HIV I: Molecular Biology and Pathogenesis: Clinical Applications (eBook)

Cover 1
Copyright Page 5
Contents 6
Contributors 16
Preface 20
Chapter 1. HIV Therapeutics: Past, Present, and Future 24
I. Individual Drugs and Their Pharmacology 25
II. Clinical Studies 41
III. Current Recommendations for Treating HIV-1 Infection 48
Chapter 2. HIV Drug Resistance and Viral Fitness 64
I. Introduction 64
II. Methods of Assessment of Viral Fitness 68
III. Resistance to Nucleoside Analogs 70
IV. Resistance to Other Reverse Transcriptase Inhibitors 75
V. Resistance to Protease Inhibitors 76
VI. In Vivo Consequences of Resistance-Associated Loss of HIV Fitness 80
References 83
Chapter 3. Inhibitors of HIV-1 Reverse Transcriptase 90
I. Introduction 90
II. The Target 91
III. Nucleoside Reverse Transcriptase Inhibitors (NRTI) 93
IV. Nonnucleoside HIV-1 RT Inhibitors (NNRTI) 107
V. Conclusions and Future Directions 121
References 123
Chapter 4. HIV-1 Protease: Maturation, Enzyme Specificity, and Drug Resistance 134
I. Introduction 134
II. Organization of the Gag-Pol Precursor and Molecular Structure of the Mature PR 135
III. Mechanism and Regulation of PR Maturation 137
IV. Substrate/Inhibitor Interactions 149
V. Enzyme Specificity 151
VI. Drug Resistance 156
References 163
Chapter 5. HIV-1 Integrase Inhibitors: Past, Present, and Future 170
I. Introduction 170
II. Chemistry of Retroviral Integration 172
III. Role of Divalent Metals: Stoichiometry and Catalysis 174
IV. Inhibitor Development 177
V. Perspectives 183
References 184
Chapter 6. Selection of HIV Replication Inhibitors: Chemistry and Biology 190
I. Introduction 190
II. RNA-Protein Interactions as a Target for Therapeutic Interventions 194
III. TAR RNA Ligands as Tat Antagonists 195
IV. Encoded One-Bead/One-Compound Combinatorial Library Approach in Discovery of HIV Replication Inhibitors 205
V. Ligands for RRE RNA as Inhibitors of Rev-RRE Interactions 211
VI. Summary and Perspectives 213
References 214
Chapter 7. Therapies Directed against the Rev Axis of HIV Autoregulation 222
I. Introduction 222
II. Transdominant Rev Mutants and Modified Rev Proteins 224
III. Antisense Oligonucleotides 229
IV. Antisense RNA 232
V. Ribozymes 233
VI. RRE Decoys 236
VII. Intracellular Antibodies against Rev 240
VIII. Small Molecules Directed against the Rev Axis 241
IX. Therapies against Rev Cofactors 241
X. Rev-Activated Suicide and Antiviral Therapies 241
XI. Miscellaneous Anti-Rev Effects 243
XII. Clinical Trials 243
XIII. Conclusion 244
References 244
Chapter 8. HIV-1 Gene Therapy: Promise for the Future 252
I. Introduction 252
II. HIV-1 Infection and Conventional Pharmaceutical Agents 253
III. Genetic Antivirals to Block HIV-1 Replication 256
IV. Genetic GunsŽ to Deliver Genetic Antivirals 265
V. Animal Model Systems 272
VI. Clinical Trials 274
References 275
Chapter 9. Assessment of HIV Vaccine Development: Past, Present, and Future 286
I. Introduction 286
II. Virus–Host Interaction 287
III. Envelope Glycoprotein 290
IV. Viral Vaccine Strategies 297
V. Progress in AIDS Vaccine Development 299
VI. Factors to Consider in Designing an Envelope-Based Vaccine 313
VII. Concluding Remarks 318
References 319
Chapter 10. HIV-1-Associated Central Nervous System Dysfunction 338
I. Introduction 338
II. HIV-1-Associated CNS Disease 339
III. Cellular Aspects of HIV-1 CNS Infection 349
IV. Chemotherapeutic Treatment of HIVD 382
V. Summary 385
References 387
Chapter 11. Molecular Mechanisms of Human Immunodeficiency Virus Type 1 Mother–Infant Transmission 410
I. Introduction 410
II. Timing of HIV-1 Mother–Infant Transmission 412
III. Factors In.uencing HIV-1 Mother–Infant Transmission 414
IV. Effect of Smoking on HIV-1 Mother–Infant Transmission 415
V. Diagnosis of HIV-1 Infection in Perinatally Infected Infants 417
VI. Immunologic Abnormalities in HIV-1-Infected Infants 417
VII. Clinical Manifestations in HIV-1-Infected Infants 418
VIII. Prevention of HIV-1 Mother–Infant Transmission by Antiretroviral Therapy 418
IX. Pathogenesis of HIV-1 Infection and Disease Progression 419
X. Molecular and Biological Characterization of HIV-1 Involved in Mother-to-Infant Transmission 421
XI. Chemokine Receptors and HIV-1 Mother–Infant Transmission 425
XII. Genetic Analysis of HIV-1 Regions Following Mother-to-Infant Transmission 426
References 431
Chapter 12. Molecular Epidemiology of HIV-1: An Example of Asia 440
I. Introduction 440
II. Countries in the Advanced Stage of the HIV-1 Epidemic 442
III. Countries with a High Potential for Rapid Heterosexual Transmission 446
IV. Countries with Low HIV Prevalence Rates 449
References 455
Chapter 13. Simian Immunodeficiency Virus Infection of Monkeys as a Model System for the Study of AIDS Pathogenesis, Treatment, and Prevention 460
I. Introduction 460
II. SIV as a Model for Human AIDS 464
III. Viral Load Measurements as a Prognostic Indicator 471
IV. Modulation of Viral Replication by Partially Protective Vaccines 481
V. Antiviral Therapy 486
VI. Summary 489
References 490
Chapter 14. Animal Models for AIDS Pathogenesis 502
I. Introduction 502
II. Primate Lentiviruses Cause AIDS 504
III. SIV Infection of Rhesus Monkeys 506
IV. HIV Infection of Macaques 507
V. SHIV Infection of Macaques 510
VI. HSIV 511
VII. HIV Infection of Chimpanzees 512
VIII. HIV Infection of SCID Mice 516
IX. HIV Infection of Rabbits 522
X. Mice Transgenic for Primate Lentivirus Genes 522
References 528
Index 538
Contents of Previous Volumes 550