Cell Death During HIV Infection

CELL DEATH DURING

HIV INFECTION

© 2006 by Taylor & Francis Group, LLC

CELL DEATH DURING

HIV INFECTION edited by

Andrew D. Badley

© 2006 by Taylor & Francis Group, LLC

Published in 2006 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2006 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-2827-6 (Hardcover) International Standard Book Number-13: 978-0-8493-2827-5 (Hardcover) Library of Congress Card Number 2005044006 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Cell death during HIV infection / edited by Andrew D. Badley. p. cm. Includes bibliographical references and index. ISBN 0-8493-2827-6 (alk. paper) 1. HIV infections. 2. Apoptosis. 3. Immunodeficiency. 4. T cells. I. Badley, Andrew D. QR201.A37.C453 2005 616.97'9207--dc22

2005044006

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Editor Andrew D. Badley, M.D., is a consultant in the Division of Infectious Diseases, Department of Medicine, at the Mayo Clinic in Rochester, Minnesota. He is professor of medicine at the Mayo Clinic College of Medicine and associate director of the Mayo Clinic Translational Immunovirology and Biodefense Program, a National Institutes of Health Center of Excellence, as well. His duties include overseeing an active clinical practice, which focuses on the care of patients immunocompromised by human immunodeficiency virus infection, transplant recipients, and a research laboratory that currently is funded by the National Institutes of Health and private grants. A Canadian by birth, Dr. Badley completed his undergraduate and medical studies at Dalhousie University in Halifax, Nova Scotia. After completing his internship in Halifax, he moved to the Mayo Clinic in Rochester, Minnesota, for his residency and clinical investigator fellowship. Following this fellowship, he returned to Canada for a position at Ottawa General Hospital that included clinical practice and basic research. In 2002, he returned to the Mayo Clinic as a consultant with his own laboratory. He actively mentors both clinical and research trainees who may be residents, fellows, or graduate students. To date, he has published approximately 70 papers on human immunodeficiency virus, general infectious disease, infections in immunocompromised hosts, immunotherapy, and apoptosis dysregulation during infectious diseases. He has also been the principal or coinvestigator of numerous clinical trials.

© 2006 by Taylor & Francis Group, LLC

Contributors Andrew D. Badley, M.D. Mayo Clinic College of Medicine Rochester, Minnesota Andreas Baur, M.D. University of Miami School of Medicine Department of Microbiology and Immunology Miami, Florida

Andrea Cossarizza, Ph.D. Biomedical Sciences University of Modena Modena, Italy Demetre C. Daskalakis, M.D. Massachusetts General Hospital Division of Infectious Diseases Boston, Massachusetts

José A. M. Borghans, Ph.D. Department of Immunology University Medical Centre Utrecht Utrecht, The Netherlands

Claude Desgranges, Ph.D. Centre National de la Recherche Scientifique UFR Biomédical Paris, France

Catherine Brenner, Ph.D. Centre National de la Recherche Scientifique Université de Versailles/St. Quentin Versailles, France

Marie-Lise Dion Université de Montréal Laboratoire d’Immunologie, CR-CHUM Montréal, Quebec, Canada

David Camerini, Ph.D. Department of Molecular Biology and Biochemistry University of California Irvine, California Xian-Ming Chen, M.D. Mayo Clinic College of Medicine Rochester, Minnesota Shailesh K. Choudhary, Ph.D. Department of Molecular Biology and Biochemistry University of California Irvine, California Luchino Y. Cohen, Ph.D. Université de Montréal Laboratoire d’Immunologie, CR-CHUM Montréal, Quebec, Canada Jacques Corbeil, Ph.D. Université Laval Quebec, Canada

© 2006 by Taylor & Francis Group, LLC

Dara Ditsworth, M.S. Abramson Family Cancer Research Institute University of Pennsylvania Philadelphia, Pennsylvania David H. Dockrell, M.D. Division of Genomic Medicine University of Sheffield Medical School Sheffield, United Kingdom Gilad Doitsh, Ph.D. Gladstone Institute of Virology and Immunology University of California San Francisco, California Rebecca L. Elstrom Abramson Family Cancer Research Institute University of Pennsylvania Philadelphia, Pennsylvania ^ Estaquier, Ph.D Jérome Unite de Physiopathologie des Infections Lentivirales Institute Pasteur Paris, France

Gregory J. Gores, M.D. Mayo Clinic College of Medicine Rochester, Minnesota Daniel B. Graham, Ph.D. Mayo Clinic College of Medicine Rochester, Minnesota Walter C. Greene, M.D., Ph.D. Gladstone Institute of Virology and Immunology University of California San Francisco, California Maria Eugenia Guicciardi, Ph.D. Mayo Clinic College of Medicine Rochester, Minnesota Mette D. Hazenberg, M.D., Ph.D. Gladstone Institute of Virology and Immunology University of California San Francisco, California Georges Herbein, M.D. Department of Virology Université de Franche-Compte Besançon, France Gareth Jones, Ph.D. Department of Microbiology and Infectious Diseases University of Calgary Calgary, Alberta, Canada Scott H. Kaufmann, M.D., Ph.D. Mayo Clinic College of Medicine Rochester, Minnesota Laurene M. Kelly Research Institute for Genetic and Human Therapy IRCCS Policlinic S. Matteo Pavia, Italy Jason F. Kreisberg, B.S. Gladstone Institute of Virology and Immunology University of California San Francisco, California

© 2006 by Taylor & Francis Group, LLC

Guido Kroemer, M.D., Ph.D. Institut Gustave Roussy Centre National de la Recherche Scientifique Villejuif, France Nicholas F. LaRusso, M.D. Mayo Clinic College of Medicine Rochester, Minnesota Christophe Lemaire, Ph.D. Centre National de la Recherche Scientifique Université de Versailles/St. Quentin Versailles, France Michael J. Lenardo, M.D. Laboratory of Immunology National Institutes of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland Julianna Lisziewicz Research Institute for Genetic and Human Therapy IRCCS Policlinic S. Matteo Pavia, Italy Franco Lori, M.D. Research Institute for Genetic and Human Therapy IRCCS Policlinic S. Matteo Pavia, Italy Julain J. Lum, Ph.D. Abramson Family Cancer Research Institute University of Pennsylvania Philadelphia, Pennsylvania David J. McKean, Ph.D. Mayo Clinic College of Medicine Rochester, Minnesota David R. McNamara, M.D. Mayo Clinic College of Medicine Rochester, Minnesota Xue Wei Meng, M.D., Ph.D. Mayo Clinic College of Medicine Rochester, Minnesota

Frank Miedema, Ph.D. Department of Immunology University Medical Centre Utrecht Utrecht, The Netherlands

Roger J. Pomerantz, M.D. Thomas Jefferson University Institute for Human Virology and Biodefense Philadelphia, Pennsylvania

Sylviane Muller, Ph.D. Institut de Biologie Moleculaire et Cellulaire Centre National de la Recherche Scientifique Strasbourg, France

Christopher Power, M.D. Department of Clinical Neurosciences University of Calgary Calgary, Alberta, Canada

Zilin Nie, M.D. Mayo Clinic College of Medicine Rochester, Minnesota

Eric S. Rosenberg, M.D. Massachusetts General Hospital Division of Infectious Diseases Boston, Massachusetts

David Nolan, M.D. Center for Clinical Immunology and Biomedical Statistics Royal Perth Hospital and Murdoch University Perth, Western Australia

Keiko Sakai, Ph.D. National Institutes of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland

Giuseppe Nunnari, M.D. Thomas Jefferson University Institute for Human Virology and Biodefense Philadelphia, Pennsylvania

David Schnepple, M.S. Mayo Clinic College of Medicine Rochester, Minnesota

Savita Pahwa, M.D. University of Miami School of Medicine Department of Microbiology and Immunology Miami, Florida

Rafick-Pierre Sekaly, M.D. Université de Montréal Laboratoire d’Immunologie, CR-CHUM Montréal, Quebec, Canada

Jean-Luc Perfettini, Ph.D. Institut Gustave Roussy Centre National de la Recherche Scientifique Villejuif, France Barbara N. Phenix, Ph.D. North Shore LIJ Research Institute Manhasset, New York Michael J. Pinkoski, Ph.D. Apoptosis Research Centre Children’s Hospital of Eastern Ontario Ottawa, Ontario, Canada Eric M. Poeschla, M.D. Mayo Clinic College of Medicine Rochester, Minnesota

© 2006 by Taylor & Francis Group, LLC

Matthew Smith-Raska Laboratory of Immunology National Institutes of Allergy and Infectious Diseases National Institutes of Health Bethesda, Mary land Craig B. Thompson, M.D. Abramson Family Cancer Research Institute University of Pennsylvania Philadelphia, Pennsylvania Anne J. Tunbridge, M.B. Division of Genomic Medicine University of Sheffield Medical School Sheffield, United Kingdom

Stacey R. Vlahakis, M.D. Mayo Clinic College of Medicine Rochester, Minnesota

Sara Warren, B.S. Mayo Clinic College of Medicine Rochester, Minnesota

Nienke Vrisekoop Department of Clinical Viro-Immunology Laboratory of the Academic Medical Center Amsterdam University of Amsterdam Amsterdam, The Netherlands

John Zaunders, Ph.D. Centre for Immunology St. Vincent’s Hospital Darlington, New South Wales, Australia

© 2006 by Taylor & Francis Group, LLC

Introduction Establishing that the human immunodeficiency virus (HIV) is the etiologic agent of acquired immunodeficiency syndrome (AIDS) was the beginning of a revolution in science. Since then, the advances made in retrovirology have led to major advances in therapy for HIV, which, in turn, have allowed thousands worldwide to live longer lives. The advances in immunologic sciences have been rapid as well, and within a few short years, those advances will likely translate into immune-based therapies for use in clinical practice. In comparison, the study of apoptosis dysregulation during HIV-induced immunodeficiency has been less intense. Nevertheless, important lessons have been learned. Most scientists and clinicians now accept that cell death is not a passive process but, rather, a tightly coordinated and regulated one. As such, apoptotic cell death may be amenable to therapeutic intervention. In non-HIV disease states, clinical trials of apoptosis modifying agents used for HIV disease are already underway. In HIV disease, enhanced understanding of the apoptotic pathways that are involved may lead to novel treatment strategies. It is apparent, however, that multiple, likely simultaneous, processes contribute to the enhanced CD4 T cell apoptosis, which together contribute to immune deficiency. In all likelihood, apoptotic dysregulations are cell-type dependent, because those cells that become latent reservoirs for HIV, by definition, do not succumb to the proapoptotic effects of infection. Such complexities offer multiple avenues for intervention: antiapoptotic approaches to limit HIVinduced T cell depletion and proapoptotic approaches designed to eradicate latent infections. When I was approached by Taylor & Francis regarding this project, I envisioned soliciting coauthors who were conducting the most current and exciting bench science in apoptosis and HIV. I have taken their work and attempted to form a volume that may be used both as a reference source and as an incubator to stimulate future work. Thus, the book is divided into four sections: Basic Concepts, Mechanisms of HIV-Associated Cell Death, Clinical Consequences of HIV-Induced Cell Death, and Therapeutic Issues. Section 2, Mechanisms of HIV-Associated Cell Death, has three component parts: Viral Factors, Immune Mechanisms, and Infected vs. Uninfected Death. Each of the authors in this book is a leader in his or her respective field. Their efforts ensure that each chapter meets the highest standards of scientific scholarship. I gratefully recognize those efforts and am sure that they will be appreciated by readers as well. I am indebted to them all. I am equally indebted to the contributions of my many collaborators, colleagues, and past, present, and future members of my laboratory who were, over the years, a source of personal and professional inspiration and motivation. Early in my medical career, I was involved in the care of an HIV-positive patient at a time when no effective therapies existed and none were in development. The sense of hopelessness then and, again, more recently in the era of antiretroviral resistance was a recurring source of motivation to increase my understanding of the disease. To these patients and the numerous other patients who volunteered for clinical- and laboratory-based studies, I offer my sincere thanks and best wishes. I also wish to thank Mark McClees and Carrie Rogness, from Mayo Clinic’s Division of Infectious Diseases, for their efforts in assembling this edition and working with the contributing authors and publisher. Without their efforts, this volume would not be in print. Finally, I acknowledge the support and love of my parents, my wife Nanci, and my children, Lauren, Andrew, Adrianne, and Caitlin. Their patience and understanding have allowed me to pursue my passions and obsessions; to each, I am eternally indebted. Andrew D. Badley Rochester, Minnesota

© 2006 by Taylor & Francis Group, LLC

Table of Contents Section 1 Basic Concepts Chapter 1 Lentiviral Biology and Cell Death...............................................................................3 Eric M. Poeschla Chapter 2 Regulation of Apoptosis .............................................................................................21 Maria Eugenia Guicciardi and Gregory J. Gores Chapter 3 Approaches Used to Detect Apoptosis ......................................................................35 Scott H. Kaufmann and Xue Wei Meng Chapter 4 Consequences of HIV Infection on Thymus Function and T Cell Development.....55 Daniel B. Graham and David J. McKean Chapter 5 Deadly Intentions: Apoptosis in the Peripheral Immune System .............................77 Michael J. Pinkoski Section 2 Mechanisms of HIV-Associated Cell Death Viral Factors Chapter 6 Cell Death in HIV Infection: gp120 ..........................................................................95 Stacey R. Vlahakis Chapter 7 Vpr ............................................................................................................................109 Julian J. Lum and Andrew D. Badley Chapter 8

Interference of the Nef Protein of HIV-1 with Pro- and Antiapoptotic Pathways of T Cells .................................................................................................127 Andreas Baur Chapter 9 HIV-1 Tat and Apoptotic Death ...............................................................................143 Sylviane Muller and Claude Desgranges Chapter 10 HIV Protease (PR) and Cell Death..........................................................................155 Zilin Nie, David R. McNamara, and Andrew D. Badley Immune Mechanisms Chapter 11 Immune Activation ...................................................................................................171 Barbara N. Phenix and Savita Pahwa

© 2006 by Taylor & Francis Group, LLC

Chapter 12 Impairment of HIV-Specific Immune Effector Cell Function.................................185 Demetre C. Dakalakis and Eric S. Rosenberg Infected vs. Uninfected Death Chapter 13 Mechanisms of HIV-Infected vs. Uninfected T Cell Killing ..................................207 Jason F. Kreisberg, Gilad Doitsh, and Warner C. Greene Chapter 14 Elevated Apoptosis of CD8+ T Lymphocytes during HIV-1 Infection ...................229 John Zaunders, Jérôme Estaquier, and Jacques Corbeil Chapter 15 Autologous Cell-Mediated Killing...........................................................................253 Georges Herbein Chapter 16 Molecular Mechanisms of HIV-1 Syncytial Apoptosis ...........................................271 Christophe Lemaire, Jean-Luc Perfettini, Guido Kroemer, and Catherine Brenner Chapter 17 Nonapoptotic HIV-Induced T Cell Death ................................................................279 Keiko Sakai, Matthew Smith-Raska, and Michael J. Lenardo Chapter 18 Apoptosis in Organ Culture and Animal Models of HIV Disease .........................293 Shailesh K. Choudhary and David Camerini Section 3 Clinical Consequences of HIV-Induced Cell Death Chapter 19 T Cell Dynamics and the Role of Apoptosis in HIV Infection ..............................319 Nienke Vrisekoop, Mette D. Hazenberg, Frank Miedema, and José A.M. Borghans Chapter 20 Alteration of the Apoptotic Pathways in the Thymus during HIV Infection .........335 Luchino Y. Cohen, Marie-Lise Dion, and Rafick-Pierre Sekaly Chapter 21 Correlations between Apoptosis and HIV Disease Progression..............................355 David H. Dockrell and Anne J. Tunbridge Chapter 22 HIV-1 Infection and Cell Death in the Nervous System.........................................381 Gareth Jones and Christopher Power Chapter 23 Involvement of Apoptosis in Complications of HIV and Its Treatment .................405 David Nolan Chapter 24 Apoptosis as a Pathogenic Mechanism of HIV-Associated Opportunistic Infections ...........................................................................................421 Sara Warren, Xian-Ming Chen, Nicholas F. LaRusso, and Andrew D. Badley

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Section 4 Therapeutic Issues Chapter 25 Direct Effects of Anti-HIV Therapeutics on Apoptosis ..........................................441 David Schnepple and Andrew D. Badley Chapter 26 HIV-1 Reservoirs and Residual Viral Replication during Highly Active Antiretroviral Therapy ..............................................................................................457 Roger J. Pomerantz and Giuseppe Nunnari Chapter 27 Therapeutic Approaches to Modulation of Cell Death (non-HIV) .........................475 Dara Ditsworth, Rebecca L. Elstrom, and Craig B. Thompson Chapter 28 Immunotherapy of HIV Disease ..............................................................................505 Franco Lori, Laurene M. Kelly, Andrea Cossarizza, and Julianna Lisziewicz

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Section I Basic Concepts

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Biology 1 Lentiviral and Cell Death Eric M. Poeschla CONTENTS Introduction ........................................................................................................................................3 Lentiviral Biology and Pathogenesis .................................................................................................3 The Origins of HIV-1 and the Emergence of Lentiviral Disease in Primates ..........................5 Replication and Pathogenesis: A Comparative Lentiviral Perspective ......................................5 Viral Life Cycle .................................................................................................................................6 Early Events ................................................................................................................................6 Uncoating and Transport to the Nucleus....................................................................................8 Integration ...................................................................................................................................8 Latency........................................................................................................................................9 Late Events................................................................................................................................10 Conclusion........................................................................................................................................11 Acknowledgment..............................................................................................................................11 References ........................................................................................................................................11

INTRODUCTION The Lentivirus genus was named to connote the slow and inexorable progression of the degenerative diseases its members cause in a number of mammalian species. The median time to progression to acquired immunodeficiency syndrome (AIDS) after primary HIV (human immunodeficiency virus)-1 infection in humans, for example, is approximately 10 years. In other instances, however, a state of mutually benign accommodation seems to evolve, in which lentiviruses persist and replicate while causing no ill effects in host animals. The HIV-1 pandemic illustrates the pathogenicity that may ensue when a lentivirus has recently undergone cross-species transmission and remains unchecked by evolutionary coadaptation between parasite and host. Another biologically central issue, one that the prefix lenti belies, is the view we now have of HIV-1 replication and turnover in the body, where the process is anything but slow. Rather, a highly dynamic replication process is apparent, and the amount of HIV-1 circulating in plasma correlates very well with disease progression. This chapter will present an overview of these and other selected aspects of HIV-1 virology. The intent is to introduce the basic molecular biology of HIV-1 within a comparative lentiviral framework as a basis for considering the complex question that is the theme of the succeeding chapters in this volume: how do cells die from HIV-1 infection?

LENTIVIRAL BIOLOGY AND PATHOGENESIS Lentiviruses were the first retroviruses associated with disease and were among the first filterable disease agents identified.1 Three groups of lentiviruses infect primates, ungulates, and felines, 3

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4

Cell Death during HIV Infection

TABLE 1.1 Lentiviruses: Classification and Disease Virus

Host

Primate HIV-1

Humans

HIV-2

Humans

SIVcpz

Chimpanzee; ancestral to HIV-1 Macaques in captivity

Cell Tropism

Disease Features

CD4+ T cell depletion, dementia, wasting

Sootey mangabey; ancestral to HIV-2

Macrophages, CD4+ T cells Macrophages, CD4+ T cells Macrophages, CD4+ T cells Macrophages, CD4+ T cells Macrophages, CD4+ T cells

Ungulate EIAV Maedi-visna CAEV BIV, Jembrana

Horses Sheep Goats Cattle

Macrophages Macrophages Macrophages Macrophages

Anemia, wasting Encephalitis, lung disease, mastitis, wasting Encephalitis, arthritis, mastitis, wasting Probably none in Bos taurus (BIV), anemia and wasting in Bos javanicus (Jembrana)

Feline FIV

Feline species

Macrophages, CD4+ T, CD8+ T, and B cells

CD4+ T cell depletion–AIDS in domestic cat; asymptomatic in numerous other Felidae

SIVmac SIVsm

CD4+ T cell depletion, dementia, wasting; less pathogenic and transmissible than HIV-1 None CD4+ T cell depletion, dementia, wasting None

respectively (Table 1.1). The term “slow virus” was first applied by Bjorn Sigurdsson in the 1950s during his studies of a maedi-visna virus (MVV) epidemic that illustrates well the potentially severe effects of introducing lentiviruses into naive populations or species.2 Importation of asymptomatic sheep from the European continent to Iceland in 1933 led to the subsequent death of more than 100,000 Icelandic sheep over several decades from MVV, which causes a pneumonic disease (maedi in Icelandic)3 and chronic encephalitis (visna).4,5 Both equine infectious anemia virus (EIAV), the disease agent described by Vallée and Carré in 1904,1 and MVV were studied as model slow viruses before primate lentiviruses were discovered.2–10 Feline immunodeficiency virus (FIV) and bovine lentiviruses (bovine immunodeficiency virus [BIV] and Jembrana disease virus) were isolated and characterized in the post-AIDS era.11–13 Lentiviruses differ in a number of respects from other retroviruses. Among the most striking difference is their ability to replicate in terminally differentiated, nondividing cells.14,15 Recognition of this signature property inspired development of replication-defective vectors capable of permanent transgene integration in diverse nondividing cells of relevance to gene therapy.16–18 All lentiviruses infect nondividing tissue macrophages, which are the principal reservoirs in vivo for the ungulate lentiviruses. For example, the primary pathology caused by EIAV is a cyclical hemolytic anemia caused by antigen–antibody complexes that bind to the surfaces of erythrocytes; however, the primary EIAV producer cell is the macrophage.19,20 Lentiviral tropism is determined by receptor utilization. (See early events below.) FIV and the primate lentiviruses have evolved additional tropisms for lymphocytes. FIV has the broadest tropism, as it infects B cells and CD8+ T cells in addition to macrophages and CD4+ T cells.21 HIV-1 infects CD4+ T cells and macrophages and glial cells, although a variety of other cell types have been reported to be infected to a lesser extent in vivo.

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Lentiviral Biology and Cell Death

THE ORIGINS

OF

HIV-1

AND THE

5

EMERGENCE

OF

LENTIVIRAL DISEASE

IN

PRIMATES

Each lentivirus has a rather narrow host range.22 Infrequent interspecies transmissions give rise to new viruses and diseases. This potential is best illustrated by the origins of HIV-1 and HIV-2 in separate transmissions of ancestral nonhuman primate lentiviruses to humans.23,24 HIV-1 and HIV-2 each seem to have arisen several times.24–26 The three distinct genetic groups of HIV-1 (M, N, and O) resulted from independent cross-species transmission events.27 The best estimates from maximumlikelihood phylogenetic methods place the last common ancestor of the M (“main”) group before 1940.25,26 Severe pathology (AIDS) was also observed when simian lentiviruses, which do not cause evident disease in their Old World host species, infected Asian macaques in captivity.28 Similarly, FIV infects many large feline species throughout the world, but only domestic cats develop clearly recognizable disease, which is severe and closely mimics human AIDS clinically and virologically.29,30

REPLICATION

AND

PATHOGENESIS: A COMPARATIVE LENTIVIRAL PERSPECTIVE

Analyses of temporal and quantitative aspects of HIV-1 ribonucleic acid (RNA) in plasma before and after the institution of highly active antiretroviral therapy (HAART) have led to the realization that HIV-1 replication is highly dynamic in vivo, supplanting earlier notions that too little virus existed to account for the severity of the disease.31–35 Plasma viral RNA will decrease by approximately 2 log units within 2 weeks of instituting HAART. Various estimates derived from such studies place the half-life of HIV-1 virions in vivo on the order of minutes to a few hours.31–33 The half-life of productively infected cells is also very short, approximately a day or two. Most plasma virus is produced quite recently.31–33 The relationship of viral load to HIV-1 to prognosis has been made clear in numerous studies.36,37 Individual patients reliably establish a particular viral “set point,” in which the plasma viral load remains fairly consistent over time within half a log unit after the resolution of the primary infection. Viral loads can exceed 107 RNA copies per ml of plasma during primary infection; set point values average between 104 and 105 but vary an order of magnitude or more in each direction. A single measurement of plasma RNA before treatment reliably reflects the steady state and also strongly predicts the rate of CD4+ lymphocyte depletion and progression to AIDS and death.36,37 Regardless of the starting level, however, viremia can be reliably suppressed to undetectable (