author(s): Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Source: The Journal of Experimental Medicine. 2003 August 4; 198(3): 513-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900525&dopt=Abstract

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Ultrastructural localization of the herpes simplex virus type 1 UL31, UL34, and US3 proteins suggests specific roles in primary envelopment and egress of nucleocapsids. Author(s): Reynolds AE, Wills EG, Roller RJ, Ryckman BJ, Baines JD. Source: Journal of Virology. 2002 September; 76(17): 8939-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163613&dopt=Abstract

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Uncontrolled herpes simplex virus-2 as a cofactor in HIV transmission. Author(s): Gisselquist D, Potterat JJ. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2003 May 1; 33(1): 119-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792367&dopt=Abstract

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Unilateral acute retinal necrosis occurring 2 years after herpes simplex type 1 encephalitis. Author(s): Kim C, Yoon YH. Source: Ophthalmic Surgery and Lasers. 2002 May-June; 33(3): 250-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12027110&dopt=Abstract

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Unusual herpes simplex virus infection mimicking foreign body reaction after cosmetic lip augmentation with expanded polytetrafluoroethylene threads. Author(s): Rudolph CM, Mullegger RR, Schuller-Petrovic S, Kerl H, Soyer HP. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2003 February; 29(2): 195-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562355&dopt=Abstract

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Unusual, rapidly growing ulcerative genital mass due to herpes simplex virus in a human immunodeficiency virus-infected woman. Author(s): Lanzafame M, Mazzi R, Di Pace C, Trevenzoli M, Concia E, Vento S. Source: The British Journal of Dermatology. 2003 July; 149(1): 216-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12890233&dopt=Abstract

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Use of a single monoclonal antibody to determine the susceptibilities of herpes simplex virus type 1 and type 2 clinical isolates to acyclovir. Author(s): Chutkowski C, Olson B, McDonough A, Mahoney J, McSharry JJ. Source: Clinical and Diagnostic Laboratory Immunology. 2002 November; 9(6): 1379-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12414779&dopt=Abstract

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Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer. Author(s): Coukos G, Makrigiannakis A, Kang EH, Caparelli D, Benjamin I, Kaiser LR, Rubin SC, Albelda SM, Molnar-Kimber KL. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1999 June; 5(6): 1523-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10389942&dopt=Abstract

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Use of immunostimulatory sequence-containing oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection. Author(s): Pyles RB, Higgins D, Chalk C, Zalar A, Eiden J, Brown C, Van Nest G, Stanberry LR. Source: Journal of Virology. 2002 November; 76(22): 11387-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388699&dopt=Abstract

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Use of the herpes simplex viral genome to construct gene therapy vectors. Author(s): Burton EA, Huang S, Goins WF, Glorioso JC. Source: Methods in Molecular Medicine. 2003; 76: 1-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526156&dopt=Abstract

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Use of the highly sensitive PCR method to detect the Herpes simplex virus type 1 genome and its expression in samples from Behcet disease patients. Author(s): Nomura Y, Kitteringham N, Shiba K, Goseki M, Kimura A, Mineshita S. Source: J Med Dent Sci. 1998 March; 45(1): 51-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12160245&dopt=Abstract

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Val193 and Phe195 of the gamma 1 34.5 protein of herpes simplex virus 1 are required for viral resistance to interferon-alpha/beta. Author(s): Cheng G, Brett ME, He B. Source: Virology. 2001 November 10; 290(1): 115-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11882996&dopt=Abstract

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Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Author(s): Conant MA, Schacker TW, Murphy RL, Gold J, Crutchfield LT, Crooks RJ; International Valaciclovir HSV Study Group. Source: International Journal of Std & Aids. 2002 January; 13(1): 12-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11802924&dopt=Abstract

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Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years' experience with acyclovir. Author(s): Tyring SK, Baker D, Snowden W. Source: The Journal of Infectious Diseases. 2002 October 15; 186 Suppl 1: S40-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353186&dopt=Abstract

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Valacyclovir in the treatment of facial herpes simplex virus infection. Author(s): Laiskonis A, Thune T, Neldam S, Hiltunen-Back E. Source: The Journal of Infectious Diseases. 2002 October 15; 186 Suppl 1: S66-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353189&dopt=Abstract

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Valacyclovir prophylaxis for herpes simplex virus infection or infection recurrence following laser skin resurfacing. Author(s): Beeson WH, Rachel JD. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2002 April; 28(4): 331-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11966791&dopt=Abstract

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Valacyclovir prophylaxis for the prevention of Herpes simplex virus reactivation in recipients of progenitor cells transplantation. Author(s): Dignani MC, Mykietiuk A, Michelet M, Intile D, Mammana L, Desmery P, Milone G, Pavlovsky S. Source: Bone Marrow Transplantation. 2002 February; 29(3): 263-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11859400&dopt=Abstract

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Viral infections of the CNS with special emphasis on herpes simplex infections. Author(s): Schmutzhard E. Source: Journal of Neurology. 2001 June; 248(6): 469-77. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11499636&dopt=Abstract

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Viremia in neonatal herpes simplex virus infections. Author(s): Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Source: The Pediatric Infectious Disease Journal. 1999 June; 18(6): 487-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10391175&dopt=Abstract

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Visual outcome in herpes simplex virus and varicella zoster virus uveitis: a clinical evaluation and comparison. Author(s): Miserocchi E, Waheed NK, Dios E, Christen W, Merayo J, Roque M, Foster CS. Source: Ophthalmology. 2002 August; 109(8): 1532-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12153807&dopt=Abstract

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Voxel-based morphometry of herpes simplex encephalitis. Author(s): Gitelman DR, Ashburner J, Friston KJ, Tyler LK, Price CJ. Source: Neuroimage. 2001 April; 13(4): 623-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11305891&dopt=Abstract

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What triggers recurrences of herpes simplex keratitis. Author(s): Raizman MB. Source: Archives of Ophthalmology. 2000 December; 118(12): 1682. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11115264&dopt=Abstract

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What's your assessment? The diagnosis is herpes simplex. Author(s): Bielan B. Source: Dermatology Nursing / Dermatology Nurses' Association. 1999 April; 11(2): 123-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10670331&dopt=Abstract

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Why do we lack an effective vaccine against herpes simplex virus infections? Author(s): Deshpande SP, Kumaraguru U, Rouse BT. Source: Microbes and Infection / Institut Pasteur. 2000 July; 2(8): 973-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10962281&dopt=Abstract

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Wild-type herpes simplex virus 1 blocks programmed cell death and release of cytochrome c but not the translocation of mitochondrial apoptosis-inducing factor to the nuclei of human embryonic lung fibroblasts. Author(s): Zhou G, Roizman B. Source: Journal of Virology. 2000 October; 74(19): 9048-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10982349&dopt=Abstract

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Will taking the amino acid supplement lysine prevent or treat the herpes simplex virus? Author(s): Marcason W. Source: Journal of the American Dietetic Association. 2003 March; 103(3): 351. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616258&dopt=Abstract

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You're the flight surgeon. Herpes simplex virus type 2(HSV-2). Author(s): Fisher CR Jr. Source: Aviation, Space, and Environmental Medicine. 1999 April; 70(4): 351-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10223273&dopt=Abstract

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Zhangfei: a second cellular protein interacts with herpes simplex virus accessory factor HCF in a manner similar to Luman and VP16. Author(s): Lu R, Misra V. Source: Nucleic Acids Research. 2000 June 15; 28(12): 2446-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10871379&dopt=Abstract

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CHAPTER 2. NUTRITION AND HERPES SIMPLEX Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and herpes simplex.

Finding Nutrition Studies on Herpes Simplex The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “herpes simplex” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7 Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following information is typical of that found when using the “Full IBIDS Database” to search for “herpes simplex” (or a synonym): •

A cell type-specific and gap junction-independent mechanism for the herpes simplex virus-1 thymidine kinase gene/ganciclovir-mediated bystander effect. Author(s): Laboratory of Medical Chemistry and Medical Oncology, University of Liege, Belgium. Source: Princen, F Robe, P Lechanteur, C Mesnil, M Rigo, J M Gielen, J Merville, M P Bours, V Clin-Cancer-Res. 1999 November; 5(11): 3639-44 1078-0432

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A novel permissive role for glucocorticoids in induction of febrile and behavioral signs of experimental herpes simplex virus encephalitis. Author(s): Department of Neurology, Hadassah Hebrew University Hospital, Jerusalem, Israel. [email protected] Source: Ben Hur, T Cialic, R Itzik, A Barak, O Yirmiya, R Weidenfeld, J Neuroscience. 2001; 108(1): 119-27 0306-4522

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Aborted genital herpes simplex virus lesions: findings from a randomised controlled trial with valaciclovir. Author(s): Department of Dermatology and Venereology, University Hospital, Uppsala, Sweden. [email protected] Source: Strand, A Patel, R Wulf, H C Coates, K M Sex-Transm-Infect. 2002 December; 78(6): 435-9 1368-4973

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Activities of Korean medicinal herbs and traditional prescriptions against Herpes simplex virus type-1. Source: Kang, B.J. Lee, H.H. Kim, N.J. Kong, W.S. Park, K.J. Pharm-biol. Lisse, the Netherlands : Swets & Zeitlinger, c1998-. October 1998. volume 36 (4) page 287-294. 1388-0209

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AlaArg motif in the carboxyl terminus of the gamma(1)34.5 protein of herpes simplex virus type 1 is required for the formation of a high-molecular-weight complex that dephosphorylates eIF-2alpha. Author(s): Department of Microbiology and Immunology, College of Medicine, The University of Illinois at Chicago, Chicago, Illinois 60612, USA. Source: Cheng, G Gross, M Brett, M E He, B J-Virol. 2001 April; 75(8): 3666-74 0022-538X

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Anti-herpes simplex virus effect of an aqueous extract of propolis. Author(s): Institute for Applied Biosciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. [email protected] Source: Huleihel, M Isanu, V Isr-Med-Assoc-J. 2002 November; 4(11 Suppl): 923-7 15651088

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Antiviral activity of characterized extracts from echinacea spp. (Heliantheae: Asteraceae) against herpes simplex virus (HSV-I). Author(s): Department of Biology, University of Ottawa, Ottawa, Canada. Source: Binns, S E Hudson, J Merali, S Arnason, J T Planta-Med. 2002 September; 68(9): 780-3 0032-0943

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Asymptomatic shedding of herpes simplex virus into the oral cavity of patients with atopic dermatitis. Author(s): Department of Dermatology, School of Medicine, Kinki University, Osaka, Japan. Source: Yoshida, M Amatsu, A J-Clin-Virol. 2000 February; 16(1): 65-9 1386-6532

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Characterization and transduction of a retroviral vector encoding human interleukin4 and herpes simplex virus-thymidine kinase for glioma tumor vaccine therapy. Author(s): Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA. [email protected] Source: Okada, H Attanucci, J Tahara, H Pollack, I F Bozik, M E Chambers, W H Lotze, M T Cancer-Gene-Ther. 2000 March; 7(3): 486-94 0929-1903

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Characterization of RNA determinants recognized by the arginine- and proline-rich region of Us11, a herpes simplex virus type 1-encoded double-stranded RNA binding protein that prevents PKR activation. Author(s): Department of Microbiology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016, USA. Source: Khoo, D Perez, C Mohr, I J-Virol. 2002 December; 76(23): 11971-81 0022-538X

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Comparative bioavailability of acyclovir from oral valacyclovir and acyclovir in patients treated for recurrent genital herpes simplex virus infection. Author(s): Department of Pharmacology, University of Manitoba, Winnipeg, Canada. Source: Bras, A P Sitar, D S Aoki, F Y Can-J-Clin-Pharmacol. 2001 Winter; 8(4): 207-11 1198-581X

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Comparison of microbicides for efficacy in protecting mice against vaginal challenge with herpes simplex virus type 2, cytotoxicity, antibacterial properties, and sperm immobilization. Author(s): Population Council, New York, New York 10021, USA. Source: Maguire, R A Bergman, N Phillips, D M Sex-Transm-Dis. 2001 May; 28(5): 25965 0148-5717

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Contribution of a combination of ponicidin and acyclovir/ganciclovir to the antitumor efficacy of the herpes simplex virus thymidine kinase gene therapy system. Author(s): Department of Virology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. [email protected] Source: Hayashi, Kyoko Hayashi, Toshimitsu Sun, Han Dong Takeda, Yoshio HumGene-Ther. 2002 February 10; 13(3): 415-23 1043-0342

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Cytotoxicities and anti-herpes simplex virus activities of diterpenes isolated from Euphorbia species. Source: Mucsi, I. Molnar, J. Hohmann, J. Redei, D. Planta-med. Stuttgart : Georg Thieme Verlag,. October 2001. volume 67 (7) page 672-674. 0032-0943

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Distinct sites of opiate reward and aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1. Author(s): Division of Molecular Psychiatry, Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut 06508, USA. [email protected] Source: Carlezon, W A Haile, C N Coppersmith, R Hayashi, Y Malinow, R Neve, R L Nestler, E J J-Neurosci. 2000 March 1; 20(5): RC62 1529-2401

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Early therapy with valaciclovir or famciclovir reduces but does not abrogate herpes simplex virus neuronal latency. Author(s): Centre for Veterinary Science, Cambridge University Veterinary School. Source: Field, H J Thackray, A M Nucleosides-Nucleotides-Nucleic-Acids. 2000 JanFebruary; 19(1-2): 461-70 1525-7770

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Enhancement of the herpes simplex virus thymidine kinase/ganciclovir bystander effect and its antitumor efficacy in vivo by pharmacologic manipulation of gap junctions. Author(s): Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Source: Touraine, R L Vahanian, N Ramsey, W J Blaese, R M Hum-Gene-Ther. 1998 November 1; 9(16): 2385-91 1043-0342

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Environmental influence on immune inhibition of release of herpes simplex virus from cells. Author(s): Department of Infection, Medical School, University of Birmingham, Birmingham, UK. [email protected] Source: Benitez, J Ahmad, A Davies, J Skinner, G R Intervirology. 1998; 41(2-3): 120-6 0300-5526

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Establishment of a quiescent herpes simplex virus type 1 infection in neurallydifferentiated PC12 cells. Author(s): Department of Oral Health Practice, University of Kentucky College of Dentistry, Lexington 40536-0084, USA. Source: Danaher, R J Jacob, R J Miller, C S J-Neurovirol. 1999 June; 5(3): 258-67 1355-0284

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Expression of herpes simplex virus glycoprotein B gene in yeast. Source: Nozaki, C. Makizumi, K. Kino, Y. Nakatake, H. Eto, T. Mizuno, K. Hamada, F. Ohtomo, N. Virus-Res. Amsterdam : Elsevier Science Publishers B.V. December 1985. volume 4 (1) page 107-113. 0168-1702

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Gene therapy of bladder pain with herpes simplex virus (HSV) vectors expressing preproenkephalin (PPE). Author(s): Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Source: Yoshimura, N Franks, M E Sasaki, K Goins, W F Goss, J Yokoyama, T Fraser, M O Seki, S Fink, J Glorioso, J de Groat, W C Chancellor, M B Urology. 2001 June; 57(6 Suppl 1): 116 1527-9995

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Genital herpes simplex virus infection in the adolescent: special considerations for management. Author(s): Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas 77555-0351, USA. [email protected] Source: Stanberry, L R Rosenthal, S L Paediatr-Drugs. 2002; 4(5): 291-7 1174-5878

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Heat stress activates production of herpes simplex virus type 1 from quiescently infected neurally differentiated PC12 cells. Author(s): Department of Oral Health Practice, University of Kentucky College of Dentistry, Lexington 40536-0297, USA. Source: Danaher, R J Jacob, R J Chorak, M D Freeman, C S Miller, C S J-Neurovirol. 1999 August; 5(4): 374-83 1355-0284

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Herpes simplex virus infection. Author(s): Department of Pediatrics, University of Alabama at Birmingham, USA. [email protected] Source: Whitley, R J Semin-Pediatr-Infect-Dis. 2002 January; 13(1): 6-11 1045-1870

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Histologic and immunohistochemical analysis of tissue response to adenovirusmediated herpes simplex thymidine kinase gene therapy of ovarian cancer. Author(s): Department of Obstetrics and Gynecology, Freiburg University Medical Center, Hugstetter Strasse 55, D-79106 Freiburg, Germany. [email protected] Source: Hasenburg, A Fischer, D C Tong, X W Rojas Martinez, A Nyberg Hoffman, C Orlowska Volk, M Kohlberger, P Kaufman, R H Ramzy, I Aguilar Cordova, E Kieback, D G Int-J-Gynecol-Cancer. 2002 Jan-February; 12(1): 66-73 1048-891X

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Hydroxyurea significantly enhances tumor growth delay in vivo with herpes simplex virus thymidine kinase/ganciclovir gene therapy. Author(s): Department of Pharmacology, University of Michigan Medical Center, Ann Arbor 48109-0504, USA. Source: Boucher, P D Ostruszka, L J Murphy, P J M Shewach, D S Gene-Ther. 2002 August; 9(15): 1023-30 0969-7128

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ICP27 interacts with the RNA export factor Aly/REF to direct herpes simplex virus type 1 intronless mRNAs to the TAP export pathway. Author(s): Department of Microbiology and Molecular Genetics, Medical Sciences I, College of Medicine, University of California, Irvine, CA 92697-4025, USA. Source: Chen, I H Sciabica, K S Sandri Goldin, R M J-Virol. 2002 December; 76(24): 12877-89 0022-538X

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In vitro antiviral effect of flavonoid-rich extracts of Vitex polygama (Verbenaceae) against acyclovir-resistant herpes simplex virus type 1. Author(s): Instituto de Microbiologia Professor Paulo de Goes, Departamento de Virologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Source: Goncalves, J L Leitao, S G Monache, F D Miranda, M M Santos, M G Romanos, M T Wigg, M D Phytomedicine. 2001 November; 8(6): 477-80 0944-7113

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Induction and prevention of apoptosis in human HEp-2 cells by herpes simplex virus type 1. Author(s): Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA. Source: Aubert, M O'Toole, J Blaho, J A J-Virol. 1999 December; 73(12): 10359-70 0022538X

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Infection due to acyclovir resistant herpes simplex virus in patients undergoing allogeneic hematopoietic stem cell transplantation. Author(s): Unite mixte de recherche 7565 UHP-CNRS, laboratoire de bacteriologievirologie, faculte de medecine, Vandoeuvre-les-Nancy, France. [email protected] Source: Venard, V Dauendorffer, J N Carret, A S Corsaro, D Edert, D Bordigoni, P Le Faou, A Pathol-Biol-(Paris). 2001 September; 49(7): 553-8 0369-8114

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Infection of human NT2 cells and differentiated NT-neurons with herpes simplex virus and replication-incompetent herpes simplex virus vectors. Author(s): Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. Source: Weir, J P J-Neurovirol. 2001 February; 7(1): 43-51 1355-0284

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Inhibitory effect of anti-pyretic and anti-inflammatory herbs on herpes simplex virus replication. Author(s): Department of Microbiology, China Medical College, Taichung, Taiwan. Source: Hsiang, C Y Hsieh, C L Wu, S L Lai, I L Ho, T Y Am-J-Chin-Med. 2001; 29(3-4): 459-67 0192-415X

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Interleukin-18 protects mice against acute herpes simplex virus type 1 infection. Author(s): Fujisaki Institute, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan. Source: Fujioka, N Akazawa, R Ohashi, K Fujii, M Ikeda, M Kurimoto, M J-Virol. 1999 March; 73(3): 2401-9 0022-538X

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Interrelation of diet and herpes simplex virus pathogenesis in mice. Source: Fischer, K.J. Wright, S.M. Kelleher, J.J. Proc-N-D-Acad-Sci. Grand Forks, N.D. : The Academy. April 1988. volume 42 page 48. 0096-9214

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Local periocular vaccination protects against eye disease more effectively than systemic vaccination following primary ocular herpes simplex virus infection in rabbits. Author(s): Ophthalmology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA. Source: Nesburn, A B Slanina, S Burke, R L Ghiasi, H Bahri, S Wechsler, S L J-Virol. 1998 October; 72(10): 7715-21 0022-538X

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Mapping of functional regions in the amino-terminal portion of the herpes simplex virus ICP27 regulatory protein: importance of the leucine-rich nuclear export signal and RGG Box RNA-binding domain. Author(s): Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. Source: Lengyel, J Guy, C Leong, V Borge, S Rice, S A J-Virol. 2002 December; 76(23): 11866-79 0022-538X

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Metal complexes of bovine lactoferrin inhibit in vitro replication of herpes simplex virus type 1 and 2. Author(s): Institute of Microbiology, University of Rome La Sapienza, Italy. Source: Marchetti, M Pisani, S Antonini, G Valenti, P Seganti, L Orsi, N Biometals. 1998 April; 11(2): 89-94 0966-0844

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Microtubule reorganization during herpes simplex virus type 1 infection facilitates the nuclear localization of VP22, a major virion tegument protein. Author(s): Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA. Source: Kotsakis, A Pomeranz, L E Blouin, A Blaho, J A J-Virol. 2001 September; 75(18): 8697-711 0022-538X

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Mitochondrial distribution and function in herpes simplex virus-infected cells. Author(s): Laboratory of Virology, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 4668550, Japan. Source: Murata, T Goshima, F Daikoku, T Inagaki Ohara, K Takakuwa, H Kato, K Nishiyama, Y J-Gen-Virol. 2000 February; 81 Pt 2401-6 0022-1317

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Morphine reduces herpes simplex virus-1 pathogenesis in the murine flank. Author(s): Adelphi University, Division of Science and Mathematics, Department of Biology, Garden City, NY 11530, USA. [email protected] Source: Weeks, B S Alston, N I Cadet, P Zhu, W Rialas, C Stefano, G B Int-J-Mol-Med. 2001 September; 8(3): 303-7 1107-3756

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Noninvasive bioluminescence imaging of herpes simplex virus type 1 infection and therapy in living mice. Author(s): Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

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Source: Luker, G D Bardill, J P Prior, J L Pica, C M Piwnica Worms, D Leib, D A J-Virol. 2002 December; 76(23): 12149-61 0022-538X •

Nuclear and nucleolar localization of an African swine fever virus protein, I14L, that is similar to the herpes simplex virus-encoded virulence factor ICP34.5. Source: Goatley, L.C. Marron, M.B. Jacobs, S.C. Hammond, J.M. Miskin, J.E. Abrams, C.C. Smith, G.L. Dixon, L.K. J-gen-virol. Reading : Society for General Microbiology. Mar 1999. volume 80 (pt.3) page 525-535. 0022-1317

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Ocular herpes simplex. Author(s): Specialist Eye Centre, Christ Church, Barbados. Source: Barker, N Clin-Evid. 2002 June; (7): 597-604 1462-3846

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Plant extracts antiviral activity against Herpes simplex virus type 1 and African swine fever virus. Source: Silva, O. Barbosa, S. Diniz, A. Valdeira, M.L. Gomes, E. Int-j-pharmacogn. Lisse, Netherlands : Swets & Zeitlinger B.V., 1991-. January 1997. volume 35 (1) page 12-16. 0925-1618

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Properties and evolutionary relationships of the Marek's disease virus homologues of protein kinase, glycoprotein D and glycoprotein I of herpes simplex virus. Source: Ross, L.J.N. Binns, M.M. J-Gen-Virol. Reading : Society for General Microbiology. April 1991. volume 72 (pt.4) page 939-947. 0022-1317

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Recurrent herpes simplex virus infection. Suppressive, reactive, and preventive antiviral regimens. Author(s): Forum Health, Northside Medical Center, Youngstown, Ohio, USA. Source: Guerriere Kovach, P M Brodell, R T Postgrad-Med. 2000 May 15; 107(6): 139-40, 143, 147 0032-5481

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Regions of the herpes simplex virus type 1 latency-associated transcript that protect cells from apoptosis in vitro and protect neuronal cells in vivo. Author(s): Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. Source: Ahmed, Maryam Lock, Martin Miller, Cathie G Fraser, Nigel W J-Virol. 2002 January; 76(2): 717-29 0022-538X

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Signals that dictate nuclear, nucleolar, and cytoplasmic shuttling of the gamma(1)34.5 protein of herpes simplex virus type 1. Author(s): Department of Microbiology and Immunology, College of Medicine, The University of Illinois at Chicago, Chicago, Illinois 60612, USA. Source: Cheng, G Brett, M E He, B J-Virol. 2002 September; 76(18): 9434-45 0022-538X

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Studies on the constituents of seeds of Pachyrrhizus erosus and their anti herpes simplex virus (HSV) activities. Author(s): Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. Source: Phrutivorapongkul, A Lipipun, V Ruangrungsi, N Watanabe, T Ishikawa, T Chem-Pharm-Bull-(Tokyo). 2002 April; 50(4): 534-7 0009-2363

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Subcellular localization of herpes simplex virus type 1 UL51 protein and role of palmitoylation in Golgi apparatus targeting. Author(s): Laboratory of Virology, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Showa-ku, Nagoya 466-8550, Japan. Source: Nozawa, N Daikoku, T Koshizuka, T Yamauchi, Y Yoshikawa, T Nishiyama, Y JVirol. 2003 March; 77(5): 3204-16 0022-538X

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Synergy between the herpes simplex virus tk/ganciclovir prodrug suicide system and the topoisomerase I inhibitor topotecan. Author(s): Clinical Gene Therapy Branch/National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1851, USA. [email protected] Source: Wildner, O Blaese, R M Morris, J C Hum-Gene-Ther. 1999 November 1; 10(16): 2679-87 1043-0342

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T lymphocyte transduction with herpes simplex virus-thymidine kinase (HSV-tk) gene: comparison of four different infection protocols. Author(s): Department of Clinical and Experimental Medicine, Perugia University, Italy. Source: Di Ianni, M Di Florio, S Venditti, G Falzetti, F Mannoni, P Martelli, M F Tabilio, A J-Hematother-Stem-Cell-Res. 1999 December; 8(6): 645-52 1525-8165

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The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) blocks apoptosis in hippocampal neurons, involving activation of the MEK/MAPK survival pathway. Author(s): Departments of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. Source: Perkins, D Pereira, E F R Gober, M Yarowsky, P J Aurelian, L J-Virol. 2002 February; 76(3): 1435-49 0022-538X

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The regulation of burn-associated infections with herpes simplex virus type 1 or Candida albicans by a non-toxic aconitine-hydrolysate, benzoylmesaconine. Part 1: Antiviral and anti-fungal activities in thermally injured mice. Author(s): Department of Internal Medicine, University of Texas Medical Branch, Galveston 77555-0835, USA. Source: Kobayashi, M Mori, K Kobayashi, H Pollard, R B Suzuki, F Immunol-Cell-Biol. 1998 June; 76(3): 202-8 0818-9641

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Two-drug combinations that increase apoptosis and modulate bak and bcl-X(L) expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase. Author(s): Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA. Source: McMasters, R A Wilbert, T N Jones, K E Pitlyk, K Saylors, R L Moyer, M P Chambers, T C Drake, R R Cancer-Gene-Ther. 2000 April; 7(4): 563-73 0929-1903

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Ultraviolet-B radiation induces modulation of antigen presentation of herpes simplex virus by human epidermal cells. Author(s): Center for Electron Microscopy, Leiden University Medical Center, Leiden, The Netherlands. [email protected] Source: van der Molen, R G Out Luiting, C Claas, F H Norval, M Koerten, H K Mommaas, A M Hum-Immunol. 2001 June; 62(6): 589-97 0198-8859

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Use of oral valaciclovir in a 12-year-old boy with herpes simplex encephalitis. Author(s): Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. Source: Chan, P K Chow, P C Peiris, J S Mak, A W Huen, K F Hong-Kong-Med-J. 2000 March; 6(1): 119-21 1024-2708

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Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Author(s): University of California San Francisco Medical Center, San Francisco, CA 94143, USA. Source: Conant, M A Schacker, T W Murphy, R L Gold, J Crutchfield, L T Crooks, R J Int-J-STD-AIDS. 2002 January; 13(1): 12-21 0956-4624

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Valacyclovir inhibition of recovery of ocular herpes simplex virus type 1 after experimental reactivation by laser in situ keratomileusis. Author(s): Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15203, USA. [email protected] Source: Dhaliwal, D K Romanowski, E G Yates, K A Hu, D Mah, F S Fish, D N Gordon, Y J J-Cataract-Refract-Surg. 2001 August; 27(8): 1288-93 0886-3350

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Valacyclovir prophylaxis for the prevention of Herpes simplex virus reactivation in recipients of progenitor cells transplantation. Author(s): Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. Source: Dignani, M C Mykietiuk, A Michelet, M Intile, D Mammana, L Desmery, P Milone, G Pavlovsky, S Bone-Marrow-Transplant. 2002 February; 29(3): 263-7 0268-3369

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMD®Health: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

The following is a specific Web list relating to herpes simplex; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Vitamins Vitamin A Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10066,00.html

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Minerals Quercetin Source: Prima Communications, Inc.www.personalhealthzone.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com

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Food and Diet Chocolate Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND HERPES SIMPLEX Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to herpes simplex. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to herpes simplex and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “herpes simplex” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to herpes simplex: •

A comparative multi-centre study of the efficacy of propolis, acyclovir and placebo in the treatment of genital herpes (HSV). Author(s): Vynograd N, Vynograd I, Sosnowski Z. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2000 March; 7(1): 1-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10782483&dopt=Abstract

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A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. Author(s): Gambhir SS, Bauer E, Black ME, Liang Q, Kokoris MS, Barrio JR, Iyer M, Namavari M, Phelps ME, Herschman HR.

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Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 March 14; 97(6): 2785-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10716999&dopt=Abstract •

An antiviral principle present in a purified fraction from Melia azedarach L. leaf aqueous extract restrains herpes simplex virus type 1 propagation. Author(s): Alche LE, Barquero AA, Sanjuan NA, Coto CE. Source: Phytotherapy Research : Ptr. 2002 June; 16(4): 348-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112291&dopt=Abstract

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Anti-Herpes simplex virus activity of Bidens pilosa and Houttuynia cordata. Author(s): Chiang LC, Chang JS, Chen CC, Ng LT, Lin CC. Source: The American Journal of Chinese Medicine. 2003; 31(3): 355-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943167&dopt=Abstract

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Anti-herpes simplex virus effect of a seed extract from the tropical plant Licania tomentosa (Benth.) Fritsch (Chrysobalanaceae). Author(s): Miranda MM, Goncalves JL, Romanos MT, Silva FP, Pinto L, Silva MH, Ejzemberg R, Granja LF, Wigg MD. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2002 October; 9(7): 641-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487329&dopt=Abstract

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Anti-herpes simplex virus effect of an aqueous extract of propolis. Author(s): Huleihel M, Isanu V. Source: Isr Med Assoc J. 2002 November; 4(11 Suppl): 923-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12455181&dopt=Abstract

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Antiherpes simplex virus type 2 activity of casuarinin from the bark of Terminalia arjuna Linn. Author(s): Cheng HY, Lin CC, Lin TC. Source: Antiviral Research. 2002 September; 55(3): 447-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12206882&dopt=Abstract

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Anti-herpes simplex virus type-1 flavonoids and a new flavanone from the root of Limonium sinense. Author(s): Lin LC, Kuo YC, Chou CJ. Source: Planta Medica. 2000 May; 66(4): 333-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10865449&dopt=Abstract

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Antiviral activity of Australian tea tree oil and eucalyptus oil against herpes simplex virus in cell culture. Author(s): Schnitzler P, Schon K, Reichling J.

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Source: Pharmazie. 2001 April; 56(4): 343-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11338678&dopt=Abstract •

Antiviral activity of characterized extracts from echinacea spp. (Heliantheae: Asteraceae) against herpes simplex virus (HSV-I). Author(s): Binns SE, Hudson J, Merali S, Arnason JT. Source: Planta Medica. 2002 September; 68(9): 780-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357386&dopt=Abstract

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Combined herbal preparation for topical treatment of Herpes labialis. Author(s): Saller R, Buechi S, Meyrat R, Schmidhauser C. Source: Forschende Komplementarmedizin Und Klassische Naturheilkunde = Research in Complementary and Natural Classical Medicine. 2001 December; 8(6): 373-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11799306&dopt=Abstract

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Cytotoxicities and anti-herpes simplex virus activities of diterpenes isolated from Euphorbia species. Author(s): Mucsi I, Molnar J, Hohmann J, Redei D. Source: Planta Medica. 2001 October; 67(7): 672-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11582549&dopt=Abstract

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Does the extract of the plant Echinacea purpurea influence the clinical course of recurrent genital herpes? Author(s): Vonau B, Chard S, Mandalia S, Wilkinson D, Barton SE. Source: International Journal of Std & Aids. 2001 March; 12(3): 154-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11231867&dopt=Abstract

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Evaluation of 2LHERP in preventing recurrences of genital herpes. Institut International 3IDI. Author(s): Jenaer M, Henry MF, Garcia A, Marichal B. Source: Br Homeopath J. 2000 October; 89(4): 174-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11055774&dopt=Abstract

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Experimental laser-assisted in situ keratomileusis induces the reactivation of latent herpes simplex virus. Author(s): Dhaliwal DK, Romanowski EG, Yates KA, Hu D, Goldstein M, Gordon YJ. Source: American Journal of Ophthalmology. 2001 April; 131(4): 506-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11292417&dopt=Abstract

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Fatal herpes simplex virus hepatitis complicating chemotherapy with weekly docetaxel. Author(s): Hofer S, Hunziker S, Tornillo L, Ludwig CU.

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Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 February; 14(2): 340. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562665&dopt=Abstract •

Genital herpes simplex virus infection in the adolescent: special considerations for management. Author(s): Stanberry LR, Rosenthal SL. Source: Paediatric Drugs. 2002; 4(5): 291-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11994034&dopt=Abstract

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Glycyrrhizin increases survival of mice with herpes simplex encephalitis. Author(s): Sekizawa T, Yanagi K, Itoyama Y. Source: Acta Virol. 2001 February; 45(1): 51-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11394578&dopt=Abstract

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Herpes simplex replication and dissemination is not increased by corticosteroid treatment in a rat model of focal Herpes encephalitis. Author(s): Thompson KA, Blessing WW, Wesselingh SL. Source: Journal of Neurovirology. 2000 February; 6(1): 25-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10786994&dopt=Abstract

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Human pharmacokinetic and dosimetry studies of [(18)F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression. Author(s): Yaghoubi S, Barrio JR, Dahlbom M, Iyer M, Namavari M, Satyamurthy N, Goldman R, Herschman HR, Phelps ME, Gambhir SS. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2001 August; 42(8): 1225-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11483684&dopt=Abstract

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Improved herpes simplex virus type 1 amplicon vectors for proportional coexpression of positron emission tomography marker and therapeutic genes. Author(s): Jacobs AH, Winkeler A, Hartung M, Slack M, Dittmar C, Kummer C, Knoess C, Galldiks N, Vollmar S, Wienhard K, Heiss WD. Source: Human Gene Therapy. 2003 February 10; 14(3): 277-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639307&dopt=Abstract

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Improving the outcome of facial resurfacing--prevention of herpes simplex virus type 1 reactivation. Author(s): Gilbert S. Source: The Journal of Antimicrobial Chemotherapy. 2001 February; 47 Suppl T1: 29-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11160033&dopt=Abstract

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In vitro antiviral activity of Phyllanthus orbicularis extracts against herpes simplex virus type 1. Author(s): Fernandez Romero JA, Del Barrio Alonso G, Romeu Alvarez B, Gutierrez Y, Valdes VS, Parra F. Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 980-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680841&dopt=Abstract

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In vitro antiviral effect of flavonoid-rich extracts of Vitex polygama (Verbenaceae) against acyclovir-resistant herpes simplex virus type 1. Author(s): Goncalves JL, Leitao SG, Monache FD, Miranda MM, Santos MG, Romanos MT, Wigg MD. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2001 November; 8(6): 477-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11824525&dopt=Abstract

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In vivo antiviral activity of Stephania cepharantha against herpes simplex virus type1. Author(s): Nawawi A, Nakamura N, Meselhy MR, Hattori M, Kurokawa M, Shiraki K, Kashiwaba N, Ono M. Source: Phytotherapy Research : Ptr. 2001 September; 15(6): 497-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11536378&dopt=Abstract

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Inhibitory effect of anti-pyretic and anti-inflammatory herbs on herpes simplex virus replication. Author(s): Hsiang CY, Hsieh CL, Wu SL, Lai IL, Ho TY. Source: The American Journal of Chinese Medicine. 2001; 29(3-4): 459-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11789588&dopt=Abstract

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Inhibitory effect of sulfated galactans from the marine alga Bostrychia montagnei on herpes simplex virus replication in vitro. Author(s): Duarte ME, Noseda DG, Noseda MD, Tulio S, Pujol CA, Damonte EB. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2001 January; 8(1): 53-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11292240&dopt=Abstract

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LongoVital and herpes labialis: a randomised, double-blind, placebo-controlled study. Author(s): Pedersen A. Source: Oral Diseases. 2001 July; 7(4): 221-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11575872&dopt=Abstract

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Microtubule reorganization during herpes simplex virus type 1 infection facilitates the nuclear localization of VP22, a major virion tegument protein. Author(s): Kotsakis A, Pomeranz LE, Blouin A, Blaho JA.

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Source: Journal of Virology. 2001 September; 75(18): 8697-711. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11507215&dopt=Abstract •

Mistletoe lectins enhance immune responses to intranasally co-administered herpes simplex virus glycoprotein D2. Author(s): Lavelle EC, Grant G, Pusztai A, Pfuller U, Leavy O, McNeela E, Mills KH, O'Hagan DT. Source: Immunology. 2002 October; 107(2): 268-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12383207&dopt=Abstract

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Monitoring adenoviral DNA delivery, using a mutant herpes simplex virus type 1 thymidine kinase gene as a PET reporter gene. Author(s): Liang Q, Nguyen K, Satyamurthy N, Barrio JR, Phelps ME, Gambhir SS, Herschman HR. Source: Gene Therapy. 2002 December; 9(24): 1659-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12457279&dopt=Abstract

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Novel mechanism of antibody-independent complement neutralization of herpes simplex virus type 1. Author(s): Friedman HM, Wang L, Pangburn MK, Lambris JD, Lubinski J. Source: Journal of Immunology (Baltimore, Md. : 1950). 2000 October 15; 165(8): 4528-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11035093&dopt=Abstract

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NP-1, a rabbit alpha-defensin, prevents the entry and intercellular spread of herpes simplex virus type 2. Author(s): Sinha S, Cheshenko N, Lehrer RI, Herold BC. Source: Antimicrobial Agents and Chemotherapy. 2003 February; 47(2): 494-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543649&dopt=Abstract

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Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1. Author(s): Farassati F, Yang AD, Lee PW. Source: Nature Cell Biology. 2001 August; 3(8): 745-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11483960&dopt=Abstract

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Oncolytic herpes simplex virus-1 lacking ICP34.5 induces p53-independent death and is efficacious against chemotherapy-resistant ovarian cancer. Author(s): Coukos G, Makrigiannakis A, Kang EH, Rubin SC, Albelda SM, MolnarKimber KL. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 August; 6(8): 3342-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10955822&dopt=Abstract

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Oncolytic viral therapy for human ovarian cancer using a novel replication-competent herpes simplex virus type I mutant in a mouse model. Author(s): Nawa A, Nozawa N, Goshima F, Nagasaka T, Kikkawa F, Niwa Y, Nakanishi T, Kuzuya K, Nishiyama Y. Source: Gynecologic Oncology. 2003 October; 91(1): 81-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14529666&dopt=Abstract

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Optimizing prostate cancer suicide gene therapy using herpes simplex virus thymidine kinase active site variants. Author(s): Pantuck AJ, Matherly J, Zisman A, Nguyen D, Berger F, Gambhir SS, Black ME, Belldegrun A, Wu L. Source: Human Gene Therapy. 2002 May 1; 13(7): 777-89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11975845&dopt=Abstract

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Patient and physician partnerships in managing genital herpes. Author(s): Alexander L, Naisbett B. Source: The Journal of Infectious Diseases. 2002 October 15; 186 Suppl 1: S57-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353188&dopt=Abstract

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Positron emission tomography-based imaging of transgene expression mediated by replication-conditional, oncolytic herpes simplex virus type 1 mutant vectors in vivo. Author(s): Jacobs A, Tjuvajev JG, Dubrovin M, Akhurst T, Balatoni J, Beattie B, Joshi R, Finn R, Larson SM, Herrlinger U, Pechan PA, Chiocca EA, Breakefield XO, Blasberg RG. Source: Cancer Research. 2001 April 1; 61(7): 2983-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11306477&dopt=Abstract

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Possible mode of antiviral activity of acidic protein bound polysaccharide isolated from Ganoderma lucidum on herpes simplex viruses. Author(s): Eo SK, Kim YS, Lee CK, Han SS. Source: Journal of Ethnopharmacology. 2000 October; 72(3): 475-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10996289&dopt=Abstract

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Potent oncolytic activity of multimutated herpes simplex virus G207 in combination with vincristine against human rhabdomyosarcoma. Author(s): Cinatl J Jr, Cinatl J, Michaelis M, Kabickova H, Kotchetkov R, Vogel JU, Doerr HW, Klingebiel T, Driever PH. Source: Cancer Research. 2003 April 1; 63(7): 1508-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12670897&dopt=Abstract

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Reductions in herpes simplex virus type 2 antibody titers after cognitive behavioral stress management and relationships with neuroendocrine function, relaxation skills, and social support in HIV-positive men. Author(s): Cruess S, Antoni M, Cruess D, Fletcher MA, Ironson G, Kumar M, Lutgendorf S, Hayes A, Klimas N, Schneiderman N.

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Source: Psychosomatic Medicine. 2000 November-December; 62(6): 828-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11139003&dopt=Abstract •

Region of herpes simplex virus type 1 latency-associated transcript sufficient for wild-type spontaneous reactivation promotes cell survival in tissue culture. Author(s): Inman M, Perng GC, Henderson G, Ghiasi H, Nesburn AB, Wechsler SL, Jones C. Source: Journal of Virology. 2001 April; 75(8): 3636-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11264353&dopt=Abstract

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Regions of the herpes simplex virus type 1 latency-associated transcript that protect cells from apoptosis in vitro and protect neuronal cells in vivo. Author(s): Ahmed M, Lock M, Miller CG, Fraser NW. Source: Journal of Virology. 2002 January; 76(2): 717-29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11752162&dopt=Abstract

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Regulation of herpes simplex virus type 1 replication in Vero cells by Psychotria serpens: relationship to gene expression, DNA replication, and protein synthesis. Author(s): Kuo YC, Chen CC, Tsai WJ, Ho YH. Source: Antiviral Research. 2001 August; 51(2): 95-109. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11431035&dopt=Abstract

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Samarangenin B from Limonium sinense suppresses herpes simplex virus type 1 replication in Vero cells by regulation of viral macromolecular synthesis. Author(s): Kuo YC, Lin LC, Tsai WJ, Chou CJ, Kung SH, Ho YH. Source: Antimicrobial Agents and Chemotherapy. 2002 September; 46(9): 2854-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183238&dopt=Abstract

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Two-drug combinations that increase apoptosis and modulate bak and bcl-X(L) expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase. Author(s): McMasters RA, Wilbert TN, Jones KE, Pitlyk K, Saylors RL, Moyer MP, Chambers TC, Drake RR. Source: Cancer Gene Therapy. 2000 April; 7(4): 563-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10811474&dopt=Abstract

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Virucidal effect of peppermint oil on the enveloped viruses herpes simplex virus type 1 and type 2 in vitro. Author(s): Schuhmacher A, Reichling J, Schnitzler P. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2003; 10(6-7): 504-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13678235&dopt=Abstract

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Will taking the amino acid supplement lysine prevent or treat the herpes simplex virus? Author(s): Marcason W. Source: Journal of the American Dietetic Association. 2003 March; 103(3): 351. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616258&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMD®Health: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to herpes simplex; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview AIDS and HIV Source: Integrative Medicine Communications; www.drkoop.com Cervical Dysplasia Source: Integrative Medicine Communications; www.drkoop.com Cold Sores Source: Healthnotes, Inc.; www.healthnotes.com

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Cold Sores Source: Integrative Medicine Communications; www.drkoop.com Genital Herpes Source: Healthnotes, Inc.; www.healthnotes.com Herpes Alternative names: Genital Herpes, Cold Sores Source: Prima Communications, Inc.www.personalhealthzone.com Herpes Simplex Virus Source: Integrative Medicine Communications; www.drkoop.com Meningitis Source: Integrative Medicine Communications; www.drkoop.com Proctitis Source: Integrative Medicine Communications; www.drkoop.com Rectal Inflammation Source: Integrative Medicine Communications; www.drkoop.com Sexually Transmitted Diseases Source: Integrative Medicine Communications; www.drkoop.com Shingles and Postherpetic Neuralgia Source: Healthnotes, Inc.; www.healthnotes.com STDs Source: Integrative Medicine Communications; www.drkoop.com •

Homeopathy Dulcamara Source: Healthnotes, Inc.; www.healthnotes.com Graphites Source: Healthnotes, Inc.; www.healthnotes.com Hepar Sulphuris Calcareum Source: Healthnotes, Inc.; www.healthnotes.com Mercurius Solubilis Source: Healthnotes, Inc.; www.healthnotes.com Natrum Muriaticum Source: Healthnotes, Inc.; www.healthnotes.com Rhus Toxicodendron Source: Healthnotes, Inc.; www.healthnotes.com

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Herbs and Supplements Acyclovir Oral Source: Healthnotes, Inc.; www.healthnotes.com Acyclovir Topical Source: Healthnotes, Inc.; www.healthnotes.com Adenosine Monophosphate Source: Healthnotes, Inc.; www.healthnotes.com Aloe Alternative names: Aloe vera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Aloe Alternative names: Aloe vera, Aloe barbadensis Source: Healthnotes, Inc.; www.healthnotes.com Amino Acid K Source: Integrative Medicine Communications; www.drkoop.com Amino Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10003,00.html Antiviral Drugs Source: Healthnotes, Inc.; www.healthnotes.com Arginine Source: Healthnotes, Inc.; www.healthnotes.com Arginine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10005,00.html Astragalus Source: Prima Communications, Inc.www.personalhealthzone.com Betula Alternative names: Birch; Betula sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Blue-Green Algae Source: Healthnotes, Inc.; www.healthnotes.com Blue-Green Algae Source: Integrative Medicine Communications; www.drkoop.com

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Echinacea Alternative names: Echinacea angustifolia, Echinacea pallida, Echinacea purpurea, Purple Coneflower Source: Integrative Medicine Communications; www.drkoop.com Echinacea Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,775,00.html Echinacea Angustifolia Source: Integrative Medicine Communications; www.drkoop.com Echinacea Pallida Source: Integrative Medicine Communications; www.drkoop.com Echinacea Purpurea Source: Integrative Medicine Communications; www.drkoop.com Elderberry Alternative names: Sambucus nigra Source: Healthnotes, Inc.; www.healthnotes.com Eucalyptus Alternative names: Eucalyptus globulus Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza1 Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Goldenseal Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,791,00.html Lemon Balm Alternative names: Melissa officinalis Source: Healthnotes, Inc.; www.healthnotes.com Lemon Balm Alternative names: Melissa officinalis, Melissa Source: Integrative Medicine Communications; www.drkoop.com Licorice Alternative names: Glycyrrhiza glabra, Glycyrrhiza uralensis Source: Healthnotes, Inc.; www.healthnotes.com Liquorice Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca

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L-lysine Source: Integrative Medicine Communications; www.drkoop.com Lysine Source: Healthnotes, Inc.; www.healthnotes.com Lysine Alternative names: Amino Acid K, L-Lysine Source: Integrative Medicine Communications; www.drkoop.com Lysine Source: Prima Communications, Inc.www.personalhealthzone.com Lysine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,862,00.html Melaleuca Alternative names: Tea Tree Oil; Melaleuca alternifolia Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Melissa Source: Integrative Medicine Communications; www.drkoop.com Melissa Source: Prima Communications, Inc.www.personalhealthzone.com Melissa Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10043,00.html Melissa Officinalis Source: Integrative Medicine Communications; www.drkoop.com Phytolacca Alternative names: Poke root, Endod; Phytolacca dodecandra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Potentilla Alternative names: Cinquefoil, Silverweed; Potentilla sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Prunella Alternative names: Self Heal; Prunella vulgaris L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Purple Coneflower Source: Integrative Medicine Communications; www.drkoop.com

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Pygeum Alternative names: African Prune; Pygeum africanum Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Sambucus Alternative names: Black Elderberry; Sambucus nigra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Spirulina Alternative names: Blue-green Algae Source: Integrative Medicine Communications; www.drkoop.com St. John's Wort Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,824,00.html Thuja Occid Alternative names: Arbor Vitae; Thuja occidentalis Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Turmeric Alternative names: Curcuma longa Source: Healthnotes, Inc.; www.healthnotes.com Valacyclovir Source: Healthnotes, Inc.; www.healthnotes.com Verbascum Alternative names: Mullein; Verbascum thapsus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON HERPES SIMPLEX Overview In this chapter, we will give you a bibliography on recent dissertations relating to herpes simplex. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “herpes simplex” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on herpes simplex, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Herpes Simplex ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to herpes simplex. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A Role for Nuclear Factor-kappab in Apoptosis Modulation during Herpes Simplex Virus Type 1 Infection by Goodkin, Margot L.; PhD from Mount Sinai School of Medicine of New York University, 2002, 208 pages http://wwwlib.umi.com/dissertations/fullcit/3058862

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Analysis of the Genes Encoding the Latency Associated Transcript of Bovine Herpesvirus Type 1 (bhv-1) and Herpes Simplex Type 1: Their Anti-apoptotic Activity and a Novel Function Identified for the Bhv-1 Latency Related Gene by Inman, Melissa Anne; PhD from University of Nebraska Medical Center, 2002, 234 pages http://wwwlib.umi.com/dissertations/fullcit/3068773

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Anti-apoptotic Activity of the Herpes Simplex Virus Type 2 Gene Icp10 Pk: Implications for Therapy of Neurological Disorders That Involve Apoptosis by Perkins, Dana Stela; PhD from University of Maryland, Baltimore, 2002, 321 pages http://wwwlib.umi.com/dissertations/fullcit/3048445

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Antigens of Herpes Simplex Virus by Rigby, Charlotte; PhD from University of Ottawa (Canada), 1971 http://wwwlib.umi.com/dissertations/fullcit/NK10694

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Antiviral Activities of Selected Hong Kong Marine Algae against Herpes Simplex Viruses and Other Viruses and Their Possible Antiviral Mechanisms by Zhu, Wen; PhD from Chinese University of Hong Kong (People's Republic of China), 2002, 249 pages http://wwwlib.umi.com/dissertations/fullcit/3052129

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Biochemical and Genetic Characterization of Temperature-sensitive Mutants of Herpes Simplex Virus Type 1 Defective in the Shutoff of Cellular Macromolecular Synthesis by Daksis, Jasmine Ilga; PhD from University of Toronto (Canada), 1987 http://wwwlib.umi.com/dissertations/fullcit/NL39717

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Characterization of Presynaptic C-afferent Fiber Responses: a Recombinant Herpes Simplex Virus-1 Approach by Jones, Toni L.; PhD from University of Illinois at Chicago, Health Sciences Center, 2003, 191 pages http://wwwlib.umi.com/dissertations/fullcit/3083945

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Characterization of the Herpes Simplex Virus Ribonucleotide Reductase by Huszar, Dennis; PhD from McMaster University (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NL17587

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Dissecting the Functions of Neurovirulent Factor Icp34.5 Protein of Herpes Simplex Virus 1 by Cheng, Guofeng; PhD from University of Illinois at Chicago, Health Sciences Center, 2003, 121 pages http://wwwlib.umi.com/dissertations/fullcit/3083941

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Factors Affecting the Prevalence of Herpes Simplex Virus Type 2 Antibody a Seroepidemiologic Survey by Chiavetta, Jo Anne; PhD from The University of Western Ontario (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL33044

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Functional Analysis of Ul9, the Origin-binding Protein of Herpes Simplex Virus-1 by Marintcheva, Boriana Davidova; PhD from the University of Connecticut, 2002, 239 pages http://wwwlib.umi.com/dissertations/fullcit/3076711

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Herpes Simplex Virus Type 1 (hsv-1) U(l)31, U(l)33, and U(l)34 Proteins Play Essential Roles in Herpesvirion Morphogenesis by Reynolds, Ashley Elizabeth; PhD from Cornell University, 2002, 195 pages http://wwwlib.umi.com/dissertations/fullcit/3059106

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Herpes Simplex Virus Type-1 Icp34.5 Modulates Neuroinvasiveness in Vivo, Viral Plaque Size, Efficiency of Glycoprotein Processing, and Viral Release in Tissue Culture by Mao, Hanwen; PhD from Kent State University, 2002, 239 pages http://wwwlib.umi.com/dissertations/fullcit/3068690

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Herpes Simplex Virus-based Vectors in Neurons and Glia: Transgene Expression and Immune Response by Harvey, Brandon Keith; PhD from The University of Rochester, 2003, 247 pages http://wwwlib.umi.com/dissertations/fullcit/3078411

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Hijacking of the Ubiquitin-proteasome System by Herpes Simplex Virus 1: Description and Characterization of Two Discrete E3 Ubiquitin Ligase Activities Encoded by Infected Cell Protein 0 by Hagglund, Ryan; PhD from The University of Chicago, 2003, 201 pages http://wwwlib.umi.com/dissertations/fullcit/3088740

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Identification and Characterization of Protein Interaction Domains in the Herpes Simplex Virus Type I Transcription Factor Icp4 by Bruce, James William; PhD from The Medical College of Wisconsin, 2002, 241 pages http://wwwlib.umi.com/dissertations/fullcit/3041767

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Inhibition of the Herpes Simplex Virus Type I by Three Ndga Derivatives: Mal.4, M(4)n, and G(4)n by Park, Richard; PhD from The Johns Hopkins University, 2003, 135 pages http://wwwlib.umi.com/dissertations/fullcit/3068194

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Intranuclear Localization of the Herpes Simplex Virus Icp8 Protein by Taylor, Travis J.; PhD from Harvard University, 2002, 253 pages http://wwwlib.umi.com/dissertations/fullcit/3051302

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Mechanism of Herpes Simplex Virus Type 1 Latency in Transgenic Mouse Models by Loiacono, Christina Marie; PhD from University of Missouri - Columbia, 2002, 104 pages http://wwwlib.umi.com/dissertations/fullcit/3052194

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Mechanisms of Herpes Simplex Virus Retinitis in a Mouse Model by Archin, Nancie Marie; PhD from The University of Texas Health Science Center at San Antonio, 2002, 186 pages http://wwwlib.umi.com/dissertations/fullcit/3070649

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Molecular Characterization of Glycoproteins of Herpes Simplex Virus by Zwaagstra, John Clarence; PhD from University of Alberta (Canada), 1987 http://wwwlib.umi.com/dissertations/fullcit/NL41173

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Molecular Mechanism of Recombination in Herpes Simplex Virus Type-1 by Nimonkar, Amitabh Vijay; PhD from University of Miami, 2003, 136 pages http://wwwlib.umi.com/dissertations/fullcit/3096356

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Processivity of the Herpes Simplex Virus Dna Polymerase: Role of High-affinity Dna Binding by the Processivity Subunit by Randell, John Cranston Wall; PhD from Harvard University, 2003, 126 pages http://wwwlib.umi.com/dissertations/fullcit/3076910

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Quantitating Herpes Simplex Virus Type 1 Thymidine Kinase Reporter Gene Expression in Living Animals Using Positron Emission Tomography and a Tracer Kinetic Model for Radiolabeled Acyclic Guanosine Analogues by Green, Leeta Alison; PhD from University of California, Los Angeles, 2003, 218 pages http://wwwlib.umi.com/dissertations/fullcit/3094197

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Radiohalogenated Pyrimidine Nucleosides As Potential Non-invasive Diagnostic Agents for Herpes Simplex Encephalitis by Samuel, John; PhD from University of Alberta (Canada), 1985 http://wwwlib.umi.com/dissertations/fullcit/NL22934

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Recombinational and Packaging Signals in Herpes Simplex Virus Deoxyribonucleic Acid by Varmuza, Susannah Louise; PhD from Mcmaster University (Canada), 1985 http://wwwlib.umi.com/dissertations/fullcit/NL24111

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Signaling Mechanisms Essential for Reactivation of Latent Herpes Simplex Virus Type 1 in Neuronal Cultures by Hunsperger, Elizabeth Anne; PhD from Colorado State University, 2002, 112 pages http://wwwlib.umi.com/dissertations/fullcit/3053429

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Stress and Stress-associated Neuroendocrine Hormones Modulate the Function of Herpes Simplex Virus-specific Memory Cytotoxic T Lymphocytes by Wonnacott, Keith Merrell; PhD from The Pennsylvania State University, 2002, 233 pages http://wwwlib.umi.com/dissertations/fullcit/3051762

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Stress-induced Reactivation of Latent Herpes Simplex Virus Infection in Lumbar Ganglia of Rats by Blondeau, Joseph Moses; PhD from The University of Manitoba (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL51624

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Structural Determinants of Nectin-1 and Nectin-2 Required for Entry of Herpes Simplex Virus and Other Alphaherpesviruses by Martinez, Wanda M.; PhD from Northwestern University, 2002, 169 pages http://wwwlib.umi.com/dissertations/fullcit/3050560

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Structure-based Analysis of Herpes Simplex Virus Glycoprotein D and Its Hvea/hvem Receptor by Connolly, Sarah Ann; PhD from University of Pennsylvania, 2003, 188 pages http://wwwlib.umi.com/dissertations/fullcit/3087386

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Studies on Latent Herpes Simplex Virus in the Human Nervous System by Lewis, Marcia Ellen; PhD from University of Alberta (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK67540

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Studies on the Anti-herpes Simplex Virus (hsv) Constituents from a Chinese Herbal Medicine, Prunella Vulgaris by Zhang, Yongwen; PhD from Chinese University of Hong Kong (People's Republic of China), 2003, 190 pages http://wwwlib.umi.com/dissertations/fullcit/3095430

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Study about the Mechanism of Liver Toxicity Induced by the Treatment with Herpes Simplex Virus Thymidine Kinase Plus Ganciclovir by Herraiz Bayod, Maite; DR from Universidad De Navarra (Spain), 2002, 144 pages http://wwwlib.umi.com/dissertations/fullcit/f403153

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The Association of Herpes Simplex Virus with Cervical Cancer a Mathematical Model, and Exploration of an Approach to Retrieve Viral Genetic Information from Transformed Cells by Campione-Piccardo, Jose; PhD from McMaster University (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK54139

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The Mechanisms of Ablation of Antiviral Effects of Interferon by Herpes Simplex Virus Type 1 by Chee, Ana Virginia; PhD from The University of Chicago, 2003, 131 pages http://wwwlib.umi.com/dissertations/fullcit/3077047

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The Role of Herpes Simplex Virus Type 2 (hsv-2) As a Cofactor in HIV Transmission by Mbopi-Keou, Francois-Xavier; PhD from Open University (United Kingdom), 2002 http://wwwlib.umi.com/dissertations/fullcit/f803585

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The Role of Perforin and Chemokines in the Pathogenesis of Chronic Corneal Inflammation Induced by Herpes Simplex Virus Type-1 Infection by Chang, Eddie; PhD from University of Missouri - Columbia, 2003, 155 pages http://wwwlib.umi.com/dissertations/fullcit/3091911

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Transcriptional Analysis of Herpes Simplex Virus Type 1 Expression and Host Cell Response to Infection Using a Dna Microarray by Stingley, Samuel Wayne; PhD from University of California, Irvine, 2002, 258 pages http://wwwlib.umi.com/dissertations/fullcit/3039229

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Use of Expresser Cell Lines to Functionally Characterize the Herpes Simplex Virus Transcription-activating Protein by Persson, Roy H; PhD from McMaster University (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL52142

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Vp16 Localization during Herpes Simplex-1 Infection by Greensides, Dawn Renee; MS from Michigan State University, 2002, 209 pages http://wwwlib.umi.com/dissertations/fullcit/1409511

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. CLINICAL TRIALS AND HERPES SIMPLEX Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning herpes simplex.

Recent Trials on Herpes Simplex The following is a list of recent trials dedicated to herpes simplex.8 Further information on a trial is available at the Web site indicated. •

Assessment of oral acyclovir in neonates with HSV involving the CNS Condition(s): Herpes Simplex Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to test whether long-term treatment (6 months) with oral acyclovir improves the outcome for infants with HSV infection of the brain or spinal cord (central nervous system, or CNS disease). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00031460

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HERPEVAC Trial for Women Condition(s): Herpes Simplex; Sexually Transmitted Diseases Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The primary purpose of this study is to see if the vaccine is safe and prevents genital herpes disease in women who are not infected.

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These are listed at www.ClinicalTrials.gov.

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Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00057330 •

Oral acyclovir for neonatal HSV disease of the skin,eyes and mouth Condition(s): Herpes Simplex Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to test whether long-term treatment with oral acyclovir improves the outcome for infants with HSV disease of the skin, eyes, and mouth (SEM disease). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00031447

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Phase III Randomized Study of Oral Acyclovir in Infants With Herpes Simplex Virus Infection Involving the Central Nervous System Condition(s): Herpes Simplex Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); UAB Comprehensive Cancer Center Purpose - Excerpt: Objectives: I. Determine the efficacy of long term suppressive therapy with oral acyclovir in infants with herpes simplex virus infection involving the central nervous system. II. Determine whether neurologic outcome is improved in these patients when treated with this regimen. III. Determine whether continuous administration of this drug suppresses recurrent skin lesions in these patients. IV. Determine the safety of this regimen in these patients. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006132

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Phase III Randomized Study of Oral Acyclovir in Infants With Herpes Simplex Virus Infection Limited to Skin, Eyes, and Mouth Condition(s): Herpes Simplex Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); UAB Comprehensive Cancer Center Purpose - Excerpt: Objectives: I. Determine the efficacy of long term suppressive therapy with oral acyclovir in infants with herpes simplex virus infection limited to skin, eyes, and mouth. II. Determine the neurologic outcome in these patients when treated with

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this regimen. III. Evaluate the significance of a positive cerebrospinal fluid (CSF) polymerase chain reaction (PCR) result when all other CSF parameters remain normal in these patients. IV. Correlate the time to first positive CSF PCR result in the first 12 months of life with clinical neurological assessment in these patients when treated with this regimen. V. Determine whether the continuous administration of this drug suppresses recurrent skin lesions in these patients. VI. Determine the safety of this regimen in these patients. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006135 •

Structure of the Herpes Simplex Virus Receptor Condition(s): Encephalitis; Herpes Simplex; Keratitis; Mouth Disease; Skin Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will examine the structure of the receptor molecule for the herpes simplex virus (HSV) and determine if the receptor's structure is related to susceptibility to infection with the virus. There are two types of herpes virus-HSV-1 and HSV-2. HSV-1 commonly causes cold sores, and HSV-2 usually causes genital herpes. The herpes virus enters (infects) cells through protein molecules on the cell's surface. This study will explore possible differences between the structure of the HSV receptor molecule in different people to understand better how infection occurs. The study will also look at proteins on white blood cells (Fc receptors, cytokines and mannose binding protein) that may influence the risk of infection with HSV. Information from this study may lead to new treatments to prevent HSV infection. People 18 years of age and older who are infected with HSV and people who are not infected with the virus may be eligible for this study. Participants will have blood drawn to confirm whether or not they have been infected with the virus. The blood sample will also be used to study the genes for the HSV receptor, Fc receptors, cytokines, mannose binding protein and related proteins on the white blood cells. No more than 40 milliliters (8 teaspoons) of blood will be drawn. Participants who are found to have antibodies to HSV-2 will be offered counseling and advice on practicing safe sex techniques to help prevent sexually transmitted diseases, including HSV-2 infection. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001648

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Valacyclovir for longterm therapy of Herpes simplex encephalitis Condition(s): Encephalitis, Herpes Simplex Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to see if giving Valacyclovir (VACV) to patients with herpes simplex encephalitis (HSE) can increase the survival rates of these patients and reduce brain and nervous system damage. A sub-study will also be

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performed to look at the relationship between the level of herpes virus in the blood and "long-term" brain damage injury caused by the HSE infection. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00031486 •

A Study of Valacyclovir as Treatment for Genital Herpes Simplex Virus in HIVInfected Patients Condition(s): Herpes Simplex; HIV Infections; Herpes Genitalis Study Status: This study is no longer recruiting patients. Sponsor(s): Glaxo Wellcome Purpose - Excerpt: The purpose of this study is to see if valacyclovir (Valtrex) is a safe and effective treatment for ano-genital HSV infections (herpes simplex virus infections of the anus and external genitals) in HIV-infected patients. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005663

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Herpetic Eye Disease Study (HEDS) II Condition(s): Keratitis, Herpetic; Ocular Herpes Simplex; Herpes Simplex Study Status: This study is no longer recruiting patients. Sponsor(s): National Eye Institute (NEI) Purpose - Excerpt: To determine whether early treatment (with oral acyclovir) of herpes simplex virus (HSV) ulcerations of the corneal epithelium prevents progression to the blinding complications of stromal keratitis and iridocyclitis. To determine the efficacy of low-dose oral acyclovir in preventing recurrent HSV eye infection in patients with previous episodes of herpetic eye disease. To determine the role of external factors (such as ultraviolet light or corneal trauma) and behavioral factors (such as life stress) on the induction of ocular recurrences of HSV eye infections and disease. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000139

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HIV and Genital Herpes Among High-Risk Men Who Have Sex With Men (MSM) in Lima, Peru Condition(s): HIV Infections; Herpes Genitalis; HIV Seronegativity; Syphilis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID)

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Purpose - Excerpt: The purpose of this study is to provide biomedical and behavioral information that is necessary for planning and starting HIV prevention trials in Lima, Peru. The occurrence of HIV is high among men who have sex with men (MSM) in Lima, Peru, and bacterial sexually transmitted diseases (STDs) and HSV-2 (genital herpes) are very prevalent in HIV-positive and -negative MSM there. Methods to reduce both HIV and STDs are urgently needed among MSM in Peru. The information gained from this study is very important for future HIV prevention and vaccine trials that will take place in Peru. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023582 •

A Comparative Trial of Valacyclovir Hydrochloride ( 256U87 ) and Acyclovir for the Suppression of Anogenital Herpes Infections in HIV-Infected Patients Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Glaxo Wellcome Purpose - Excerpt: To determine the safety and efficacy of oral valacyclovir hydrochloride ( 256U87 ) compared to acyclovir in the treatment of recurrent anogenital herpes in HIV-infected patients with CD4 counts = or > 100 cells/mm3. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002084

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A Phase I/II Study of the Safety and Efficacy of Topical 1-(S)-(3-Hydroxy-2phosphonylmethoxypropyl)cytosine Dihydrate (Cidofovir; HPMPC) in the Treatment of Refractory Mucocutaneous Herpes Simplex Disease in Patients With AIDS Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Gilead Sciences Purpose - Excerpt: To evaluate the safety and tolerance of topical cidofovir (HPMPC) therapy for refractory mucocutaneous herpes simplex virus disease in AIDS patients. To determine whether topical HPMPC therapy can induce re-epithelialization and healing of refractory mucocutaneous herpes simplex virus disease in AIDS patients. To evaluate the virologic effects of topical HPMPC therapy on herpes simplex virus shedding from refractory lesions. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002116

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A Study to Compare the Efficacy and Safety of Valacyclovir Hydrochloride ( 256U87 ) Versus Acyclovir in the Treatment of Recurrent Anogenital Herpes Infections in HIV Infected Patients Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Glaxo Wellcome Purpose - Excerpt: To evaluate the safety and efficacy of oral valacyclovir hydrochloride (256U87) vs. acyclovir in the treatment of recurrent anogenital herpes in HIV-infected patients (CD4 greater than or equal to 100). Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002000

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An Open Study of Foscarnet Treatment of Acyclovir-Resistant Herpes Simplex Virus in Patients With the Acquired Immunodeficiency Syndrome and Other Immunodeficiencies Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Astra USA Purpose - Excerpt: To evaluate the safety and efficacy of intermittent intravenous (IV) foscarnet in the treatment of acyclovir-resistant herpes simplex virus (HSV) infections in AIDS patients and other immunocompromised patients. To evaluate the necessity, efficacy, and safety of IV maintenance foscarnet therapy in preventing recurrent disease. To confirm the pharmacokinetics of intermittent induction and maintenance IV regimens. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002021

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An Open, Multicenter Study of Foscarnet Treatment of Acyclovir-Resistant Herpes Simplex Virus in Patients With the Acquired Immunodeficiency Syndrome and Other Immunodeficiencies Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Astra USA Purpose - Excerpt: To evaluate the safety and efficacy of intermittent intravenous (IV) foscarnet in the treatment of acyclovir-resistant herpes simplex virus (HSV) infections in AIDS patients and other immunocompromised patients. To evaluate the necessity, efficacy, and safety of IV maintenance foscarnet therapy in preventing recurrent disease. To confirm the pharmacokinetics of intermittent induction and maintenance IV regimens. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002272

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Cidofovir as a Treatment for Herpes Simplex in Patients with AIDS Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Gilead Sciences Purpose - Excerpt: The purpose of this study is to see if cidofovir gel (Forvade) is safe and effective in treating herpes simplex in patients with AIDS who do not respond to acyclovir. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002181

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Comparison of Foscarnet Versus Vidarabine in the Treatment of Herpes Infection in Patients with AIDS Who Have Not Had Success with Acyclovir Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To compare the safety and effectiveness of foscarnet and vidarabine treatments for AIDS patients who have herpes simplex virus infections that are resistant to standard treatment with acyclovir. Foscarnet is a drug that inhibits viruses and has been shown to be effective against infection with Cytomegalovirus and also against infection with the Herpes simplex virus in several patients with AIDS. Vidarabine has been shown to have activity against the Herpes simplex virus in patients who do not have AIDS, but it has not been studied in patients who do have AIDS. This study compares foscarnet and vidarabine treatments for AIDS patients who have herpes simplex infection that has not responded to therapy with acyclovir in the hope that one of these two drugs will help to stop further progression of the herpes simplex infection and may have fewer side effects. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000985

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Double-Blind Placebo-Controlled Study Comparing the Combination of 15% SP-303 Gel with Acyclovir Versus Acyclovir Alone for the Treatment of Recurrent Herpes Simplex Virus (HSV) Infections in Subjects with Acquired Immunodeficiency Syndrome (AIDS) Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Shaman Pharmaceuticals Purpose - Excerpt: To evaluate the safety of topically applied SP-303 gel and to compare the efficacy of SP-303 gel in combination with acyclovir, relative to acyclovir alone, for the treatment of recurrent Herpes Simplex Virus (HSV) 1 and 2 infections, affecting the genital, perianal and neighboring areas, in patients with AIDS. Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002186 •

Herpetic Eye Disease Study (HEDS) I Condition(s): Keratitis, Herpetic; Ocular Herpes Simplex Study Status: This study is completed. Sponsor(s): National Eye Institute (NEI) Purpose - Excerpt: To evaluate the efficacy of topical corticosteroids in treating herpes simplex stromal keratitis in conjunction with topical trifluridine. To evaluate the efficacy of oral acyclovir in treating herpes simplex stromal keratitis in patients receiving concomitant topical corticosteroids and trifluridine. To evaluate the efficacy of oral acyclovir in treating herpes simplex iridocyclitis in conjunction with treatment with topical corticosteroids and trifluridine. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000138

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Phase I/II Study of High-Dose Acyclovir for Central Nervous System or Disseminated Neonatal Herpes Simplex Virus Infection Condition(s): Herpes Simplex Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: Objectives: I. Evaluate whether high-dose acyclovir decreases acute and long-term morbidity and mortality in neonates with central nervous system or disseminated herpes simplex virus (HSV) infection. II. Evaluate whether high-dose acyclovir is safe and tolerated in the newborn. III. Assess resistance to antiviral medication. IV. Amplify disease classification for the purpose of predicting prognosis. V. Assess any changes in viral excretion patterns. VI. Evaluate whether antigens and antibodies specific for HSV glycoproteins within the cerebrospinal fluid (CSF) predict long-term neurologic outcome. VII. Evaluate whether specific antigens and antibodies in the CSF appear late after treatment and are indicative of insidious reactivation of virus in the brain. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004644

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Phase III Randomized, Placebo-Controlled Study of Acyclovir Oral Suspension for Neonatal Herpes Simplex Virus Infection Limited to the Skin, Eyes, and Mouth Condition(s): Herpes Simplex Study Status: This study is completed.

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Sponsor(s): National Center for Research Resources (NCRR); National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: Objectives: I. Determine whether acyclovir (ACV) oral suspension suppresses recurrent skin lesions and improves neurologic outcome in neonates with localized herpes simplex virus type 2 infection when administered for 6 months in a placebo-controlled study. II. Determine whether the prevention of recurrent skin lesions reduces long-term neurologic morbidity. III. Determine whether resistant disease develops after oral ACV therapy. IV. Evaluate the natural history of recurrent skin lesions. V. Measure any adverse effects and laboratory abnormalities associated with long-term oral ACV therapy in infants and young children. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004757 •

SP-303T Applied to the Skin of Patients with Herpes Simplex Virus (HSV) Infection and AIDS Who Have Not Had Success with Acyclovir Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Shaman Pharmaceuticals Purpose - Excerpt: To evaluate the safety and tolerance of topically applied SP-303T in AIDS patients. To observe the effect of this drug on herpes simplex virus lesions in patients who have failed to heal in response to oral or intravenous acyclovir therapy. The lack of alternative treatments for herpes simplex virus infection in patients with AIDS and the development of resistance to acyclovir for patients requiring repeated treatment presents a therapeutic dilemma for physicians. SP-303T has good in vitro activity against resistant strains and offers a convenient and inexpensive means of drug administration in comparison to the use of intravenous medication. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002310

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The Effect of Acyclovir Treatment of the Herpes Simplex Virus (HSV) Infection on HIV Levels in the Blood Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: Part A: To evaluate the impact of HSV suppression with acyclovir ( ACV ) on HIV burden in patients with asymptomatic HSV infection and at high risk for HSV reactivation. Part B: To characterize the change in plasma HIV RNA levels and other measures of HIV burden during and after a 10 day course of ACV treatment for acute HSV infection. Approximately 70% of patients infected with HIV are concurrently infected with HSV. There is new evidence to suggest that HSV may act as a co-factor in HIV disease progression. This study will attempt to determine if the upregulation of HIV RNA that occurs during symptomatic HSV reactivation also occurs during

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asymptomatic HSV reactivation and if suppression of HSV will result in decreased levels of HIV RNA. There is a need to determine the patterns of association between HSV and HIV. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001115 •

The Effect of Valacyclovir on the Detection of HIV from Genital Herpes Lesions in HIV-Infected Patients Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Glaxo Wellcome Purpose - Excerpt: The purpose of this study is to see if valacyclovir affects the detection of HIV in genital herpes lesions in HIV-infected patients. Valacyclovir is used to treat recurrent genital herpes. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002404

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The Pilot Study of Foscarnet Cream in the Treatment of Mucocutaneous Herpes Simplex Virus Infections in Immunocompromised Patients Unresponsive to Acyclovir Treatment Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): Astra USA Purpose - Excerpt: PRIMARY: To evaluate the clinical activity of foscarnet cream on the index lesion of mucocutaneous herpes simplex virus (HSV) infections in immunocompromised patients previously unresponsive to acyclovir treatment. SECONDARY: To evaluate the clinical activity and virologic activity of foscarnet cream on all treated lesions in this patient population. To evaluate the local tolerance and side effects of treatment with foscarnet cream in this patient population. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002144

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The Safety and Effectiveness of Valacyclovir HCl in the Treatment of Herpes Simplex or Varicella/Zoster Infections in HIV-1 Infected Children Condition(s): Herpes Simplex; HIV Infections; Chickenpox Study Status: This study is terminated. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Glaxo Wellcome

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Purpose - Excerpt: To obtain tolerance, safety, and pharmacokinetic data for oral valacyclovir hydrochloride ( 256U87 ) in HIV-1 infected children with herpes simplex virus infections ( cold sores ) and/or varicella / zoster virus infections ( chicken pox / shingles ). Varicella and zoster are common problems in HIV-infected children. It is believed that chronic oral therapy with acyclovir may result in subtherapeutic concentrations of acyclovir, resulting in resistance to that drug. Valacyclovir hydrochloride, which converts to acyclovir in the body, increases acyclovir bioavailability by 3-5 fold. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001054 •

The Tolerance of HIV-Infected Patients with Herpes Group Virus Infections to Oral Doses of FIAU Condition(s): Herpes Simplex; HIV Infections; Hepatitis B Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Oclassen Pharmaceuticals Purpose - Excerpt: To determine the tolerance of HIV-infected patients to TID oral doses of FIAU syrup at 4 different dose levels. To determine the peak and trough blood levels of FIAU and its metabolites during two weeks of oral dosing with FIAU. The pyrimidine nucleoside analog FIAC and its primary deaminated uracil metabolite FIAU are highly and specifically active compounds in vitro against several herpes group viruses, particularly herpes simplex virus (HSV) types 1 and 2, varicella zoster (VZV), and cytomegalovirus (CMV), as well as hepatitis B virus (HBV). Since FIAU is the primary metabolite of FIAC and the administration of FIAU simplifies the metabolism of FIAC, it is anticipated from clinical studies of FIAC that FIAU will be tolerated at least as well as FIAC. A single-dose, pharmacokinetic (blood level) study showed that FIAC, when taken orally, is readily absorbed into the bloodstream, and most of it is converted to FIAU. Daily oral doses are expected to provide concentrations of FIAU exceeding the in vitro minimum inhibitory concentration for nearly all the herpes group viruses. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000654

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Treating Genital Herpes to Decrease Risk of HIV Transmission Condition(s): HIV Infections; Herpes Genitalis Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will test whether treating genital herpes decreases the chances of a person getting HIV. Phase(s): Phase III Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00068965 •

Treatment of Acyclovir-Resistant Mucocutaneous Herpes Simplex Disease in Patients With AIDS: Open Label Pilot Study of Topical Trifluridine Condition(s): Herpes Simplex; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Glaxo Wellcome Purpose - Excerpt: To determine the safety, effectiveness, and toxicity of topical (local) trifluridine in treating mucocutaneous (at the nasal, oral, vaginal, and anal openings) Herpes simplex virus ( HSV ) disease that has shown resistance to acyclovir in HIVinfected patients. HSV infection in patients with AIDS is often associated with skin sores and frequent recurrences. Treatment with the drug acyclovir results in healing for most patients, but repeated treatment sometimes results in resistance of the virus to acyclovir. Thus, when this happens, other treatments need to be used. Trifluridine is an antiviral drug that is used for the treatment of Herpes infections that occur in the eye. This study attempts to determine if trifluridine is useful for treating HSV sores that have not healed after treatment with acyclovir. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000635

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Valaciclovir to Prevent Transmission of Herpes Simplex Virus Condition(s): Herpes Simplex Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will evaluate the effectiveness of the drug valaciclovir in preventing transmission of genital herpes from an infected to an uninfected sexual partner. Genital herpes is caused by the herpes simplex virus 2 (HSV-2), or, infrequently herpes simplex virus 1 (HSV-1). Valaciclovir prevents the herpes virus from multiplying and may also reduce its transmission between partners. Couples 18 years of age and older in which one partner is infected with HSV-2 (source partner) and the other is not (susceptible partner), may be eligible for this study. Candidates will be screened with blood tests for routine laboratory studies and to verify the presence or absence of HSV-2 or HSV-1 infection. Participants will give a medical history, undergo a physical examination, including genital examination, and receive counseling on safer sex practices and how to recognize signs and symptoms of a possible first episode of genital herpes. Source partners will also be counseled on transmission of genital herpes, and susceptible partners will be interviewed about their sexual history and practices. The source partner will be randomly assigned to take either a 500-mg tablet of valaciclovir or placebo (a pill with no active ingredient) daily for 8 months. All participants will be given diary cards to complete for a month-the source partner will record any drug side effects and the susceptible partner will record any signs or symptoms of possible HSV infection. Participants will be seen in the clinic once a month for 8 months. At these visits, source partners will 1) return unused study medication and the completed diary card; 2) discuss any adverse drug side effects experienced in the last month; 3) review

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medications other than the study drug taken in the last month; 4) undergo counseling on safer sex practices, transmission of genital herpes, and recognizing signs and symptoms of a first episode of genital herpes; and 5) review symptoms and recurrences of genital herpes experienced during the last month. During the final visit, they will also provide a blood sample for routine testing and possible use in future studies. Susceptible partners will 1) have a blood sample drawn for HSV testing; 2) undergo safer sex counseling; 3) review any symptoms experienced over the last month; 4) be interviewed about sexual exposure and practices; and 5) return the completed diary card. Source partners who have a recurrence of genital HSV while on the study will be asked to have their lesions cultured and will be offered open-label valaciclovir treatment. Susceptible partners who contract genital herpes from the source partner during the study will have a genital examination to verify a fist episode of genital herpes and will receive 10 days of open-label treatment with valaciclovir. Cultures will be taken from the mouth and genitals, current medical conditions will be reviewed, blood samples will be drawn on treatment days 1 and 10, and treatment side effects will be reviewed on days 5 and 10. At the end of the study, infected partners will be offered a 12-month course of valaciclovir, one 500-mg tablet daily. Participants will be followed in the clinic once every 3 months to provide blood samples, return unused study medication and the diary card, discuss any drug side effects, review medications taken besides the study drug, and review symptoms or recurrences of genital herpes. All participants will be asked to complete a questionnaire for gathering information about people with genital herpes and people at risk for the infection. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001649

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “herpes simplex” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON HERPES SIMPLEX Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “herpes simplex” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on herpes simplex, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Herpes Simplex By performing a patent search focusing on herpes simplex, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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example of the type of information that you can expect to obtain from a patent search on herpes simplex: •

4-hydroxycinnoline-3-carboxyamides as antiviral agents Inventor(s): Larsen; Scott D. (Kalamazoo, MI), Nair; Sajiv K. (Kalamazoo, MI), Vaillancourt; Valerie A. (Kalamazoo, MI) Assignee(s): Pharmacia & Upjohn Company (Kalamazoo, MI) Patent Number: 6,458,788 Date filed: March 15, 2001 Abstract: Certain novel 4-hydroxycinnoline-3-carboxyamides. The compounds are particularly effective in the treatment or prevention of viral infections, particularly infections caused by herpes viruses including herpes simplex virus types 1 and 2, human herpes virus types 6, 7 and 8, varicello zoster virus, human cytomegalovirus or Epstein-Barr virus. Excerpt(s): The present invention provides novel cinnolines, which are useful as antiviral agents (e.g. as agents against viruses of the herpes family). The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV7, and HHV-8), have been shown to infect humans. U.S. Pat. No. 4,826,837 discloses 4hydroxycinnoline-3-carboxamides and their use for the treatment of neoplastic diseases and acute and chronic infections of both bacterial and viral origin in mammals. Web site: http://www.delphion.com/details?pn=US06458788__

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Anti-apoptotic compositions comprising the R1 subunit of herpes simplex virus ribonucleotide reductase or its N-terminal portion; and uses thereof Inventor(s): Langelier; Yves (Montreal, CA), Massie; Bernard (Montreal, CA) Assignee(s): Centre de Recherche du Centre Hospitalier de l'Universite de Montreal (Montreal, CA) Patent Number: 6,524,821 Date filed: April 6, 2001 Abstract: An anti-apoptotic agent and a composition derived therefrom, and methods to prevent apoptosis in vivo and in vitro are provided. The anti-apoptotic agent comprises R1 subunit of Herpes simplex virus (HSV) ribonucleotide reductase, or its N-terminal portion of about 350 amino acids. HSV-R1 inhibited TNF-.alpha. induced apoptosis, and blocked caspase 8 activation induced by TNF-.alpha. and Fas-L expression. Excerpt(s): This application claims priority to International Application No PCT/CA99/00673, filed Jul. 23, 1999 (Publ. No. WO 00/07618), and Canadian Application No 2,239,248, filed Jul. 31, 1998. The mechanisms for establishment of latent herpes simplex virus infection in neurons and the subsequent reactivation are very poorly understood. Recent studies have shown that the pattern of gene expression during reactivation is not similar to the one seen in the lytic cycle: the expression of early (E) genes, notably the gene for the subunit 1 (R1) of ribonucleotide reductase,

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begins several hours before detectable expression of the immediate early (IE) genes (1-3). HSV can be reactivated by numerous stress conditions including NGF deprivation, hyperthermia and cadmium (4) which are also known to induce neuronal cell apoptosis. Therefore, it might be advantageous for the virus to encode protein(s), which are able to block the apoptotic pathways activated by these stimuli. In addition, such proteins could be important to counteract the action of cytotoxic T lymphocytes (CTL) which prevent virus dissemination in cells of the mucosal epithelia where it replicates after being released from neurons (5). The HSV ribonucleotide reductase converts ribonucleoside diphosphates to the corresponding deoxyribonucleotides and plays a key role in the synthesis of viral DNA (reviewed in (6). The association of two subunits, R1 and R2, the former of which contains the active site, forms the holoenzyme. The R1 subunits of HSV-1 and HSV-2 possess an NH2 domain of about 350 amino acids. This is a unique feature which is not found in R1 of other species, including those of other herpes viruses (7, 8). The role of HSV ribonucleotide reductase has been extensively studied with ribonucleotide reductase null mutants. Studies first done with cultured cells showed that the enzyme is required for efficient replication in non dividing cells. Subsequently, works using animal models demonstrated that the enzyme is required for efficient pathogenicity, is essential for viral reactivation from the neurons, but is not essential for the establishment of latency (9-16). The observations that a mutant virus bearing a deletion of the reductase domain of the R1 gene (hrR3) exhibited the same phenotype in cell culture or in animal models as a virus with a deletion of both the NH2 and the reductase domains (ICP6.DELTA.) has suggested that the NH2 domain may play only a minor role in viral pathogenesis (9, 10, 13). However, as viral mutants which contain deletions only of the R1 NH2 domain have not yet been characterized for their capacity to reactivate, an important role of this domain in HSV reactivation could have been masked by the ribonucleotide reductase deficiency of the two mutants which by itself completely prevents viral replication in the latently infected neurons. Web site: http://www.delphion.com/details?pn=US06524821__ •

Combined hepatitis and herpesvirus antigen compositions Inventor(s): Stephenne; Jean (Rixensart, BE), Wettendorff; Martine Anne Cecile (RhodeSaint-Genese, BE) Assignee(s): SmithKline Beecham Biologicals S.A. (Rixensart, BE) Patent Number: 6,451,320 Date filed: October 27, 2000 Abstract: Novel combined vaccine compositions preferentially for administration to adolescents are provided, comprising a hepatitis B viral antigen and a herpes simplex viral antigen and optionally in addition one or more of the following: an EBV antigen, a hepatitis A antigen or inactivated attenuated virus, an HPV antigen, a VZV antigen, an HCMV antigen, a Toxoplasma gondii antigen. The vaccine compositions are formulated with an adjuvant which is a preferential stimulator of TH1 cell response such as 3DMPL and QS21. Excerpt(s): This application is a 371 of International Application PCT/EP99/01406, filed Mar. 4, 1999, which claims priority from GB 9805105.5, filed Mar. 9, 1998 and GB 9813561.9, filed Jun. 23, 1998. This invention relates to novel vaccine formulations, methods for preparing them and their use in therapy. In particular the present invention relates to combination vaccines for administration to adolescents. Genital herpes is estimated to occur in about 5 million people in the U.S.A. alone with 500,000 clinical

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cases recorded every year (primary and recurrent infection). Primary infection typically occurs after puberty and is characterised by the localised appearance of painful skin lesions, which persist for a period of between 2 to 3 weeks. Within the following six months after primary infection 50% of patients will experience a recurrence of the disease. About 25% of patients may experience between 10-15 recurrent episodes of the disease each year. In immunocompromised patients the incidence of high frequency recurrence is statistically higher than in the normal patient population. Web site: http://www.delphion.com/details?pn=US06451320__ •

Combined therapy with a chemotherapeutic agent and an oncolytic virus for killing tumor cells in a subject Inventor(s): Kaiser; Larry (Wynnewood, PA), Molnar-Kimber; Katherine (Worcester, PA), Toyoizumi; Takane (Philadelphia, PA) Assignee(s): The Trustees of the University of Pennsylvania (Philadelphia, PA) Patent Number: 6,428,968 Date filed: November 8, 1999 Abstract: The invention includes methods, compositions, and kits for killing tumor cells in a subject such as a human patient. The methods comprise administering both a chemotherapeutic agent and an oncolytic virus other than an adenovirus to a subject which has tumor cells. The agent and virus exhibit oncolytic activities that are at least additive, and that may be synergetic. The oncolytic virus may, for example, be a herpes simplex virus (type 1 or 2), a vaccinia virus, a vesicular stomatitis virus, or a Newcastle disease virus. The compositions and kits comprise a chemotherapeutic agent and an oncolytic virus other than an adenovirus, either in admixture or separately. Excerpt(s): The field of the invention is killing tumor cells in a subject. Cancer remains one of the leading causes of morbidity and mortality of humans worldwide. Known cancer therapies include chemotherapy, radiation, surgery, and gene therapy. The combined use of chemotherapy, radiation, and surgery has augmented the benefits of these therapies in some types of cancer, but in only a few types of cancer has it resulted in eradication of the tumor. Despite the promise afforded by gene therapy anti-cancer strategies, various shortcomings in virus vectors and other gene vectors have limited the efficacy of gene therapy methods for eradicating tumor cells from subjects such as humans afflicted with cancer. Recent advances in virology and molecular biology have made possible the engineering of recombinant virus with specific properties, creating new interest in virus-based therapy of solid tumors. One promising approach is the use of genetically modified herpes simplex virus-1 (HSV-1) to treat central nervous system (CNS) malignancies (Mineta et al., 1995, Nature Med. 1:938-943; Martuzza et al., 1991, Science 252:854-856; Market et al., 1992, J. Neurosurg. 77:590-594; Randazzo et al., 1995, Virology 211:94-101; Kesari et al., 1995, Lab. Invest. 73:636-648). Mutant HSV-1 viruses, such as HSV-1716, HSV-3616, HSV-4009, HSV-3410 and HSV-G207 have a deletion or impaired function in the gene encoding ICP34.5 which is a major determinant of pathogenicity (MacLean et al., 1991, J. Gen. Virol. 72:630-639; Chambers et al., 1995, Proc. Natl. Acad. Sci. USA 92:1411-1415; Meignier et al., 1988, J. Infect. Dis. 158:602-614; Mineta et al., 1995, Nature Med. 1:938-943). Web site: http://www.delphion.com/details?pn=US06428968__

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Electrical stimulation apparatus and method Inventor(s): Mo; Y. Joseph (Princeton, NJ) Assignee(s): NexMed Holdings, Inc. (Robbinsville, NJ) Patent Number: 6,594,527 Date filed: April 2, 2001 Abstract: An electrical stimulation apparatus and method for providing electrical stimulation to tissue. The electrical stimulation apparatus includes a base unit and an electrode module. The base unit is configured to be hand portable and contains a first electrical circuit and a first battery for supplying electrical energy to the first electrical circuit. A second electrical circuit and a second battery provide a time/date function. The base unit supports an LCD to provide a visual indication of the various functions of the electrical stimulation apparatus. The electrode module is programmable to enable the prescribing physician to set the treatment protocol for the electrical stimulation apparatus. The present apparatus is particularly well suited for the treatment of herpes simplex and herpes zoster. Excerpt(s): This invention relates to the electrical stimulation of tissue for the treatment of selected physiological conditions and, more particularly, to a novel electrical stimulation apparatus and method having an interchangeable electrode module, the electrode module serving as an activation key and being preprogrammable to deliver a predetermined treatment protocol for the particular physiological condition. Various skin lesions such as those resulting from acne and herpes virus are known to be amenable to treatment through the use of electrical stimulation. Although various theories have been advanced to explain this phenomena, to date, no satisfactory explanation has been put forth as a rationale for why these types of skin conditions can be successfully treated using electrical stimulation. In spite of this lack of explanation, various devices have been developed for the delivery of electrical stimulation to tissue. For example, U.S. Pat. No. 5,117,826 teaches a device for the combined nerve fiber treatment and body stimulation while U.S. Pat. No. 5,133,352 teaches a method for treating herpes simplex. A small size, low frequency curing apparatus is shown in U.S. Pat. No. 4,922,906. An electrotherapeutic treatment apparatus is shown in U.S. Pat. No. 5,107,835. U.S. Pat. No. 4,913,148 discloses the treatment of herpes simplex I and II as well as herpes zoster. A low frequency electrotherapeutic device is disclosed in U.S. Pat. No. 5,133,351. Each of these devices apparently resulted from the search for a device that could be used for the various therapeutic purposes as disclosed in the description of the device and its intended use. It is clear from the foregoing that electrical stimulation can be beneficial if appropriately applied to the area requiring treatment. Appropriate application includes, for example, predetermining the correct voltage of the electrical stimulation, the pulse waveform, if any, the amperage, and the application duration, to name several. Clearly, each application requires that each of the foregoing elements of the electrical stimulation must be tailored to meet the specific requirements for each patient. Web site: http://www.delphion.com/details?pn=US06594527__

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Herpes simplex virus ORF P is a repressor of viral protein synthesis Inventor(s): Bruni; Renato (Chicago, IL), Roizman; Bernard (Chicago, IL) Assignee(s): Arch Development Corporation (Chicago, IL) Patent Number: 6,383,738 Date filed: December 7, 1998 Abstract: The present invention is directed to methods and compositions relating to the treatment of herpes simplex virus infections and the screening of compounds for activity that inhibit or promote viral latency. The previously identified ORF P gene product now has been shown to interact with certain eukaryotic splicing factors and, in a cell infected with a herpesvirus containing a derepressed ORF P gene, ORF P can limit the splicing of at least two viral products. Given this function, it now is possible to screen for inhibitors and inducers of ORF P and, further, provide methods for maintaining and preventing viral latency. Excerpt(s): The present invention relates to the fields of molecular and cell biology generally, and more specifically, it addresses mechanisms for growth control in eurkaryotic cells. In particular, there are provided viral genes that inhibit viral protein synthesis and methods for use thereof. Herpes simplex viruses, designated with subtypes 1 and 2, are enveloped viruses that are among the most common infectious agents encountered by humans, infecting millions of human subjects worldwide. These viruses cause a broad spectrum of disease which ranges from relatively insignificant to severe and life-threatening. Clinical outcome of herpes infections is dependent upon early diagnosis and prompt initiation of antiviral therapy. Despite some successful efforts in treating HSV infectious, dermal and epidermal lesion often recur, and HSV infections of neonates and infections of the brain are associated with high morbidity and mortality. Herpes simplex virus 1 (HSV-1) causes two kinds of infection. The first, exemplified most dramatically after first exposure to the virus, results in productive infection at the portal of entry of the virus into the body. In productive infection, approximately 80 different genes are expressed, viral protein and DNA are made, viral progeny is assembled and, ultimately, the cell is destroyed. The second type of infection, latent infection, takes place only in sensory neurons populated by viruses brought to that sites by retrograde transport along axons from the portal of entry. In latently infected cells, viral DNA is maintained as an episome, and the only products detected to date are transcripts arising from two copies of a 8.5 kB domain of the DNA. Recombinants lacking sequences encoding the promoters and 5' domains of these RNAs, however, are capable of establishing latent infections. These finding suggested that either as yet unknown viral gene products or cellular gene products are responsible for the establishment of the latent state (Roizman and Sears, 1995). Web site: http://www.delphion.com/details?pn=US06383738__

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Herpes simplex virus VP22 vaccines and methods of use Inventor(s): Burke; Rae Lyn (San Francisco, CA), Tigges; Michael A. (Oakland, CA) Assignee(s): Chiron Corporation (Emeryville, CA) Patent Number: 6,635,258 Date filed: May 26, 1998

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Abstract: Vaccines containing herpes simplex virus (HSV) VP22 polypeptides capable of eliciting a cellular immune response and methods for treating and preventing HSV infections using the vaccines are disclosed. The vaccines can include additional HSV polypeptides, such as HSV glycoproteins. Also disclosed are methods of DNA immunization. Excerpt(s): The present invention relates generally to herpesvirus vaccine compositions. In particular, the invention pertains to vaccines containing VP22 polypeptides and methods for treating and preventing herpes simplex virus infections using the vaccines. Herpes simplex virus (HSV) infections are extremely prevalent and have a range of manifestations from apparently asymptomatic acquisition to severe disease and lifethreatening infections in the immunocompromised individual and the neonate. These infections are caused by two viruses, herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). HSV-1 is the predominant cause of oral infections and is usually acquired in childhood, whereas HSV-2 infections are usually sexually transmitted genital infections. These distinctions are blurred, however, and up to 25% of genital herpes is caused by HSV-1. Following initial infection, the virus establishes a life-long latent state and periodically reactivates, causing clinically apparent lesional episodes or asymptomatic virus shedding. Despite the availability of the antiviral agent, acyclovir, the incidence of HSV-2 in the population ranges from 8-50% and is increasing. The apparent reason for this increase is that most individuals are unaware of their infection. Moreover, the majority of transmission occurs from virus shed asymptomatically. Web site: http://www.delphion.com/details?pn=US06635258__ •

Herpes simplex virus-1 deletion variants and vaccines thereof Inventor(s): Brown; Susanne M. (Glasgow, GB), MacLean; Alasdair R. (Glasgow, GB) Assignee(s): The University Court of the University of Glasgow (Glasgow, GB) Patent Number: 6,423,528 Date filed: June 16, 1999 Abstract: Novel Herpes simplex viruses and vaccines based on such novel HSV-1 strains are described. In particular, viruses having a deletion in the terminal portion of R.sub.L are provided. The virus can be further modified to express heterologous antigens and also engineered to overproduce HSV Light particles. This is achieved by incorporating a ts mutation into the UL26 gene. Excerpt(s): This invention relates to variants of herpes simplex virus type 1 (HSV-1) which lack neurovirulence. Such variants are of value in the preparation of live attenuated vaccines for the prevention of HSV infections in humans. Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are important human pathogens which infect more than 80% of the general population and cause recurrent mucocutaneous lesions. Following replication HSV enters the peripheral nervous system where active replication is turned off by an unknown mechanism. Thereafter a latent infection in neurons is established which persists for the life of the host. HSV can reactivate from the latent state to produce infectious lesions. HSV is responsible for a broad spectrum of clinical diseases ranging from relatively benign cutaneous lesions to fatal viral encephalitis. A considerable amount of research has already been devoted to elucidation of the genetic organisation of both HSV-1 and HSV-2. The HSV-1 genome is a linear double stranded DNA molecule of approximately 152 kilobase pairs consisting of two

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components L and S. Each component consists of unique sequences U.sub.1 and U.sub.s, flanked by inverted repeats. The organisation of the HSV-2 genome is similar but not identical. For a detailed description of the genetic organisation of HSV-1 and HSV-2 (see McGeoch, 1987). Web site: http://www.delphion.com/details?pn=US06423528__ •

HIgR and related domain which binds glycoprotein D of herpes simplex virus Inventor(s): Cocchi; Francesca (Sasso Marconi, IT), Fiume; Gabriella Campadelli (Bologna, IT), Lopez; Marc (Marseilles, FR), Menotti; Laura (Bologna, IT) Assignee(s): Inserm Institut National de la Sante et de la Recherche Medicale (Paris, FR), Universita' Degli Studi di Bologna (Bologna, IT) Patent Number: 6,469,155 Date filed: November 9, 1999 Abstract: The present invention relates to an immunoglobulin-like protein useful in preventing or treating pathologies concerned with herpes simplex virus 1, herpes simplex virus 2 infections in humans. Excerpt(s): The present invention relates to HIgR (herpesviris immunoglobulin-like receptor) for the manufacture of medicaments for preventing or treating HSV-1, HSV-2 infections. The present invention also relates to a novel immunoglobulin-like protein and medicaments which incorporate said antibodies and are useful in preventing or treating pathologies concerned with herpes simplex virus 1, herpes simplex virus 2 infections in humans. The invention also relates to methods for obtaining cell lines resistant to HSV-1, HSV-2 and BHV-1 infections and to cell lines expressing specific receptors which mediate entry of said virus within cellular environment to test efficacy of antiherpes drugs and antibodies, antiherpesvirus vaccines and herpesvirus-based vectors. Alphaherpesviruses which includes HSV-1, HSV-2, PRV, and BHV-1, infect a variety of cells resulting in efficient virus production in a short replicative cycle. Infection in the mammals results in lesion of the mucocutaneous tissue, and specifically in humans produces lesion on the mucosal surfaces, with spread of virus to the nervous system and establishment of latent infections in neurons. Infections may lead in some cases, to encephalitis or meningitis, with an often fatal outcome. Web site: http://www.delphion.com/details?pn=US06469155__

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Identification of a transforming fragment of herpes simplex type 2 and detection thereof in clinical specimens Inventor(s): Coutlee; Fran.cedilla.ois (Montreal, CA), Dipaolo; Joseph A. (Bethesda, MD), Kessous; Allegria (Cote St-Luc, CA) Assignee(s): The United States of America as represented by the Department of Health and (Washington, DC), Universite de Montreal () Patent Number: 6,617,103 Date filed: August 13, 1999 Abstract: The present invention relates to oligonucleotide probes derived from HSV-2, capable of selectively hybridizing thereto and to a subsequence of HSV-2 BglII N from which the oligonucleotide probes were derived. Further, the invention relates to an

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optimized assay of nudeic acid amplification permitting the sensitive and specific detection in clinical specimens of HSV-2 as well as a specific typing of the HSV in the sample. The present invention further relates to kits for the detection and typing of the HSV in a sample. In addition, the invention provides the nucleic acid and amino acid sequence of a subsequence of HSV-2 BglII N having transforming activity. Further, the invention teaches diagnostic and therapeutic methods for genital cancer comprising the use of these sequences or ligands directed thereto. Excerpt(s): The present invention relates to the detection of Herpes Simplex type 2 (HSV-2), more particularly, the invention relates to a transforming fragment of HSV-2 and to the detection thereof in clinical specimens. Nearly one fifth of adults in the United States are infected with herpes simplex virus type 2 (HSV-2). Although HSV-2 is the most common cause of genital ulceration in developed countries, subclinical HSV-2 infections are suspected to affect a more important proportion of infected individuals. HSV-2 has also been proposed as a causative agent of genital cancer (Guibinga et al., 1995, Arch. STD/HIV Res. 9:163-179). However conflicting results from in vitro and in vivo studies have shed doubts on the role of this agent in cancer of the uterine cervix (Guibinga et al., 1995, Arch. STD/HIV Res. 9:163-179). A transforming region of the HSV-2 genome--the 7.6 kb BglII N (m.u. 0.58-0.63) segment--has been identified, using transfection experiments. This was further supported by studies showing that BglII N sequences can also cooperate with oncogenic papillomas viruses to transform cells (DiPaolo et al., 1990, Virol. 777-779). Initially, the transforming ability of HSV-2 was thought to be located on the left-end (Xho-3 subfragment) of the BglII N segment (Galloway et al., 1983, Nature 392:21-24; Ibid., 1984, Proc. Natl. Acad. Sci. USA 81:47364740). However, neither the presence of a viral protein (Galloway et al., 1982, J. Virol. 42:530-537; Vonka et al., 1987, Adv. Cancer Res. 48:149-191) nor the persistence or integration (Galloway et al., 1983; Vonka et al., 1987) of specific HSV sequences, seemed to be required for the maintenance of the transformed phenotype (Pilon et al., 1989, Biochem. Biophys. Res. Comm. 159:1249-1261). The transforming ability of HSV-2 was left unexplained. Transfection of NIH 3T3 cells with the right-end (Kessous-Elbaz et al., 1989, J. Gen. Virol. 70:2171-2177; Pilon et al., 1989; Saavedra et al., 1985, EMBO J. 4:34193426) of the BglII N fragment (the Xho-1 and Xho-2 subfragments) showed an increase in the number of transformed foci, and HSV-2 sequences were retained more efficiently in transformed cells (Kessous-Elbaz et al., 1989; Pilon et al., 1989; Saavedra et al., 1985). A number of clinical and epidemiologic studies have concluded that high risk papillomaviruses, such as HPV-16 and HPV-18 are necessary for the development of cervical cancer, but the long delay following infection indicates the importance of other factors (Kessler, 1986, In: Viral Etiology of Cervical Cancer, Peto et al., Eds. Cold Spring Harbor, N.Y., 55-64; and, zur Hauzen, 1989, Cancer Research 49:46774681), particularly other sexually transmitted infections (Kaufman et al., 1986, Clin. Obstet. Gynecol. 29:678-698; Macnab et al., 1989, Biomed. and Pharmacother. 43:167-172; zur Hausen, 1982, Lancet 2:1370-1372), for the development of malignancy. Although the etiologic link between herpes simplex virus-2 (HSV-2) and cervical cancer was proposed over two decades ago, the significance of the importance of HSV-2 to cervical cancer has been rather recent. The role for HSV-2 infection has been based primarily on seroepidemiological data (Nahmias et al., 1970, Am. J. Epidemiol. 91:547-552; Rawls et al., 1968, Am. J. Epidemiol. 87:647-656) and on observation of viral antigens in exfoliated cells from patients with cervical dysplasia and cancer (Royston et al., 1970, Proc. Nat. Acad. Sci. 67:204-212). The difficulty in establishing a strong association was compounded by the lack of persistence of HSV sequences in the neoplastic cervical lesions (Macnab et al., 1989, Biomed. and Pharmacother. 43:167-172). In fact, in a prospective case-control study (Vonka, 1984, Int. J. Cancer 33:61-65) the investigators

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failed to observe such an association, which was later suggested may have resulted from overmatching of the cohort of women for sexual activity that minimized the risk factor (Reeves et al., 1989, New Engl. J. Med. 320:1437-1441). In other studies the lack of correlation of HSV-2 with cervical cancer was attributed to the use of immunoglobulin G instead of immunoglobulin A as a marker for the presence of HSV-2 (Corbino et al., 1989, Eur. J. Gynaecol. Oncol. 10:103-108). Web site: http://www.delphion.com/details?pn=US06617103__ •

Immunogenic composition of interleukin-12 (IL-12), alum, herpes simplex viral (HSV) antigen, and method thereof Inventor(s): Eldridge; John H. (Fairport, NY), Mishkin; Eric M. (Monroe, NY) Assignee(s): Wyeth (Madison, NJ) Patent Number: 6,488,936 Date filed: February 10, 1999 Abstract: This invention pertains to vaccine compositions comprising a mixture of antigen, such as a herpes simplex virus antigen, and the interleukin IL-12, which may be adsorbed onto a mineral in suspension. These vaccine compositions modulate the protective immune response to the antigen. Excerpt(s): The immune system uses many mechanisms for attacking pathogens; however, not all of these mechanisms are necessarily activated after immunization. Protective immunity induced by vaccination is dependent on the capacity of the vaccine to elicit the appropriate immune response to resist or eliminate the pathogen. Depending on the pathogen, this may require a cell-mediated and/or humoral immune response. The current paradigm for the role of helper T cells in the immune response is that T cells can be separated into subsets on the basis of the cytokines they produce, and that the distinct cytokine profile observed in these cells determines their function. This T cell model Includes two major subsets: TH-1 cells that produce IL-2 and interferon.gamma. (IFN-.gamma.) which augment both cellular and humoral immune responses, and TH-2 cells that produce IL-4, IL-5 and IL-10 which augment humoral immune responses (Mosmann et al., J. Immunol. 126:2348 (1986)). It is often desirable to enhance the immunogenic potency of an antigen in order to obtain a stronger immune response in the organism being immunized and to strengthen host resistance to the antigen-bearing agent. A substance that enhances the immunogenicity of an antigen with which it is administered is known as an adjuvant. For example, certain lymphokines have been shown to have adjuvant activity, thereby enhancing the immune response to an antigen (Nencioni et al., J. Immunol. 139:800-804 (1987); EP285441 to Howard et al.). This invention pertains to vaccine compositions comprising a mixture of herpes simplex virus glycoprotein D, the interleukin IL-12 and a mineral in suspension. The IL-12 may be either adsorbed onto the mineral suspension or simply mixed therewith. In a particular embodiment of the invention, the IL-12 is adsorbed onto a mineral suspension such as alum (e.g., aluminum hydroxide or aluminum phosphate). In a particular embodiment, the IL-12 is human IL-12. The invention also pertains to vaccine compositions which further comprise a physiologically acceptable vehicle. The invention further relates to immunogenic compositions comprising a mixture of a herpes simplex virus glycoprotein D, an adjuvant amount of interleukin12, a mineral in suspension, and optionally comprising a physiologically acceptable vehicle.

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Web site: http://www.delphion.com/details?pn=US06488936__ •

Immunogenic conjugated polypeptide for treatment of herpes simplex virus Inventor(s): Rosenthal; Kenneth S. (Akron, OH), Zimmerman; Daniel H. (Bethesda, MD) Assignee(s): CEL-SCI Corporation (Vienna, VA) Patent Number: 6,572,860 Date filed: March 30, 2000 Abstract: Peptide constructs chemically synthesized to contain a Herpes Simplex Virus specific antigenic peptide, such as, the 322-332 peptide (H1) from the ICP27 protein of Herpes Simplex Virus (HSV-1) and a peptide from a T cell binding ligand (TCBL), such as.beta.-2M (aa 35-50), which elicits a TH1-like response in vitro tests in mice, were protective against challenge with HSV. Excerpt(s): This invention relates to peptide conjugates which can be used to form an immunogenic composition useful to activate the immune system of a patient exposed to or at risk of infection by Herpes Simplex Virus (HSV). More particularly, this invention relates to immunogenic conjugated peptides which contain both a herpes simplex virus specific peptide and an immunomodulatory peptide covalently linked directly or via a linking group and to compositions and diagnostic products containing and methods using such peptide conjugates in the treatment, prevention, or diagnosis of herpes simplex virus. Herpes simplex virus type 1 (HSV-1) and its close cousin, herpes simplex virus type 2 (HSV-2), cause various benign diseases, such as the common cold sore found near the lips and also genital herpes. Herpes simplex virus can also cause serious disease upon infection of the eye (e.g., keratoconjunctivitis, with the potential to lead to blindness), the brain (e.g., encephalitis). Individuals who are immunosuppressed, such as a newborn baby, AIDS patient or transplant patient, are especially vulnerable. HSV infections of immunocompromised individuals and neonates can lead to disseminated and life-threatening disease. Unlike many viruses, once an individual is infected with HSV, the virus remains latent in neurons and can be reactivated by stress or immunosuppression and cause recurrent disease. A herpes simplex virus vaccine has the potential for use as both a prophylactic to prevent initial infection as well as a treatment to prevent or ameliorate recurrent disease. No vaccine is currently available for prevention or treatment of HSV. Live vaccine development has been hampered because HSV has the capacity to establish latent infection and potentially, to promote neoplastic transformation of cells. The efficacy of live attenuated killed and subunit vaccines has been questioned due to difficulties in eliciting protective cell mediated immune responses. Web site: http://www.delphion.com/details?pn=US06572860__

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Immunological herpes simplex virus antigens and methods for use thereof Inventor(s): Corey; Lawrence (Seattle, WA), Koelle; David M. (Seattle, WA) Assignee(s): University of Washington (Seattle, WA) Patent Number: 6,375,952 Date filed: August 5, 1999

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Abstract: The invention provides HSV antigens that are useful for the prevention and treatment of HSV infection. Disclosed herein are antigens and/or their constituent epitopes confirmed to be recognized by T-cells derived from herpetic lesions or from uterine cervix. T-cells having specificity for antigens of the invention have demonstrated cytotoxic activity against cells loaded with virally-encoded peptide epitopes, and in many cases, against cells infected with HSV. The identification of immunogenic antigens responsible for T-cell specificity provides improved anti-viral therapeutic and prophylactic strategies. Compositions containing antigens or polynucleotides encoding antigens of the invention provide effectively targeted vaccines for prevention and treatment of HSV infection. Excerpt(s): Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention pertains. The invention relates to molecules, compositions and methods that can be used for the treatment and prevention of herpes simplex virus (HSV) infection. More particularly, the invention identifies epitopes of HSV proteins that can be used for the development of methods, molecules and compositions that stimulate or augment HSV-specific immunity. The complete, known DNA sequence of HSV types 1 and 2 are approximately 160 kb and encodes about 85 genes, each of which encodes at least one protein. Unknown are the immunological epitopes within these proteins, each epitope approximately 9-12 amino acids in length, that are capable of eliciting an effective T cell immune response to viral infection. Cellular immune responses are required to limit the severity of recurrent HSV infection in humans. HSV-specific CD4 T cells can be cytotoxic towards virally-infected cells (M. Yasukawa et a., 1991, J. Immunol., 146:1341-1347; M. Yasukawa et al., 1984, J. Immunol., 133:2736-42). HSV-specific T cells can also reduce the titer of HSV replication in HSV-infected, HLA-matched cells, produce lymphokines with antiviral or immunomodulatory activity, or provide specific B cell help to augment antiviral antibody responses. References relating to the antigenic specificity of HSVspecific T cells include: A. G. Langenberg et al., 1995, Ann. Int. Med. 122:889-898; A. Mikloska et al., 1998, J. Gen. Virol., 79:353-361; J. W. Torseth et al., 1987, J. Virol., 61:15321539; M. Yasukawa et al., 1985, J. Immunol., 134:2679-2687. Web site: http://www.delphion.com/details?pn=US06375952__ •

Method and reagent for inhibiting herpes simplex virus replication Inventor(s): Draper; Kenneth G. (Boulder, CO) Assignee(s): Ribozyme Pharmaceuticals, Inc. (Boulder, CO) Patent Number: 6,432,704 Date filed: June 28, 1999 Abstract: An enzymatic RNA molecule which specifically cleaves a herpes simplex virus mRNA molecule. Excerpt(s): This invention relates to reagents useful as inhibitors of herpes simplex virus (HSV) replication and gene expression. The following is a discussion of relevant art, none of which is admitted to be prior art to the pending claims. Human herpesviruses cause a wide variety of diseases which result in significant levels of morbidity and mortality worldwide. The HSV group accounts for about one million new cases of infection each year in the United States. These infections are maintained for the lifetime of the patient as latent viral infections, which can be stimulated to reactivate by a variety

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of factors. The manifestations of HSV infection range from mild infections of herpes labialis to more serious infections such as herpes encephalitis. Web site: http://www.delphion.com/details?pn=US06432704__ •

Method and topical treatment composition for herpesvirus hominis Inventor(s): Squires; Meryl (Elmhurst, IL) Assignee(s): Squires; Meryl J. (Barrington Hills, IL) Patent Number: 6,348,503 Date filed: February 12, 1996 Abstract: Improved topical treatment of active phase lesions resulting from recurrent viral infection by herpes simplex virus which includes the use of two primary agents, namely, an aqueous solution of benzalkonium halide, preferably benzalkonium chloride, and a dry form of the herb Echinacea purpurea, preferably in powder form. Active phase herpes lesions are wetted with the benzalkonium chloride solution and dusted with the powder form of Echinacea purpurea to create a coating on the wetted lesion surface. The coating is maintained on the lesion throughout treatment, and unexpected rapid resolution of the lesions results. Excerpt(s): The present invention generally relates to methods and compositions for the treatment of herpes simplex virus and, in particular, to a method and composition for topical treatment of active phase lesions resulting from recurrent viral infection caused by herpes simplex virus. Recurrent viral infection by herpes simplex virus, also known as Herpesvirus Hominis, is characterized by lesions which may appear anywhere on the skin or mucosa. Eventually, the lesion base inflames and develops clusters of small fluid-filled vesicles. Without treatment, the vesicles and lesions will resolve in several days to dry scabs. There are two known strains of herpes simplex virus (HSV), namely, HSV-1, commonly causing herpes labialis and keratitis, and HSV-2, which is usually genital herpes. Treatment of herpes lesions often includes application of topical agents such as idoxuridine, trifluorothymidine, or acyclovir. In addition, prior art patents also disclose various compositions and methods for topical treatment of symptoms of herpes simplex virus which may include use of anti-viral agents, such as benzalkonium chloride, e.g., U.S. Pat. Nos. 4,283,421, 4,585,656, 4,661,354, 4,760,079, 4,803,224 and 4,797,420. None of these compositions, however, employ the combination of treatment agents disclosed herein. Web site: http://www.delphion.com/details?pn=US06348503__

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Methods for electrokinetic delivery of medicaments Inventor(s): Henley; Julian L. (Guilford, CT) Assignee(s): Biophoretic Therapeutic Systems, LLC (Framingham, MA) Patent Number: 6,385,487 Date filed: December 4, 1998 Abstract: Drugs and a portable iontophoresis apparatus for facilitating delivery of the drugs across the cutaneous membrane into adjacent underlying tissues and blood vessels. The apparatus employs a modular, detachable non-reusable medicamentcontaining applicator electrode which is adapted to attach to a base assembly. The

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apparatus is designed to be hand-held and includes a circumferential tactile electrode band on the base assembly which provides electrical connection between the skin of the user's hand and one pole of a bipolar power source housed within the base assembly. The opposing pole of the power source is connected to the applicator electrode. When the applicator is placed against the skin of a user, the user's body completes the electrical circuit between the applicator and tactile electrodes. The apparatus employs a disposable applicator electrode which accepts a variety of antimicrobial and anesthetic agents for transdermal iontophoretic or ionosonic delivery. A method for using the device for the treatment of Herpes simplex infection and related viral infections which produce similar cutaneous lesions is presented. The apparatus, when used in accordance with the antiviral medicaments and method described herein, demonstrated >90% treatment efficacy in clinical trials. Excerpt(s): This invention relates generally to the transdermal electrokinetic mass transfer of medication into a diseased tissue and, more specifically, to iontophoretically transportable agents and a portable apparatus for the iontophoretic delivery of medication, including antimicrobial and anesthetic agents, across the skin. The apparatus provides a new method for treating and managing diseases presenting cutaneous lesions and administering anesthesia. Iontophoresis has been employed for several centuries as a means for applying medication locally through a patient's skin and for delivering medicaments to the eyes and ears. The application of an electric field to the skin is known to greatly enhance the skin's permeability to various ionic agents. The use of iontophoretic transdermal delivery techniques has obviated the need for hypodermic injection for many medicaments, thereby eliminating the concomitant problems of trauma, pain and risk of infection. Iontophoresis involves the application of an electromotive force to drive or repel oppositely charged ions through the dermal layers into a target tissue. Particularly suitable target tissue includes tissues adjacent to the delivery site for localized treatment or tissues remote therefrom in which case the medicament enters into the circulatory system and is transported to a tissue by the blood. Positively charged ions are driven into the skin at an anode while negatively charged ions are driven into the skin at a cathode. Studies have shown increased skin penetration of drugs at anodic or cathodic electrodes regardless of the predominant molecular ionic charge on the drug. This effect is mediated by polarization and osmotic effects. Web site: http://www.delphion.com/details?pn=US06385487__ •

Methods for identifying cell cycle regulators Inventor(s): Brown; Susanne M. (Glasgow, GB), Harland; June (Glasgow, GB), Maclean; Alasdair R. (Glasgow, GB) Assignee(s): The University Court of the University of Glasgow (Glasgow, GB) Patent Number: 6,641,995 Date filed: December 29, 2000 Abstract: A method is disclosed for identifying a substance capable of disrupting an interaction between (i) a herpes simplex virus (HSV) ICP34.5 polypeptide or a homologue thereof, or a derivative thereof, and (ii) proliferating cell nuclear antigen (PCNA) or a homologue thereof, or a derivative thereof, which method comprises: (a) providing an HSV ICP34.5 polypeptide or a homologue thereof, or a derivative thereof, as a first component; (b) providing PCNA, or a homologue thereof, or a derivative thereof, as a second component; (c) contacting the two components with a substance to

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be tested under conditions that would permit the two components to interact in the absence of the said substance; and (d) determining whether the said substance disrupts the interaction between the first and second components. Excerpt(s): This invention relates to methods for identifying substances capable of regulating the cell cycle. It further relates to the use of said substances in treating or preventing viral infection, cancer or cell death. Herpes simplex virus (HSV) has a virulence determining locus in the long repeat region of its genome (Ackermann et al., 1986; Chou and Roizman, 1990; McGeoch et al., 1991; Dolan et al., 1992). The virulence phenotype has been specifically assigned to the RL1 gene and its encoded protein ICP34.5 (McKie et al., 1994). Null mutants in ICP34.5 are totally avirulent in mice (Taha et al., 1989a, b; Chou et al., 1990; MacLean et al., 1991) and the function of the protein in vitro has been shown to be cell type and cell state specific, depending on the stage in the cell cycle and the differentiation state (Brown et al., 1994). One ICP34.5 function demonstrated in a human neuroblastoma cell line is the preclusion of host cell protein synthesis shut-off via the protein kinase PKR pathway following HSV infection (Chou and Roizman, 1992; Chou et al., 1995). This response to expression of ICP34.5 is however not ubiquitous and the precise molecular functions of ICP34.5 remain unknown. Web site: http://www.delphion.com/details?pn=US06641995__ •

Methods for treating subjects infected with a herpes virus Inventor(s): Docherty; John (Kent, OH), Tsai; Chun-che (Kent, OH) Assignee(s): Kent State University (Kent, OH), Northeastern Ohio Universities College of Medicine (Rootstown, OH) Patent Number: 6,599,945 Date filed: August 15, 2001 Abstract: The present invention provides a method of inhibiting the formation of infectious herpes virus particles, particularly infectious herpes simplex virus (HSV) particles, in a host cell. The method involves administering an effective amount of a hydroxylated tolan, particularly a polyhydroxylated tolan, to a herpes virus infected host cell. The present invention also provides a method of treating a herpes virus infection, particularly an HSV infection. The method comprises administering a topical composition comprising a therapeutically effective amount of a hydroxylated tolan to a herpes virus-infected site. The present invention also relates to a topical composition for treating a herpes virus infection selected from the group consisting of an HSV infection, a cytomegalovirus infection, and a varicella zoster virus infection. The present invention also provides a method of treating a subject infected with Neisseria gonorrhea. Excerpt(s): The present invention relates to compositions which inhibit replication of herpes virus and the bacterium Neisseria gonorrheae, and methods of using such compositions to treat subjects infected with these microorganisms. Human herpes viruses can infect host cells in virtually any organ of the human body. Replication of a herpes virus within an infected host cell leads to lysis of the infected cell and the release of large numbers of infectious virus. The infectious particles released from the lysed cell can infect and destroy other cells at or near the site of the initial infection. These infectious particles can also be transmitted to a non-infected individual. Human herpes viruses can also enter and remain latent, i.e., in the non-replicative state, in other cells of the afflicted individual for life. This life-long infection serves as a reservoir of infectious virus for recurrent infections in the afflicted individual and as a source of infection for

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an unwitting contact. At least four of the human herpes viruses, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), and varicella zoster virus (VZV) are known to infect and cause lesions in the eye of certain infected individuals. Together, these four viruses are the leading cause of infectious blindness in the developed world. Web site: http://www.delphion.com/details?pn=US06599945__ •

Nucleoside analogs in combination therapy of herpes simplex infections Inventor(s): Boyd; Malcolm Richard (Epsom, GB) Assignee(s): Novartis International Pharmaceutical Ltd. (Hamilton, BM) Patent Number: 6,514,980 Date filed: July 26, 2000 Abstract: A pharmaceutical product comprising a nucleoside analogue active against herpes simplex virus, such as acyclovir/valaciclovir or penciclorivir/famciclovir, and an immunosuppressant, as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of herpes simplex virus infections. Excerpt(s): This invention relates to the use of a nucleoside analogue active against herpes simplex virus (HSV), in the treatment of herpes simplex virus infections, and to pharmaceutical compositions containing the two components. The disease indication for herpes simplex subtype 1 (HSV-1) is herpes labialis (cold sores), and the disease indication for herpes simplex subtype 2 (HSV-2) is genital herpes. Herpes Labialis is a common world-wide disease characterized by repeated attacks of versicular eruptions most commonly recognised on the lips and perioral skin. Many patients report pain, swelling and significant cosmetic concerns associated with subsequent ulceration of lesions. Although generally a minor disease, in some patients the consequences of frequent severe attacks can be debilitating. The disease is naturally self-limiting in immunecompetent individuals and recurrent episodes last 7-10 days. Web site: http://www.delphion.com/details?pn=US06514980__

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Pharmaceutical composition of escherichia coli heat-labile enterotoxin adjuvant and methods of use Inventor(s): Clements; John D (New Orleans, LA) Assignee(s): The United States of America as represented by the Secretary of the Navy (Washington, DC) Patent Number: 6,413,523 Date filed: February 23, 1995 Abstract: Novel immunoregulatory utilities of Escherichi coli heat-labile enterotoxin (LT) are disclosed. This enterotoxin can be used in combination with an unrelated antigen to achieve a higher immune response to said antigen when administered as part of an oral vaccine preparation. By way of example, the efficacy of oral adjuvant therapy of LT in the development of immunological protection against herpes simplex virus was examined. In addition, the ability of LT to influence the induction and maintenance of tolerance in animals primed orally with two unrelated protein antigens administered simultaneously, OVA and BSA was examined. Simultaneous administration of LT with

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OVA was shown to prevent the induction of tolerance to OVA and to increase the serum anti-OVA IgG response to 30-90 fold over PBS primed and OVA primed animals, respectively. Excerpt(s): Oral immunization can lead to loss of systemic reactivity in response to subsequent parenteral injection of the specific antigen (Challacombe and Tomasi, 1980, J. Exp. Med. 152:1459-1472). This phenomenon of immune tolerance after ingestion of antigen has been shown to occur in numerous animal models. A variety of effects may account for this phenomenon, including (a) antigen overload, (b) induction of antigenspecific suppressor T cells, and (c) clonal deletion of antigen-specific T and B cells [recently reviewed by Siskind] (Siskind, 1984, In: Fundamental Immunology (Ed. Paul) Raven Press, New York, pp. 537-558). The abrogation of tolerance (or prevention of its induction) has also been widely examined (Green and Ptak, 1986, Immunol. Today 7:8187; La Tont, et al., 1982, J. Exp. Med. 142:1573-1578; Suzuki, 1986, Nature 320:451-454). In general, it has been observed that the the ability to influence induction of tolerance depends upon the cellular basis of the state of tolerance. Tolerance can be either complete or partial, and is influenced by antigen dose and characteristics, route of administration, physiological state of the organism, and genetic characteristics of the organism. It has also been shown that tolerance can be terminated or prevented by various manipulations, depending upon the cellular basis of the state of tolerance. Recently it has been demonstrated that administration of cholera toxin (CT) can abrogate oral tolerance to an unrelated antigen (Elson and Ealding, 1984a, J. Immunol. 132:2736-2741). CT, an 84,000 dalton polymeric protein produced by Vibrio cholerae, consists of two subunits, designated A and B. The 56,000 dalton B subunit binds the toxin to its cell surface receptor, the monosialosylganglioside G.sub.M1, and facilitates the penetration of the toxic 28,000 dalton A subunit into the cell. The A subunit catalyzes the ADP-ribosylation of the stimulatory GTP-binding protein (G.sub.S) in the adenylate cyclase enzyme complex and this results in increasing intracellular levels of adenosine 3', 5'-cyclic monophosphate (cAMP) (Finkelstein, 1973, CRC Crit. Rev. Microbiol. 2:553623; In Mechanisms of Bacterial Toxinology (Ed. Bemheimer) John Wiley and Sons, Inc., New York, pp. 53-84). Some strains of Escherichia coli produce an immunologically and structurally related heat-labile enterotoxin (LT) that has the same subunit organization and arrangement as CT and that works by the same 20 mechanism of action (Clements and Finkelstein, 1979, Infect. Immun. 24:760-769; Clements et al. 1980, Infect. Immun. 29:91-97). Although there are many similarities between CT and LT, there are also immunologic and structural differences between the two toxins (Clements and Finkelstein, 1979; Clements et al., 1980). It should be noted that the relative immunoregulatory potential of LT has not been thoroughly investigated. Recently, a clone of E. coli that produces only the binding subunit of the LT toxin (LT-B) was developed (Clements et al., 1983, Infect. Immun. 40: 653-658; Clements and El-Morshidy, Infect. Immun. 46: 564-569). Escherichia coli heat-labile enterotoxin and heat-stable enterotoxin have previously been used in compositions that are effective in providing immunologic protection in mammals against acute diarrheal disease caused by enterotoxigenic strains of E. coli. See U.S. Patents 4,053,584; 4,314,993; and 4,411,888 which are incorporated herein by reference; and Frantz et al., 1987, Infect. Immun. 55: 1077-1084, Hussaini and Sawtell, 1986, Dev. Biol. Stand. 64: 261-269. Web site: http://www.delphion.com/details?pn=US06413523__

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Phototherapeutic inactivation of ocular viruses Inventor(s): Crean; David H. (Santa Barbara, CA), Kupperman; Baruch D. (Laguna Beach, CA) Assignee(s): PDT Systems, Inc. (Santa Barbara, CA), The Regents of the University of California (Oakland, CA) Patent Number: 6,586,419 Date filed: April 16, 1997 Abstract: A method for inactivating ocular viral pathogens and for treating associated lesions on tissue by means of selectively activating a tissue-associated photosensitizing agent with light. The photosensitizing agent, preferably tin ethyl etiopurpurin, is administered to a patient to concentrate within the lesionous target tissue of the eye. The photosensitizer-laden target tissue is irradiated with photoactivating light. In preclinical in vitro studies, the photoactivated photosensitizer drug within the lesionous target tissue inactivates both cell free Herpes simplex virus (HSV) and cell-associated HSV and cytomegalovirus (CMV). The use of PDT for treating ocular viral diseases reduces the toxicity to the biological system when compared with prior art therapeutic procedures. Excerpt(s): This invention describes a method for treating ocular viral diseases using photodynamic therapy. In order to give a clinical perspective to the significance of viral ocular infections, for example, cytomegalovirus (CMV) retinitis is the most common ocular apportunistic infection and the leading cause of blindness in patients having Acquired Inmune Deficiency Syndrome (AIDS) 30,000 new case being each year in the United States alone. CMV related retinitis has been fond in 30% of AIDS patents, typically late in their diseases processes. The drugs, ganciclovir, and foscarnet, are effective in the treatment of CMV retinitis. With 82%-100% of patents exhibit an initial response to therapy with either drug. All three drugs are virostatic and require daily systemic intravenous administration for the remainder of the patients lives. Such systemic intravenous administration requires the use of an indevelling catheter which has been associated with high rates of infection. In addition all three drugs exhibit various systemic toxicity; with ganciclovir suppressing the bone marrow and both anywhere and foscarnet causing renal toxicity. The use of these compounds for untying ocular retinitisis discussed by Kupparmann, et al. in Ann I Opthalmol, 1993; 115:575-582; and by Holland et al. in Ophthalmol 1987; 94:815-823, and by Caleri et al in Ann. Intern. Med. 1977 126;257-263, A further discussion of the use of theses drugs for treating a retinitis of viral etiology is presented by various AIDS research groups in the New England journal of medicine, 1992; 326; 213-220. Prior to the advent of antiviral therapy (both anti-CMV and anti-HIV) AIDS patients wit CMV retinitis typically survived only 6 weeks after developing the latter infection. In the current setting of anti-HIV therapy and anti-CMV therapy, median survival has recently been shown to be 8.5 months for patients receiving ganciclovir and 12.6 months for patients receiving foscarnet and more recent studies suggest that median survival is now approaching two years. Longer survival has been associated with greater difficulty related to the continuous suppression of the retinitis over this extended period. Recurrence of the retinitis while on therapy has been reported to occur in 50% of patients within 3 months. (Gross, et al. Ophthalmol. 1990; 97:681-686.) Because of the high incidence of reactivation following the initial favorable response to therapy, the current measure of anti-CMV drug efficacy is based on the length of time to recurrence in addition to the initial therapeutic response to the drug. The fact that the efficacy of anti-CMV agents is, in part, measured by the agents' ability to prolong the interval for viral reactivation rather than by its

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ability to effect permanent suppression of viral activity emphasizes the marginal clinical effectiveness of current regimens wherein ganciclovir, acyclovir and foscarnet are administered intravenously. While these three drugs are preventing blindness in most AIDS patients, many patients are still losing their sight. A therapeutic procedure for controlling viral retinitis which reduces systemic toxicity over the current therapies is needed. Web site: http://www.delphion.com/details?pn=US06586419__ •

Production of recombinant proteins using herpes virus promoters and VP16 transactivators Inventor(s): Highkin; Maureen Katherine (St. Louis, MO), Hippenmeyer; Paul Jerome (St. Louis, MO) Assignee(s): G. D. Searle & Co. (Chicago, IL) Patent Number: 6,635,478 Date filed: April 30, 1996 Abstract: Stable cell lines are produced to express high levels of a gene product of interest using VP16, a herpes simplex virus transactivator, and a promoter from herpes simplex virus which is a target for VP16. The transactivator and promoter are introduced to a cell line separately using antibiotic resistance genes as selectable markers on separate vectors. Excerpt(s): This invention pertains to production of recombinant proteins and more particularly to a means of heterologous gene transactivation. The ability to efficiently produce recombinant proteins in mammalian cell culture is critical for the production of both research agents and commercial products. Several approaches and host vector systems for the production of recombinant proteins have been reviewed (Kaufman, Genetic Engineering, Principles and Methods, vol. 9, J. K, Setlow, ed., Plenum Press, New, York, 1987; Warren et al., Recombinant DNA Technology and Applications, A. Prokop, R. Bajpai and C. Ho, eds., McGraw Hill, New York, 1990). These systems include use of high copy episomal vectors such as bovine papillomavirus (Howley et al., Methods in Enzymology, vol. 101, Academic Press, New York, 1983), amplifiable vectors such as those containing the dihydrofolate reductase gene (Kaufman,supra), the asparagine synthetase gene (Andrulis, Molecular Cell Genetics, vol. 17, 1985) or the ornithine decarboxylase gene (McConlogue, Gene Transfer Vectors for Mammalian Cells. 1987) or strong constitutive promoters such as the simian virus 40 promoter (Mulligan et al., Science. vol. 209, pp. 1422-1427, 1980) or the human cytomegalovirus major early promoter (Boshart et al., Cell, vol. 41, pp. 521-530, 1985). All of these systems rely upon the levels of endogenous transactivators in the particular cell type to stimulate transcription of the promoters used to construct the expression vectors. An alternative approach to high level production would be to engineer cells with a specific transcriptional activator or transactivator. If the transactivator has a specific target promoter, then the target promoter can be linked to a gene of interest and inserted into the engineered cell. The amount of target protein produced from that cell would depend on several parameters. First, the inherent specific activity of the transactivator will be a factor in the amount of transcription from the target promoter. In addition, the amount of transactivator produced by the target cell will affect the amount of transactivation. For instance, in Chinese hamster ovary cells (CHO) there is a low level of endogenous glucocorticoid receptor/transactivator present. Transfection of a plasmid that requires the glucocorticoid receptor/transactivator results in very little expression from that

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plasmid. However, if the cells are first engineered to express high levels of the glucocorticoid receptor/transactivator, then high level expression from the same plasmid is obtained (Israel et al., Nuc. Acids Res., vol. 17, pp. 4589-4606, 1989). Therefore, the amount of transactivation depends on the amount of transactivator in the cell. The amount of transactivator will depend on the promoter used to drive expression of the transactivator and the site of the integration of the cassette in the host cell. Thirdly, the amount of target vector in a particular cell will influence how many copies will be transactivated. The site of integration of the target promoter may also play a role in the expression of the activated promoter. Web site: http://www.delphion.com/details?pn=US06635478__ •

Replication-competent herpes simplex virus Inventor(s): Parysek; Linda Marie (Cincinnati, OH), Pyles; Richard Brent (Cincinnati, OH), Warnick; Ronald E. (Loveland, OH) Assignee(s): The University of Cincinnati (Cincinnati, OH) Patent Number: 6,509,020 Date filed: September 22, 1999 Abstract: A promising approach for the therapeutic treatment of brain tumors utilizes replication-competent, neuroattenuated herpes simplex virus-1 (HSV-1) mutants. This approach requires mutation of HSV-1 to eliminate killing of normal, non-dividing cells of the brain (e.g., neurons). The present invention discloses methods for killing malignant brain tumor cells in vivo entails providing replication competent herpes simplex virus vectors to tumor cells. A replication competent herpes simplex virus vector, with defective expression of the gamma 34.5 gene and the uracil DNA glycosylase (UNG) gene, specifically destroys tumor cells, is hypersensitive to anti-viral agents, and is not neurovirulent. Excerpt(s): The present invention relates to recombinant virus strains capable of killing tumor cells. More specifically, the present invention relates to a mutated replicationcompetent viruses which contains mutations in two genes, is hypersensitive to antiviral agents such as ganciclovir, is not neurovirulent and does not replicate in non-dividing cells, yet can kill nervous system tumor cells. The present invention also relates to recombinant herpesvirus strains, vital vaccines incorporating such strains, methods for making such strains and vaccines, and methods for immunizing a human host against herpes simplex virus using the vaccines. Malignant tumors of the nervous system are generally fatal, despite many recent advances in neurosurgical techniques, chemotherapy and radiotherapy. In particular, there is no standard therapeutic modality that has substantially changed the prognosis for patients diagnosed with malignant brain tumors. For example, high mortality rates persist in malignant medulloblastomas, malignant meningiomas and neurofibrosarcomas, as well as in malignant gliomas. Gliomas are the most common primary tumors arising in the human brain. The most malignant glioma, the glioblastoma, represents 29% of all primary brain tumors, some 5,000 new cases per year in the United States alone. Glioblastomas are almost always fatal, with a median survival of less than a year and a 5-year survival of 5.5% or less. Mahaley et al., J. Neurosurg. 71: 826 (1989); Shapiro, et al., J. Neurosurg. 71: 1 (1989): Kim et al., J. Neurosurg. 74: 27 (1991). After glioblastomas are treated with radiotherapy, recurrent disease usually occurs locally; systemic metastases are rare. Hochberg et al., Neurology 30: 907 (1980). Neurologic dysfunction and death in an individual with glioblastoma is due to the local growth of the tumor.

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Web site: http://www.delphion.com/details?pn=US06509020__ •

Sun-protection formulations active against herpes simplex viruses Inventor(s): Driller; Hansjurgen (Otzberg, DE), Hitzel; Sabine (Messel, DE) Assignee(s): Merck Patent Gesellschaft (Darmstadt, DE) Patent Number: 6,500,869 Date filed: September 12, 2000 Abstract: The invention relates to sun-protection formulations in solid or liquid form, containing organic and/or inorganic sunscreen filters having a prophylactic action against herpetic diseases of the skin, and to the use of said sun-screen formulations. Excerpt(s): The present invention relates to sunscreen formulations in solid or liquid form comprising organic and/or inorganic light protection filters having prophylactic action against herpetic diseases of the skin, and to the use of these sunscreen formulations. As is known, the skin is sensitive to solar rays, which can cause simple sunburn or an erythema, but also burns of varying severity. However, solar rays also have other negative effects: they cause the skin to lose its elasticity and form wrinkles, thus leading to premature ageing. Dermatoses may also sometimes be observed. In extreme cases, some people can develop skin cancer. Web site: http://www.delphion.com/details?pn=US06500869__

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Therapeutically effective substance mixture Inventor(s): Treusch; Gernot (Empuria Erava, Falconera 59, Castello d'Empories, ES) Assignee(s): none reported Patent Number: 6,448,227 Date filed: August 20, 2001 Abstract: A substance mixture, containing S-acetyl glutathione and Aciclovir, is effective as a medication against the Herpes Simplex virus and the Varicella Zoster virus. Excerpt(s): This invention relates to a mixture containing S-acetyl glutathione and Aciclovir (ACV) as medication against the Herpes Simplex virus or the Varicella Zoster virus. A process for the manufacture of S-acetyl glutathione is disclosed in U.S. Pat No. 2,760,956. Aciclovir (ACV) is a known medication for use against the Herpes Simplex virus (HSV). Aciclovir is an abbreviated nomenclature (INN) for 9-[(2hydroxyethoxy)methyl)guanine. Web site: http://www.delphion.com/details?pn=US06448227__

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Topical formulations containing as a therapeutic active agent fatty acids or fatty alcohols or monoglyceride derivatives thereof for treating of mucosa infections Inventor(s): Kristmundsdottir; Thordis (Seltjarnarnes, IS), Thormar; Halldor (Reykjavik, IS) Assignee(s): Lipomedica ehf. (Reykjavik, IS) Patent Number: 6,596,763 Date filed: December 16, 1999 Abstract: The present invention relates to a method for counteracting infections caused by bacteria, fungi or virus such as Herpes Simplex Virus in skin or mucosal membranes, in particular genital membranes, of a mammal. The method comprises topically administering to the skin or mucosal membrane an effective amount of a formulation comprising a) at least one microbicidal lipid, b) at least one solubilizing agent which keeps the lipid dissolved in the formulation, and optionally 3) a gel-forming agent. The formulation used in the method may suitable be in the form of a hydrogel. The microbicidal lipid is preferably a C.sub.6-18 fatty acid, such as, e.g., lauric acid, or a derivative thereof, e.g., a monoglyceride such as capric acid 1-monoglyceride. The solubilizing agent may suitably be a glycofurol such as the commercially-available glycofurol 75. The invention also relates to novel pharmaceutical formulations for use in the method. Excerpt(s): This application is a 371 of PCT/PK97/00524 filed Nov. 14, 1997. This invention relates to novel valuable uses of microbicidal lipids, in particular to a method for counteracting infection of the genital mucosa of a mammal by virus, pathogenic bacteria or fungi. The invention also relates to novel pharmaceutical formulations which may be used in the method as well as for other valuable uses such as for application to skin or non-genital mucosa. The World Health Organization (WHO) has estimated that as of late 1993 15 million adults and children world-wide were infected with HIV and that, in that year, heterosexual transmission accounted for up to 90% of new infections. It is projected that by the year 2000 the cumulative number of HIV infected individuals will reach 30 to 40 million people (Report of a meeting on the development of vaginal microbicides for the prevention of heterosexual transmission of HIV, WHO/GPA/RID/CRD/94.1, Geneva, Switzerland, 1993). Infections are on the rise in the developing countries, particularly in South and Southeast Asia, where the epidemic is to an increasing extent affecting young women of childbearing age. Also in the U.S. and other western societies, heterosexual transmission is causing an increasing proportion of AIDS cases (A. R. Lifson, Preventing HIV: have we lost our way? The Lancet 343, 1306-1307, 1994). These facts emphasise the need for effective means of protection against heterosexual transmission of HIV. Web site: http://www.delphion.com/details?pn=US06596763__

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Transfer and expression of gene sequences into nervous system cells using herpes simplex virus mutants with deletions in genes for viral replication Inventor(s): Breakefield; Xandra O. (Newton, MA), Martuza; Robert L. (Lexington, MA) Assignee(s): The General Hospital Corporation (Boston, MA) Patent Number: 6,610,287 Date filed: December 27, 1994

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Abstract: This invention relates to methods of gene delivery to cells in the nervous system by introducing and expressing gene sequences mediated by herpes simplex virus 1 (HSV-1) vectors with a mutation in a gene for viral replication. The present invention further relates to methods for modulating neuronal physiology and for treating nervous system disorders. The present invention also relates to an animal model for nervous system disorders and to methods for producing such an animal model. Excerpt(s): This invention relates to methods of gene delivery into cells of the nervous system, for example, cells of the central and peripheral nervous system, by introducing and expressing gene sequences using herpes simplex virus 1 (HSV-1) mutants with deletions in gene(s) for viral replication. The delivery and expression of heterologous or native genes into cells of the nervous system to alter normal cellular biochemical and physiologic processes in a stable and controllable manner is of substantial value in the fields of medical and biological research. This genetic perturbation of the nervous system provides a means for studying the molecular aspects of neuronal function and offering therapeutic approaches to pathologic processes. Herpes simplex or other neurotropic viral vectors (Loewy et al., Proc. Soc. Neurosci. 17:603-15 (1991)) offer one potential means of delivering functional genes to alter the physiology of sensory or other neurons. Herpes simplex virus is known to be retrogradely transported from sensory terminals to sensory ganglia by a mechanism of fast axonal transport (Cook et al., Infec. and Immun. 7:272-288 (1973). HSV that reaches the nucleus of a sensory neuron, is capable of either lytic replication or latent infection. Lytic replication is characterized by the production of mature virus particles and destruction of the cell. Latent infection is characterized by the long-term stable presence of viral DNA in the nuclei of infected cells, most likely in the form of an episomal unit (Rock et al., Nature 302:523-525 (1983); Efstathiou et al., J. Virol 57(2):446-455 (1986); Mellerick et al., Virol 158:265-275 (1987)), and transcription that is limited to a specific region of the HSV genome (Croen et al., New Engl. J. Med. 317:1427-1432 (1987); Rock et al., J. Virol. 61:3820-3826 (1987); Spivak et al., J. Virol. 61:3841-3847 (1987); Stevens et al., Science 235:105-1059 (1987); Javier et al., Virol. 166:254-257 (1988); Wagner et al., J. Virol. 62(4):1194-1202 (1988); Kosz-Vnenchak et al., J. Virol. 64:5396-5402 (1990)). Web site: http://www.delphion.com/details?pn=US06610287__ •

Vaccine containing whole killed herpes viruses to prevent development of atherosclerotic plaque Inventor(s): Chaihorsky; Alexander (Garfield, NJ), Golubev; Daniel (New York, NY) Assignee(s): Bio-Virus Research Incorporated (San Matteo, CA) Patent Number: 6,471,965 Date filed: July 27, 1994 Abstract: A vaccine is disclosed for the prophylaxis against pathogenic development of atherosclerotic plaque in a mammalian subject susceptible thereto which consists essentially of a multiplicity of killed whole-virus strains, selected from the group consisting of:Herpes Simplex Virus 1;Herpes Simplex Virus 2;Herpes Simplex Virus 6;Human Cytomegalovirus; andEpstein-Barr Virus;in combination with a pharmaceutically acceptable inert vaccine carrier or diluent. Excerpt(s): This invention relates to a vaccine containing herpes virus for the prevention of atherosclerosis. More particularly the invention relates to a herpes vaccine containing

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several types of whole killed herpes viruses that affect humans and that acts as a prophylaxis against pathogenic development of atherosclerotic plaque in a mammalian subjected susceptible thereto. It is generally accepted that atherogenesis is triggered by primary injury to the endothelial lining of the arterial walls. This injury is believed to be the result of exposure of the underlying smooth muscle tells to several factors of noninfectious origin (hormones, low density lipoproteins, growth factors, among others). The prevailing view is that human atherosclerosis (AS) is a pleiotropic process with various causes. See Ross, R., The Pathogenesis of Atherosclerosis: An Update, New England J. Med.,314, 488 to 500 (1986). A fundamentally new etiological factor: herpes virus infection-was reported by Fabricant et al, who demonstrated that chickens infected with Marek Disease Virus (MDV), have an unusually high incidence of atherosclerotic plaque-(ASP) in the arteries. See Fabricant, C. G. et al, Virus-Induced Cholesterol Crystals, Science, 181, 566 to 567 (1973); and Fabricant, C. G. et al, Virus-Induced Atherosclerosis, J. Exp. Med., 148, 335 to 340 (1978). Since that time data have been accumulated suggesting the role of herpes virus in AS in humans. It was shown that different herpes viruses can alter smooth muscle cells lipid metabolism and induce cholesterol and cholesterol ester accumulation in these cells. See Fabricant, C. G. et al, Herpes Virus Infection Enhances Cholesterol and Cholesterol Ester Accumulation in Cultured Arterial Smooth Muscle Cells, Am. J. Pathol, 105, 176 to 184 (1981); Fabricant, C. G. et al, Herpes Virus-Induced Atherosclerosis in Chickens, Fed. Proc., 42, 2476 to 2479 (1983); Melnick, J. L. et al, Cytomegalovirus Antigen within Human Arterial Smooth Muscle Cells, Lancet, ii, 644 to 647 (1983); Gyorkey, F. et al, Herpesviridae in the Endothelial and Smooth Muscle Cells of Proximal Aorta in Atherosclerotic Patients, Exp. Mol. Pathol, 40, 328 to 339 (1984); Hajjar et al, Virus-Induced Atherosclerosis: Herpes Virus Infection Alters Aortic Cholesterol Metabolism and Accumulation, Am. J. Pathol., 122, 62 to 70 (1986); Adam et al, High Levels of Cytomegalovirus Antibody in Patients Requiring Vascular Surgery for Atherosclerosis, Lancet, 2, 291 to 293 (1987); Petrie, Association of Herpesvirus/Cytomegalovirus Infections with Human Atherosclerosis, Prog. Med. Virol., 35, 21 to 42 (1988); Grattan, M. T. et al, Cytomegalovirus Infection is Associated with Cardiac Allograft Rejection and Atherosclerosis, J. A. Med. Assoc., 261, 3561 to 3566 (1989); Mc Donald, K. et al, Association of Coronary Artery Disease in Cardiac Transplant Recipients with Cytomegalovirus Infection, Am. J. Cardiol., 64, 359 to 362 (1989); Visser et al, Granulocyte-Mediated Injury in Herpes Simplex VirusInfected Human Endothelium, Lab. Invest., 60, 296 to 304 (1989); Melnick, J. L. et al, Possible Role of Cytomegalovirus in Atherogenesis, J. Am. Assoc., 263, 2204 to 2207 (1990); Bruggeman, C. A. et al, The Possible Role of Cytomegalovirus in Atherogenesis, Prog. Med. Virol., 38, 1 to 26 (1991); Melnick, J. L. et al, Accelerated Graft Atherosclerosis Following Cardiac Transplantation; Do Viruses Play a Role?, Clin. Cardiol., 14 (Supp. II), 21 to 26 (1991); and Hajjar , D. P., Viral Pathogenesis of Atherosclerosis, Am. J. Pathol., 133, 1195 to 1211 (1991). Web site: http://www.delphion.com/details?pn=US06471965__

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Viral nucleotide sequences Inventor(s): Binns; Matthew McKinley (Huntingdon, GB), Griffin; Annette Mary (Huntingdon, GB), Ross; Louis Joseph Norman (Huntingdon, GB), Scott; Simon David (Huntingdon, GB) Assignee(s): Merial (Lyons, FR) Patent Number: 6,413,762 Date filed: December 26, 2000 Abstract: Various genes of herpes virus of turkeys (HVT) Marek's disease virus (MDV) and infectious laryngotracheitis virus (ILTV) have been identified as non-essential regions (and candidates for insertion sites for foreign genes) and/or as antigen-encoding regions. The former include the HVT homologue of the HSV (herpes simplex virus) gC gene, the TK (thymidine kinase) region of MDV or ILTV, ORF3 of ILTV (as defined herein), the ribonucleotide reductase (large subunit) gene of ILTV, MDV or HVT and the ribonucleotide reductase (small subunit) gene of MDV. The antigen-encoding regions include the HVT homologues of the HSV gB, gC and gH genes, the ILTV homologue of HSV gB, ORF2 of ILTV, and the HVT homologue of the HSV-1 immediate early genes IE-175 and IE-68. Manipulation of these genes allows vaccines to be prepared comprising attenuated virus or virus carrying heterologous antigen-encoding sequences. Excerpt(s): The present invention relates to viral nucleotide sequences which may be manipulated to provide vaccines against disease. Herpesviruses are large double stranded DNA viruses consisting of an icosahedral capsid surrounded by an envelope. The group has been classified as alpha, beta and gammaherpesviruses on the basis of genome structure and biological properties [Roizman, B et al (1981) Intervirology 16, 201-217]. Avian herpes viruses include Marek's Disease Virus (MDV) (a gammaherpesvirus) which causes a lymphomatous disease of considerable economic importance in chickens [reviewed in Payne, L. N. (ed) Marek's Disease (1985), Martinus Nijhoff Publishing, Boston] and Infectious Laryngotracheitis-Virus (ILTV) (an alphaherpesvirus) which causes an acute upper respiratory tract infection in chickens resulting in mortality and loss of egg production. A recent unexpected finding in out laboratory is that there is sufficient amino acid homology between MDV, ILTV and mammalian herpesviruses, particularly varicella zoster (VZV) and Herpes Simplex Virus (HSV) to allow identification of numerous conserved genes. These include the MDV and Herpesvirus of Turkeys (HVT) homologues of glycoproteins gB, gC and gH of HSV; the ILTV, MDV and HVT homologues of TK and ribonucleotide reductase genes and the ILTV homologue of gB and genes 34 and 35 of VZV (Buckmaster, A et al, (1988) J. gen. Viral, 69, 2033-2042. Web site: http://www.delphion.com/details?pn=US06413762__

Patent Applications on Herpes Simplex As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to herpes simplex: 10

This has been a common practice outside the United States prior to December 2000.

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Antimicrobial treatment for herpes simplex virus and other infectious diseases Inventor(s): Squires, Meryl J.; (Barrington Hills, IL) Correspondence: Thomas W. Tolpin; Welsh & Katz, LTD.; 22nd Floor; 120 South Riverside Plaza; Chicago; IL; 60606; US Patent Application Number: 20030099726 Date filed: March 7, 2002 Abstract: An improved medical treatment and medicine is provided to quickly and safely resolve herpes and other microbial infections. The inexpensive user-friendly medicine can be applied and maintained on the infected region until the physical symptoms of the disease disappears and the patient is comfortable and has a normal appearance. The attractive medicine comprises an antimicrobial concentrate comprising microbe inhibitors, phytochemicals or isolates. Desirably, the effective medicine comprises a surfactant and an aqueous carrier or solvent. In the preferred form, the medicine comprises Echinacea phytochemicals and benzalkonium chloride in a sterile water solution. Excerpt(s): The present invention relates to herpes virus, and more particularly, to medical treatments for herpes virus and other microbial infections. Herpes simplex virus (HSV) commonly referred to as "herpes virus" or "herpes," is an infectious disease which has reached crisis proportions nationally with estimated numbers of infected people at 70%-80% of our population as reported by the American Social Health Association (ASHA) and growing annually by 500,000 people or more. There are two common types of herpes: herpes simplex virus 1 (HSV 1) and herpes simplex virus 2 (HSV 2). Herpes enters the human body through minuscule breaks in the epidermal tissue usually by contact with an infected host and is marked by eruption of one or more vesicles, usually in groups, following an incubation period of approximately four to ten days. Typically the course of the infectious outbreak initiates with the prodromal stage; advancing to vesicular eruption; followed by: ulceration; coalescing; resolution; and the latency period. The outbreak can last for several weeks and on average lasts two-three weeks. In some immune compromised individuals the outbreak can last for months. The vesicles can appear anywhere on the skin or mucosa, typically appearing on the lips as cold sores, glands, oral mucosa, conjunctiva and cornea, genitalia, anal mucosa and perianal tissue. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Combined vaccine compositions Inventor(s): Stephenne, Jean; (Rixensart, BE), Wettendorff, Martine Anne Cecile; (RhodeSaint-Genese, BE) Correspondence: Glaxosmithkline; Corporate Intellectual Property - Uw2220; P.O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20030129199 Date filed: August 23, 2002 Abstract: Novel combined vaccine composition preferentially for administration to adolescents are provided, comprising a hepatitis B viral antigen and a herpes simplex viral antigen and optionally in addition one or more of the following: an EBV antigen, a hepatitis A antigen or inactivated attenuated virus, an HPV antigen, a V2V antigen, a

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HCMV antigen, a Toxoplasma gondii antigen. The vaccine compositions are formulated with an adjuvant which is a preferential stimulator of TH1 cell response such as 3DMPL and QS21. Excerpt(s): This invention relates to novel vaccine formulations, methods for preparing them and their use in therapy. In particular the present invention relates to combination vaccines for administration to adolescents. HSV-2 is the primary etiological agent of herpes genitalis. HSV-2 and HSV-1 (the causative agent of herpes labialis) are characterised by their ability to induce both acute diseases and to establish a latent infection, primarily in neuronal ganglia cells. Genital herpes is estimated to occur in about 5 million people in the U.S.A. alone with 500,000 clinical cases recorded every year (primary and recurrent infection). Primary infection typically occurs after puberty and is characterised by the localised appearance of painful skin lesions, which persist for a period of between 2 to 3 weeks. Within the following six months after primary infection 50% of patients will experience a recurrence of the disease. About 25% of patients may experience between 10-15 recurrent episodes of the disease each year. In immunocompromised patients the incidence of high frequency recurrence is statistically higher than in the normal patient population. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Complementing cell lines Inventor(s): Havenga, Menzo; (Alphen San Den Rijn, NL), Mehtali, Majid; (Plobsheim, FR), Vogels, Ronald; (Linschoten, NL) Correspondence: Trask Britt; P.O. Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20030119192 Date filed: October 15, 2002 Abstract: A packaging cell line capable of complementing recombinant adenoviruses based on serotypes from subgroup B, preferably adenovirus type 35. The cell line is preferably derived from primary diploid human cells transformed by adenovirus E1 sequences either operatively linked on one or two DNA molecules, the sequences operatively linked to regulatory sequences enabling transcription and translation of encoded proteins. Also, a cell line derived from PER.C6 that expresses functional Ad35E1B sequences. The Ad35-E1B sequences are driven by the E1B promoter and terminated by a heterologous poly-adenylation signal. The new cell lines are useful for producing recombinant adenoviruses. The cell lines can be used to produce human recombinant therapeutic proteins such as human antibodies. In addition, the cell lines are useful for producing human viruses other than adenovirus such as influenza, herpes simplex, rotavirus, and measles. Excerpt(s): This application is a continuation of application Ser. No. 09/713,678, filed Nov. 15, 2000, pending (the contents of the entirety of which are incorporated by this reference), now U.S. Pat. No. ______, which is a continuation-in-part of application Ser. No. 09/573,740, filed May 18, 2000, pending, which claims benefit, under 35 U.S.C.sctn. 119(e), of the filing date of U.S. Provisional Application Serial No. 60/134,764, filed May 18, 1999. The invention relates to the field of biotechnology generally and, more specifically, to adenoviral-based complementing cell lines. Typically, vector and packaging cells are adapted to one another so that they have all the necessary elements, but they do not have overlapping elements which lead to replication-competent virus by recombination. Therefore, the sequences necessary for proper transcription of the

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packaging construct may be heterologous regulatory sequences derived from, for example, other human adenovirus ("Ad") serotypes, nonhuman adenoviruses, other viruses including, but not limited to, SV40, hepatitis B virus ("HBV"), Rous Sarcoma Virus ("RSV"), cytomegalovirus ("CMV"), etc. or from higher eukaryotes such as mammals. In general, these sequences include a promoter, enhancer and polyadenylation sequences. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Composition and pharmaceutical preparation containing same for the treatment of herpes and related viral infections Inventor(s): Blay, Jonathan; (Bedford, CA), But, Paul P.H.; (N.T., HK), Foong, WaiChong; (Bedford, CA), Lee, Song F.; (Halifax, CA), Lee, Spencer H.S.; (Halifax, CA), Ooi, Vincent E.C.; (N.T., HK), Xu, Hong-Xi; (Halifax, CA), Zhang, Yongwen; (Shatin, CN) Correspondence: Foley & Lardner; P.O. Box 80278; San Diego; CA; 92138-0278; US Patent Application Number: 20030215529 Date filed: October 4, 2002 Abstract: In accordance with the present invention, novel compositions useful for the treatment of the cytopathogenic effects of an enveloped virus in mammals have been discovered by extraction and purification from the spikes of Prunella vulgaris. In particular, invention compositions comprise a lignin-carbohydrate complex as an active ingredient for inhibition of viral infection in a mammal. In accordance with an embodiment of the present invention, it has been discovered that invention compositions are effective agents for the prophylaxis and therapy in mammals of diseases caused by enveloped viruses, e.g., herpes simplex virus. Methods for producing invention compositions and uses therefor are also provided. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 09/160,210, filed Sep. 23, 1998, now pending, which claims priority from U.S. Provisional Application No. 60/059,775, filed Sep. 23, 1997, both incorporated by reference herein in their entirety. The present invention relates to a novel composition which can be extracted and purified from the spikes of Prunella vulgaris. Invention composition is an effective agent for treatment of the cytopathogenic effects of an enveloped virus in mammals. In another aspect, the present invention relates to methods for the treatment of the cytopathogenic effects of an enveloped virus and related indications in mammals, employing the invention composition as the active agent. In yet another aspect, the present invention relates to methods for the treatment of the cytopathogenic effects of an enveloped virus in mammals exposed to immunosuppressive regimens. In still another aspect, the present invention relates to methods for protecting mammals from reactivated viral infection during or following treatment with chemotherapeutic agents. In a further aspect, the present invention relates to methods for obtaining invention compositions having antiviral action from Prunella vulgaris, and formulations containing said compositions. In a still further aspect, the present invention relates to methods of purification of invention compositions from Prunella vulgaris and characterization thereof. In a particular aspect, the invention relates to compositions comprising lignin-carbohydrate complexes having anti-HSV activities. Viral infections caused by enveloped viruses are a heterogenous group of disorders characterized by viral infection of host cells. An example of such infections includes acquired herpes virus infections caused by broad categories of herpes-related viruses, including the alpha-, beta- and gamma-herpes viruses, and

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where the onset of infection is characterized by herpes simplex virus (HSV) infection of host cells. Primary herpes virus infections are normally acquired in childhood, but later enter a dormant phase (e.g., in the nerves). Reactivation of herpes virus infections result from a variety of factors, such as ultraviolet light, stress, and adult onset. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods for the diagnosis and treatment of herpes simplex virus infection Inventor(s): Day, Craig H.; (Seattle, WA), Dillon, Davin C.; (Issaquah, WA), Hosken, Nancy A.; (Seattle, WA), McGowan, Patrick; (Seattle, WA), Sleath, Paul R.; (Seattle, WA) Correspondence: Seed Intellectual Property Law Group Pllc; 701 Fifth Ave; Suite 6300; Seattle; WA; 98104-7092; US Patent Application Number: 20020090610 Date filed: June 28, 2001 Abstract: Compounds and methods for the diagnosis and treatment of HSV infection are provided. The compounds comprise polypeptides that contain at least one antigenic portion of an HSV polypeptide and DNA sequences encoding such polypeptides. Pharmaceutical compositions and vaccines comprising such polypeptides or DNA sequences are also provided, together with antibodies directed against such polypeptides. Diagnostic kits are also provided comprising such polypeptides and/or DNA sequences and a suitable detection reagent for the detection of HSV infection in patients and in biological samples. Excerpt(s): This application is related to U.S. Provisional Application No. 60/277,438 filed Mar. 20, 2001 and U.S. Provisional Application No. 60/215,458 filed Jun. 29, 2000 and are incorporated in their entirety by reference herein. The present invention relates generally to the detection and treatment of HSV infection. In particular, the invention relates to polypeptides comprising HSV antigens, DNA encoding HSV antigens, and the use of such compositions for the diagnosis and treatment of HSV infection. The herpes viruses include the herpes simplex viruses (HSV), comprising two closely related variants designated types 1 (HSV-1) and 2 (HSV-2). HSV is a prevalent cause of genital infection in humans, with an estimated annual incidence of 600,000 new cases and with 10 to 20 million individuals experiencing symptomatic chronic recurrent disease. The asymptomatic subclinical infection rate may be even higher. For example, using a typespecific serological assay, 35% of an unselected population of women attending a health maintenance organization clinic in Atlanta had antibodies to HSV type 2 (HSV-2). Although continuous administration of antiviral drugs such as acyclovir ameliorates the severity of acute HSV disease and reduces the frequency and duration of recurrent episodes, such chemotherapeutic intervention does not abort the establishment of latency nor does it alter the status of the latent virus. As a consequence, the recurrent disease pattern is rapidly reestablished upon cessation of drug treatment. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Detection of herpes simplex virus Inventor(s): Espy, Mark J.; (Rochester, MN), Smith, Thomas F.; (Rochester, MN), Uhl, Jim; (Rochester, MN), Wold, Arlo; (Charles, MN) Correspondence: Mark S. Ellinger, PH.D.; Fish & Richardson P.C., P.A.; Suite 3300; 60 South Sixth Street; Minneapolis; MN; 55402; US Patent Application Number: 20020164586 Date filed: January 31, 2002 Abstract: The invention provides methods to detect herpes simplex virus (HSV) in biological samples and further to distinguish between HSV-1 and HSV-2. Primers and probes for the differential detection of HSV-1 and HSV-2 are provided by the invention. Articles of manufacture containing such primers and probes for detecting HSV are further provided by the invention. Excerpt(s): This application claims priority under 35 U.S.C.sctn.119(e) of U.S. provisional application serial No. 60/265,376, filed Jan. 31, 2001. This invention relates to viral diagnostics, and more particularly to detection of herpes simplex virus (HSV). Herpes simplex virus (HSV) is the virus most commonly detected in diagnostic laboratories, accounting for over 40% of the viruses that were detected in cell cultures over a 25-year period. HSV causes a variety of clinical syndromes, and anatomical sites infected include the skin, lips, oral cavity, eyes, genital tract, and central nervous system. Generalized or disseminated HSV infection may occur in patients immunologically compromised by neoplasia, organ transplantation, inherited immunodeficiency disease, or AIDS, or through neonatal infection acquired by transmission of the virus through an infected birth canal. Most disseminated disease is fatal. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Eukaryotic gene expression cassette and uses thereof Inventor(s): Coffin, Robert S.; (London, GB), Latchman, David S.; (London, GB) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20030219409 Date filed: January 31, 2003 Abstract: An expression cassette comprising a herpes simplex virus latency-associated transcript P2 region, a promoter and a heterologous gene operably linked in that order. The expression cassette is incorporated into herpes simplex virus vectors to allow for delivery of heterologous genes to mammalian cells for long-term expression. Excerpt(s): The present invention relates to a gene expression cassette. The expression cassette can be used for directing long-term expression of heterologous genes in eukaryotic cells. It also relates to the use of said expression cassette in gene therapy, vaccine production, and in methods of assaying for gene function. It further relates to vectors, including viral strains, comprising said expression cassette. Herpes simplex virus (HSV) has often been suggested as a suitable gene-delivery vector for the nervous system due to its neurotrophic lifestyle and its ability to remain latent in neurons for the lifetime of the cell. This unique ability has suggested that with suitable development a once-only application of such a vector system might give a lifelong therapeutic benefit for certain conditions, such as Parkinson's disease where expression of tyrosine

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hydroxylase or GDNF in the brain has been shown to be beneficial. However, while disabled herpes viruses have been shown efficiently to deliver genes to the nervous system and to other tissues in vivo, transcription of heterologous genes expressed from the herpes genome invariably only continues in the short term (90% seroconversion by ten weeks post immunization. Immune antisera neutralized both HSV-2 and HSV-1 in cell culture. When animals were challenged with HSV-2, significant (p