HIV-1: MOLECULAR BIOLOGY A N D PATHOGENESIS CLINICAL APPLICATIONS, Second Edition

Edited by

Kuan-Teh Jeang Molecular Virology Section, LMM, NIAD, NIH Bethesda, Maryland

ADVANCES IN

PHARMACOLOGY VOLUME 56

AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevter

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

vi

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

Contents

vii

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 200 Approaches to Inhibit HIV Integration 210 Inhibitors in Clinical Trials 216 Inhibitors in Preclinical Development 217 Perspectives 218 References 219

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. Quifiones-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 331 Viral-Induced Cellular Alterations 343 Other Approaches 351 Conclusion 354 References 355

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~ / - yC"'" and NOD-SCID yC''~ 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, lleana Quinto, and Giuseppe Scala

I. II. III. IV.

Chapter Overview 423 Introduction 424 Current Strategies in Developing an HIV-1 Vaccine 429 Concluding Remarks 441 References 442

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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X

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-l 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