HIV-1: MOLECULAR BIOLOGY AND PATHOGENESIS CLINICAL APPLICATIONS, Second Edition
SERIAL EDITORS J. Thomas August
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ADVISORY BOARD R. Wayne Alexander
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Thomas F. Burke
Leroy Liu
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Anthony R. Means
G. Alan Robison
Durham, North Carolina
Houston, Texas
John A. Thomas
Thomas C. Westfall
San Antonio, Texas
St. Louis, Missouri
HIV-1: MOLECULAR BIOLOGY AND PATHOGENESIS CLINICAL APPLICATIONS, Second Edition
Edited by
Kuan-Teh Jeang Molecular Virology Section, LMM, NIAD, NIH Bethesda, Maryland
ADVANCES IN
PHARMACOLOGY VOLUME 56
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Contents
Contributors xi Preface written by Robin A. Weiss xv
Global Molecular Epidemiology of HIV: Understanding the Genesis of AIDS Pandemic Yutaka Takebe, Rie Uenishi, and Xiaojie Li
I. II. III. IV. V. VI. VII. VIII.
Chapter Overview 1 Introduction 2 Genotype Classification of HIVs 4 Global Distribution of HIV Genotypes 9 Methods for Identifying HIV Genetic Forms 11 Origin of HIVs and Genesis of HIV-1 Pandemic 13 Biological Significance of HIV-1 Variability and Recombination Conclusions 18 References 18
14
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Contents
Current Clinical Treatments of AIDS Erin-Margaret Murphy, Humberto R. Jimenez, and Stephen M. Smith
I. II. III. IV.
Chapter Overview 27 HIV Medications 28 HIV Treatment 52 Conclusion 63 References 63
HIV-1-Specific Immune Response Alexandre Harari and Giuseppe Pantaleo
I. Introduction 75 II. Humoral HIV-1-Specific Response 77 III. HIV-1-Specific T-Cell Responses 78 References 87
Targeting HIV Attachment and Entry for Therapy Julie Strizki
I. II. III. IV. V. VI. VII. VIII.
Chapter Overview 93 Background 94 Inhibition of Viral Attachment 95 Chemokine Receptors in HIV Infection 98 Targeting Coreceptor Binding 99 Fusion Inhibitors 107 Resistance to Inhibitors of Viral Entry 109 Use Entry Inhibitors as Microbicides 110 References 111
Inhibitors of HIV-1 Reverse Transcriptase Tatiana Ilina and Michael A. Parniak
I. II. III. IV. V. VI. VII.
Chapter Overview 121 Introduction 122 The Target 123 Nucleoside RT Inhibitors 127 Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Other Inhibitors of HIV-1 RT 150 Conclusion 154 References 154
140
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Development of Protease Inhibitors and the Fight with Drug-Resistant HIV-1 Variants Hiroaki Mitsuya, Kenji Maeda, Debananda Das, and Arun K. Ghosh
I. II. III. IV. V. VI. VII. VIII.
Chapter Overview 169 Introduction 170 Targeting Viral Protease 170 The Role of PIs and Challenges in HAART 174 ‘‘Boosting’’: A Critical Modification of Clinical Efficacy of PIs Viral Resistance to PIs 176 PIs with Activity Against Drug-Resistant HIV-1 182 Conclusions 189 References 191
175
HIV-1 Integrase Inhibitors: Update and Perspectives Elena A. Semenova, Christophe Marchand, and Yves Pommier
I. II. III. IV. V. VI. VII.
Chapter Overview 199 Foreword 200 Integration: A Crucial Step in the HIV Life Cycle Approaches to Inhibit HIV Integration 210 Inhibitors in Clinical Trials 216 Inhibitors in Preclinical Development 217 Perspectives 218 References 219
200
Topical Microbicides: A Promising Approach for Controlling the AIDS Pandemic via Retroviral Zinc Finger Inhibitors Jim A. Turpin, Marco L. Schito, Lisa M. Miller Jenkins, John K. Inman, and Ettore Appella
I. II. III. IV. V. VI. VII. VIII. IX. X.
Chapter Overview 229 The AIDS Pandemic and the Rationale for a Microbicide 230 Topical Microbicides in Preclinical Development 232 Characteristics of an Ideal Microbicide 237 The Retroviral Zinc Fingers of HIV-1 NCp7 as a Potential Microbicide Target 238 Characteristics of the SAMT Chemotype 240 Application of Thioesters for Microbicides 244 Target Specificity of the SAMT NCp7 Inhibitors 246 Conclusions 249 Addendum 250 References 251
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Contents
Viral Drug Resistance and Fitness Miguel E. Quin˜ones-Mateu, Dawn M. Moore-Dudley, Oyebisi Jegede, Jan Weber, and Eric J. Arts
I. Chapter Overview 257 II. Introduction 258 References 283
Gene Therapy to Induce Cellular Resistance to HIV-1 Infection: Lessons from Clinical Trials Mauro Giacca
I. Chapter Overview 297 II. Introduction: Do We Need HIV-1 Gene Therapy? 298 III. Gene Therapy of HIV Infection: Lessons from Early Clinical Trials 300 IV. Gene Therapy of HIV Infection: Current Developments 306 V. Gene Therapy for HIV Infection: Where Are We Heading? 314 References 317
Identification of Potential Drug Targets Using Genomics and Proteomics: A Systems Approach Zachary A. Klase, Rachel Van Duyne, and Fatah Kashanchi
I. II. III. IV. V. VI. VII.
Chapter Overview 327 Introduction 328 Viral Targets 329 Cellular/Viral Protein–Protein Interactions Viral-Induced Cellular Alterations 343 Other Approaches 351 Conclusion 354 References 355
331
Rapid Disease Progression to AIDS due to Simian immunodeficiency virus Infection of Macaques: Host and Viral Factors Que Dang and Vanessa M. Hirsch
I. Chapter Overview 369 II. Introduction 370 III. SIV Strain Diversity 371
Contents
IV. Biology of SIV 371 V. Pathogenesis of SIV in Macaques 373 VI. Unique Immunologic, Virological, and Pathological Features of Rapid Disease 377 VII. Host Factors That Influence Disease Progression 383 VIII. Role of Virus Genotype/Phenotype in Rapid Disease Progression 384 IX. Summary 388 References 389
Nonprimate Models of HIV-1 Infection and Pathogenesis Viet Hoang, Elizabeth Withers-Ward, and David Camerini
I. II. III. IV. V. VI. VII. VIII. IX. X.
Chapter Overview 399 Introduction 400 SCID-Hu Thy/Liv Mice 401 The hu-PBL-SCID Mouse 405 NOD/LtSz-SCID Mice 407 Rag2 / gC / and NOD-SCID gC / Mice 408 Humanized Immune Competent Mice and Rats 409 HIV-1 Tg Mice 410 Rabbit Model of HIV Pathogenesis 412 Conclusion 413 References 413
Perspectives for a Protective HIV-1 Vaccine Marco Schiavone, Ileana Quinto, and Giuseppe Scala
I. II. III. IV.
Chapter Overview 423 Introduction 424 Current Strategies in Developing an HIV-1 Vaccine Concluding Remarks 441 References 442
429
Molecular Mechanisms of HIV-1 Vertical Transmission and Pathogenesis in Infants Nafees Ahmad
I. Chapter Overview 453 II. Introduction 454 III. Timing and Mechanism of HIV-1 Vertical Transmission
456
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Contents
IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV.
Factors Associated with HIV-1 Vertical Transmission 458 HIV-1 Infection Diagnosis in Neonates and Infants 460 Prevention of HIV-1 Vertical Transmission 460 Characterization of HIV-1 Associated with Vertical Transmission 462 Chemokine Receptors and HIV-1 Vertical Transmission 464 Molecular Properties of HIV-1 from Mother–Infant Pairs Associated with Vertical Transmission 465 Characterization of Functional Domains of HIV-1 Genes Associated with Vertical Transmission 470 Properties of HIV-1 Associated with Lack of Vertical Transmission 478 Analysis of Immunologically Relevant Mutations in HIV-1 Isolates Associated with Vertical Transmission 481 Mechanisms of HIV-1 Pathogenesis and Disease Progression in Infants 485 The Future 491 References 492
The Viral Etiology of AIDS-Associated Malignancies Peter C. Angeletti, Luwen Zhang, and Charles Wood
I. II. III. IV. V. VI. VII. VIII.
Chapter Overview 509 Introduction 510 Kaposi’s Sarcoma 512 AIDS-Associated Lymphomas 520 AIDS-Associated NHL 524 HPV-Associated Cancers 527 HPV—The Causative Agent 529 Conclusions 538 References 539
Index 559 Contents of Previous Volumes 575 Color Plate Section at the end of the book
Contributors
Numbers in parentheses indicate the pages on which the authors’ contributions begin.
Nafees Ahmad (453) Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona 85724 Peter C. Angeletti (509) Nebraska Center for Virology, School of Biological Sciences, University of Nebraska–Lincoln, Lincoln, Nebraska 68588 Ettore Appella (229) Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892 Eric J. Arts (257) Division of Infectious Diseases, BRB 1029, Case Western Reserve University, Cleveland, Ohio 44106; Department of Molecular and Microbiology, BRB 1029, Case Western Reserve University, Cleveland, Ohio 44106; Center for AIDS Research, BRB 1029, Case Western Reserve University, Cleveland, Ohio 44106 David Camerini (399) Center for Virus Research, University of California, Irvine, California 92697; Center for Immunology, University of California, Irvine, California 92697; and Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697 Que Dang (369) Laboratory of Molecular Microbiology, NIAID, NIH 4 Center Drive Bethesda, Maryland 20892 Debananda Das (169) The Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892
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Contributors
Arun K. Ghosh (169) Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907 Mauro Giacca (297) Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34012 Trieste, Italy Alexandre Harari (75) Laboratory of AIDS Immunopathogenesis, Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland Vanessa M. Hirsch (369) Laboratory of Molecular Microbiology, NIAID, NIH 4 Center Drive Bethesda, Maryland 20892 Viet Hoang (399) Center for Virus Research, University of California, Irvine, California 92697; Center for Immunology, University of California, Irvine, California 92697; and Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697 Tatiana Ilina (121) Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 John K. Inman (229) Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892 Oyebisi Jegede (257) Department of Cellular and Molecular Biology, Kent State University, Kent, Ohio 44242 Humberto R. Jimenez (27) Saint Michael’s Medical Center, Newark, New Jersey 07102; Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854 Fatah Kashanchi (327) Department of Biochemistry, Medical Center, The George Washington University, Washington, DC 20037 Zachary A. Klase (327) Department of Biochemistry, Medical Center, The George Washington University, Washington, DC 20037 Xiaojie Li (1) Laboratory of Molecular Virology and Epidemiology, AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Tokyo, Japan Kenji Maeda (169) The Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 Christophe Marchand (199) Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892–4255 Erin-Margaret Murphy (27) Saint Michael’s Medical Center, Newark, New Jersey 07102
Contributors
xiii
Lisa M. Miller Jenkins (229) Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892 Hiroaki Mitsuya (169) Department of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860–8556; The Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 Dawn M. Moore-Dudley (257) Department of Molecular and Microbiology, BRB 1029, Case Western Reserve University, Cleveland, Ohio 44106 Giuseppe Pantaleo (75) Laboratory of AIDS Immunopathogenesis, Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland Michael A. Parniak (121) Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 Yves Pommier (199) Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892–4255 Miguel E. Quin˜ones-Mateu (257) Center for AIDS Research, BRB 1029, Case Western Reserve University, Cleveland, Ohio 44106; Department of Cellular and Molecular Biology, Kent State University, Kent, Ohio 44242; HIV-1 Program, Diagnostic Hybrids, Athens, Ohio 45701 Ileana Quinto (423) Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro, Italy Giuseppe Scala (423) Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro, Italy Marco Schiavone (423) Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro, Italy Marco L. Schito (229) Henry M. Jackson Foundation for the Advancement of Military Medicine, Division of AIDS, NIAID, National Institutes of Health, Bethesda, Maryland 20892 Elena A. Semenova (199) Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892–4255 Stephen M. Smith (27) The New Jersey Medical School, Newark, New Jersey 07103; Saint Michael’s Medical Center, Newark, New Jersey 07102 Julie Strizki (93) Schering-Plough Research Institute, Kenilworth, New Jersey 07033
xiv
Contributors
Yutaka Takebe (1) Laboratory of Molecular Virology and Epidemiology, AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Tokyo, Japan Jim A. Turpin (229) Preventions Sciences Program, Division of AIDS, NIAID, National Institutes of Health, Bethesda, Maryland 20892 Rie Uenishi (1) Laboratory of Molecular Virology and Epidemiology, AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Tokyo, Japan Rachel Van Duyne (327) Department of Biochemistry, Medical Center, The George Washington University, Washington, DC 20037 Jan Weber (257) HIV-1 Program, Diagnostic Hybrids, Athens, Ohio 45701 Robin A. Weiss (xv) Division of Infection and Immunity, University College London, London W1T 4JF, United Kingdom Elizabeth Withers-Ward (399) Center for Virus Research, University of California, Irvine, California 92697; Center for Immunology, University of California, Irvine, California 92697; and Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697 Charles Wood (509) Nebraska Center for Virology, School of Biological Sciences, University of Nebraska–Lincoln, Lincoln, Nebraska 68588 Luwen Zhang (509) Nebraska Center for Virology, School of Biological Sciences, University of Nebraska–Lincoln, Lincoln, Nebraska 68588
Preface
This important volume illustrates through a series of authoritative chapters how a greater understanding of the molecular biology of the human immunodeficiency virus 1 (HIV‐1) can be translated into controlling and treating infection. Although the virus is relatively simple, containing only eight genes, its interaction with the human host is complex. In the majority of cases, infection leads to death from immunodeficiency, wasting, and neurological disease––the symptoms that we call acquired immune deficiency syndrome (AIDS). Thus, the mortality rate resulting from untreated HIV‐1 infection is greater than that of Ebola or SARS, and there is no recovered immune state. In contrast to human AIDS, the progenitor of HIV‐1, SIV‐cpz, is largely nonpathogenic in its natural host, the chimpanzee. Subtle changes in the HIV‐1/SIVcpz genome, for example, in the nef gene, may have played a role in the evolution of its virulence, but the innate immune activation as opposed to control in chimpanzees appears to correlate with development of disease in humans (see ‘‘HIV‐1‐Specific Immune Response’’ by Harari and Pantaleo). At first sight it seems paradoxical that activation of immune responses eventually leads to immune collapse, but the activation is inappropriate and chronic. It is more of a wonder that progression to AIDS is not faster, which attests to the regenerative powers of the immune system. AIDS was first recognized in 1981, and has emerged from being a concern among ‘‘high‐risk’’ groups to representing a worldwide pandemic, which has already resulted in an estimated 25 million deaths. Moreover, some 40 million people are currently infected by HIV‐1 (see ‘‘Global Epidemiology of HIV: Understanding the Genesis of AIDS Epidemic’’ by Yutaka Takebe), and antiviral treatment is not yet available to the majority. Given that the greatest proportion of infected persons have acquired HIV‐1 sexually, much emphasis is placed by some political leaders on control through abstinence, being faithful and, reluctantly, use of condoms, the so‐called ABC of AIDS
xv
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Preface
prevention. While behavioral restraint is indeed a most worthy aim, it does not appear to be any more efficacious than similar exhortations were when syphilis emerged to be pandemic 500 years ago. However, most of us are motivated to go beyond moralizing and hand‐wringing to seek practical ways to impose a break upon the spread of HIV‐1. It is important to recognize the immense part that science applied to medicine has already contributed to public health measures for HIV and AIDS, as exemplified in this volume. Scientific epidemiology demonstrated the modes of transmission of the underlying cause of AIDS well before the culprit itself was identified. Within two years of the discovery of HIV‐1 in 1983, screening of blood donations was set in place in all industrialized nations, greatly reducing iatrogenic HIV infection. Monotherapy with the first antiretroviral drug, Zidovudine, went into clinical trial in 1986, although it took another ten years before combination antiretroviral therapy (ART) showed long‐term efficacy in controlling the course of infection. The introduction of ART had a huge impact: in the USA and other western countries, the mortality from HIV‐1 infection dropped by 75% and has remained at this low level; hospital facilities for AIDS patients emptied as HIV‐1 infection became a treatable, though not curable, out‐patient condition (see ‘‘Current Clinical Treatments of AIDS’’ by Murphy et al.). Those who deny that HIV‐1 is the cause of AIDS, and those who question the validity and benefit of ART, should hang their heads in shame over the needless deaths that heeding their siren voices has incurred. Yet the economic and logistic challenge facing world health is to roll out ART to all who require it. Meanwhile, as HIV‐1 gradually acquires multiple drug resistance (see ‘‘Viral Drug Resistance and Fitness’’ by Quiones‐Mateu et al.), just as bacteria become resistant to antibiotics, we need novel drugs and novel targets in order to keep ahead of HIV. In this volume, the fourth to seventh chapters point the way to promising new approaches to therapy. Certain HIV‐1 inhibitors also show promise for prophylactic use in order to prevent infection of persons exposed to the virus. Their efficacy has already been proven in greatly reducing mother‐to‐child transmission. Other inhibitors may have a role in formulations of vaginal microbicides, which should be available to women for discrete use, among them are HIV entry inhibitors (see ‘‘Targeting HIV Attachment and Entry for Therapy’’ by Julie Strizki) and possibly viral zinc finger inhibitors (see ‘‘Topical Microbicides: A Promising Approach for Controlling the AIDS Pandemic via Retroviral Zinc Finger Inhibitors’’ by Turpin et al.). Innovative genetic tools which have been developed across a range of molecular medicine targets are being applied to a better understanding and treatment of HIV/AIDS. Thus, genomic and proteomic technologies can aid HIV drug discovery (see ‘‘Identification of Potential Drug Targets Using Genomics and Proteomics: A Systems Approach’’ by Klase et al.) and provide insight into AIDS‐associated tumors (see ‘‘The Viral Etiology of
Preface
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AIDS‐Associated Malignancies’’ by Angeletti et al.). Gene therapy (see ‘‘Gene Therapy to Induce Cellular Resistance to HIV‐1 Infection: Lessons from Clinical Trials’’ by Mauro Giacca) can be considered for treatment, if bone marrow stem cells and CD4 T‐cell precursors can be rendered resistant to HIV‐1 infection by this means. Moreover, a welcome corollary of HIV research has been the development of lentivirus vectors based on the HIV‐1 genome for gene therapy and research in other diseases. Thus, HIV and AIDS are not an island unto themselves; rather, they both benefit from and provide for advances in other fields of biomedicine. The greatest scientific challenge facing AIDS researchers is to develop a vaccine that will protect us from HIV‐1 infection. The failure to date to develop a safe and efficacious HIV vaccine is not for want of trying. Rather, there are some formidable obstacles, owing to the variability of the virus (see ‘‘Global Epidemiology of HIV: Understanding the Genesis of AIDS Epidemic’’ by Yutaka Takebe) and the complexity and incomplete immune responses to lentivirus infections (see ‘‘HIV‐1‐Specific Immune Response’’ by Harari and Pantaleo and ‘‘Perspectives for a Protective HIV‐1 Vaccine’’ by Schiavone et al.). Animal models (see ‘‘Rapid Disease Progression to AIDS due to Simian Immunodeficiency Virus Infection of Macaques: Host and Viral Factors’’ by Dang and Hirsch and ‘‘Nonprimate Models of HIV‐1 Infection and Pathogenesis’’ by Hoang et al.) are crucial to gain insight into immune correlates of protection, as well as properly designed clinical trials (see ‘‘Current Clinical Treatments of AIDS’’ by Murphy et al.). In the early days of HIV/AIDS research, there were disputes over the proportion of scarce resources that should be devoted to vaccines instead of therapies, but the research and development funds now available from both governmental and charitable sources has ended this dilemma. To be sure, we need rigorous peer review, value for money, and international coordination. However, the commitment to tackle AIDS will permit us not only to combat HIV‐1 in those already infected but also to place the utmost effort in seeking to protect future generations from this major scourge of humankind. Robin A. Weiss University College London
Yutaka Takebe, Rie Uenishi, and Xiaojie Li Laboratory of Molecular Virology and Epidemiology, AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162‐8640, Tokyo, Japan
Global Molecular Epidemiology of HIV: Understanding the Genesis of AIDS Pandemic
I. Chapter Overview
________________________________________________________________________________________________
Global dissemination of the Human immunodeficiency virus (HIV) represents a dramatic and deadly example of recent genome emergence and expansion. Since HIV‐1 group M began its expansion in human population roughly 70 years ago (in early twentieth century), it has been diversifying rapidly, now comprising a number of different subtypes and
Advances in Pharmacology, Volume 56 # 2008, Elsevier Inc. All rights reserved.
1054-3589/08 $35.00 DOI: 10.1016/S1054-3589(07)56001-1
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Takebe et al.
circulating recombinant forms (CRFs). Molecular epidemiological method has been useful tool to analyze the origin of HIVs and to track a course of global HIV dissemination. It could also provide the information critical to prevention and future vaccine strategies. In this chapter, we describe the classification and distribution of HIV genotypes and the biological and public health implications of genetic variability of this deadly pathogen.
II. Introduction
____________________________________________________________________________________________________________
The HIV/AIDS pandemic continues to expand globally at a rate of 13,000 new infections everyday. The Joint United Nations Program on HIV/AIDS (UNAIDS) estimates that 40.3 (36.7–45.3) million individuals are living with HIV/AIDS, and about 25 million patients have already died (UNAIDS/WHO, 2005). A total of estimated 65 million individuals have been thus infected with HIV worldwide since the epidemic started a quarter century ago. In 2005 alone, there were 4.9 (4.3–6.6) million new HIV infections and 3.1 (2.8–3.6) million AIDS deaths (UNAIDS/WHO, 2005). This could be translated as that 9.3 new infections and 5.9 AIDS deaths occurred every minute (or a new infection every 6–7 sec and an AIDS death every 10 sec) worldwide. Figure 1 illustrates the magnitude of HIV/AIDS epidemic in different regions of the world. Heterosexual transmission remains the dominant mode of transmission and accounts for 85% of all HIV infections worldwide. Sub‐Saharan Africa is an epicenter of the pandemic and continues to have high rates of new infections [3.2 (2.8–3.9) million per year]. It accounts for 65% of new infections occurred worldwide in 2005 (Fig. 1). While HIV/AIDS epidemics came later in Asia, Asia is becoming the epicenter of second largest epidemic with 1 million infections annually, accounting for 20% of new infections in the world (Fig. 1). Outside of Sub‐Saharan Africa, one third of HIV infections are acquired through injecting drug use, most of which (an estimated 8.8 millions) are in Eastern Europe and central and Southeast Asia. The interplay between injecting drug use and unprotected sex fuels the epidemics in many countries in Asia (Fig. 1). Molecular epidemiology has been a useful tool to analyze the origin of HIVs and to track a course of global HIV spread. The study areas include the distribution of HIV genotypes in different geographic areas, route of global and regional virus spread, molecular features of emerging epidemics and regional outbreaks, and specific association with different epidemiologic features, such as risk behaviors. Recent investigations also provide the new data on the role of recombination in the generation of HIV genetic diversity and the frequency of dual and superinfections. In this chapter, we overview the recent advances in the study of global molecular epidemiology of HIV and discuss its biological and public health implications.
MSM IDU
IDU E. Europe & C. Asia 1.6 million (990 K–2.3 M) 270,000/y (140–610 K) 62,000† (39–91 K)
W. & C. Europe 720,000 (570–890 K) 22,000/y (15–39 K) 12,000† (
