HIV I: Molecular Biology and Pathogenesis: Clinical Applications -

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

Kuan-Teh Jeang (Herausgeber)

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2007 | 2. Auflage
638 Seiten
Elsevier Science (Verlag)
978-0-08-055722-9 (ISBN)
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Although it is one of the most-widely studied viruses, many mysteries still remain about HIV. Covering the latest advances and challenges associated with clinical application of new antiviral drugs and vaccines, this revised edition is a companion to Murad:HIV-1: Molecular Biology and Pathogenesis, 2E. Leading investigators in HIV research present a timely picture of the molecular mechanisms which guide HIV-1 expression and replication and provide the most current clinical strategies for combating this virus.

* The latest developments in HIV-vaccine research
* New concepts in the discovery and design of novel anti-HIV drugs
Although it is one of the most-widely studied viruses, many mysteries still remain about HIV. Covering the latest advances and challenges associated with clinical application of new antiviral drugs and vaccines, this revised edition is a companion to Murad: HIV-1: Molecular Biology and Pathogenesis, Second Edition. Leading investigators in HIV research present a timely picture of the molecular mechanisms which guide HIV-1 expression and replication and provide the most current clinical strategies for combating this virus. The latest developments in HIV-vaccine research New concepts in the discovery and design of novel anti-HIV drugs

Front Cover 1
HIV-1: Molecular Biology and Pathogenesis 4
Copyright Page 5
Contents 6
Contributors 12
Preface written by Robin A. Weiss 16
Chapter 1: Global Molecular Epidemiology of HIV: Understanding the Genesis of AIDS Pandemic 19
I. Chapter Overview 19
II. Introduction 20
III. Genotype Classification of HIVs 22
A. HIV Types (HIV-1 and HIV-2) 22
B. Genotype Classification of HIV-1s 22
C. HIV-2: Genotype Classification and Geographic Distribution 25
IV. Global Distribution of HIV Genotypes 27
A. Global HIV-1 Variability 27
B. HIV-1 Variants in Asia 27
C. Other HIV-1 Variants of Geographical Relevance 28
D. Emergence og HIV-1 Recombinants Worldwide 29
V. Methods for Identifying HIV Genetic Forms 29
A. Phylogenetic Sequeuce Analysis 29
B. Alternative Methods (Heteroduplex Mobility Assay and Serotyping) 29
VI. Origin of HIVs and Genesis of HIV-1 Pandemic 31
A. HIV/AIDS as a "Zoonosis" 31
B. Dating the Origin of Pandemic HIV-1 Strains 32
VII. Biological Significance of HIV-1 Variability and Recombination 32
A. HIV-1 Subtypes and Disease Progression 32
B. HIV-1 Dual Infection, Superinfection, and Recombination 34
C. Biological Implications of Recombination 35
VIII. Conclusions 36
Acknowledgments 36
References 36
Chapter 2: Current Clinical Treatments of AIDS 45
I. Chapter Overview 45
II. HIV Medications 46
A. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors 46
B. Nonnucleoside Reverse Transcriptase Inhibitors 54
C. Protease Inhibitors 59
III. HIV Treatment 70
A. Initiation of Therapy 71
B. Initial Regimen 72
C. Long-Term Management 77
D. Resistance 78
E. Drugs in Development 79
IV. Conclusion 81
References 81
Chapter 3: HIV-1-Specific Immune Response 93
I. Introduction 93
II. Humoral HIV-1-Specific Response 95
III. HIV-1-Specific T-Cell Responses 96
A. Protective Role of HIV-1-Specific T-Cell Responses 96
B. Kinetics of HIV-1-Specific T-Cell Responses in Primary Infection 97
C. Phenotypic and Functional Profiles of HIV-1-Specific CD4 and CD8 T-Cell Responses 98
D. Phenotype 98
E. Function 101
F. Specificity and Breadth of HIV-1-Specific T-Cell Responses 104
References 105
Chapter 4: Targeting HIV Attachment and Entry for Therapy 111
I. Chapter Overview 111
II. Background 112
III. Inhibition of Viral Attachment 113
A. gp120 Inhibitors 113
B. Targeting CD4 115
IV. Chemokine Receptors in HIV Infection 116
V. Targeting Coreceptor Binding 117
A. CXCR4 Inhibition 117
B. Targeting CCR5 for HIV Therapy 120
VI. Fusion Inhibitors 125
A. Targeting gp41 125
B. Inhibition of Membrane Fusion 126
VII. Resistance to Inhibitors of Viral Entry 127
VIII. Use Entry Inhibitors as Microbicides 128
References 129
Chapter 5: Inhibitors of HIV-1 Reverse Transcriptase 139
I. Chapter Overview 139
II. Introduction 140
III. The Target 141
A. Structure of HIV-1 RT 142
B. Mechanism of HIV-1 RT DNA Polymerase Activity 144
IV. Nucleoside RT Inhibitors 145
A. Mechanisms of NRTI Inhibition 145
B. NRTI Approved for Clinical Use 147
C. Investigational NRTI 150
D. HIV-1 Resistance to NRTIs 151
V. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) 158
A. Mechanisms of NNRTI Inhibition 158
B. NNRTI Approved for Clinical Use 161
C. Investigational NNRTI 162
D. HIV-1 Resistance to NNRTIs 164
E. Interactions Between NNRTI and NRTI Resistance Mutations 166
F. Use of NNRTI as Microbicides 167
VI. Other Inhibitors of HIV-1 RT 168
A. Inhibitors of HIV-1 RT RNH 169
B. Inhibitors of HIV-1 RT Dimerization 171
C. Inhibitors of the Initiation of Reverse Transcription 171
D. RT-Directed Mutagenic Inducers 172
VII. Conclusion 172
Acknowledgments 173
References 173
Chapter 6: Development of Protease Inhibitors and the Fight with Drug-Resistant HIV-1 Variants 187
I. Chapter Overview 187
II. Introduction 188
III. Targeting Viral Protease 188
A. Mechanism of Action of PIs 188
B. Protease Structures and Substrate-Based Inhibitors 190
C. Design of Symmetry-Based Inhibitors 190
D. Structure-Based PIs 192
IV. The Role of PIs and Challenges in HAART 192
V. "Boosting": A Critical Modification of Clinical Efficacy of PIs 193
VI. Viral Resistance to PIs 194
A. Emergence of Drug Resistance to PIs 194
B. Primary and Secondary Mutations 196
C. Active site Mutants 197
D. Nonactive Site Mutants 197
E. Cleavage Site Mutants 198
F. Noncleavage Site Mutants 199
G. Insertions in Gag-Pol Polyproteins 199
VII. PIs with Activity Against Drug-Resistant HIV-1 200
A. Mutations That Allow Discrimination of PIs from Natural Substrates 200
B. Development of Pls with Activity Against Drug-Resistant HIV 202
C. Design Rationale of Darunavir 202
D. HIV-1 Resistance to Darunavir 204
E. Tipranavir and Darunavir 206
VIII. Conclusions 207
Acknowledgments 209
References 209
Chapter 7: HIV-1 Integrase Inhibitors: Update and Perspectives 217
I. Chapter Overview 217
II. Foreword 218
III. Integration: A Crucial Step in the HIV Life Cycle 218
A. HIV-1 IN Structure 218
B. Chemistry of Retroviral Integration 219
C. Integration Occurs Within a Large Macromolecular Complex 220
IV. Approaches to Inhibit HIV Integration 228
A. Small Molecule Inhibitors of HIV IN Enzymatic Activities 228
B. Targeting the PIC 234
V. Inhibitors in Clinical Trials 234
VI. Inhibitors in Preclinical Development 235
VII. Perspectives 236
References 237
Chapter 8: Topical Microbicides: A Promising Approach for Controlling the AIDS Pandemic via Retroviral Zinc Finger Inhibitors 247
I. Chapter Overview 247
II. The AIDS Pandemic and the Rationale for a Microbicide 248
III. Topical Microbicides in Preclinical Development 250
IV. Characteristics of an Ideal Microbicide 255
V. The Retroviral Zinc Fingers of HIV-1 NCp7 as a Potential Microbicide Target 256
VI. Characteristics of the SAMT Chemotype 258
VII. Application of Thioesters for Microbicides 262
VIII. Target Specificity of the SAMT NCp7 Inhibitors 264
IX. Conclusions 267
X. Addendum 268
References 269
Chapter 9: Viral Drug Resistance and Fitness 275
I. Chapter Overview 275
II. Introduction 276
A. Entry Inhibitors 277
B. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors 287
C. Non-Nucleoside Reverse Transcriptase Inhibitors 292
D. Integrase Inhibitors 294
E. Protease Inhibitors 296
References 301
Chapter 10: Gene Therapy to Induce Cellular Resistance to HIV-1 Infection: Lessons from Clinical Trials 315
I. Chapter Overview 315
II. Introduction: Do We Need HIV-1 Gene Therapy? 316
III. Gene Therapy of HIV Infection: Lessons from Early Clinical Trials 318
A. Clinical Trials Using Dominant Negative Forms of the HIV-1 Rev Protein 320
B. Clinical Trials Using the RRE Decoy 321
C. Clinical Trials Using Antisense RNAs 322
D. Clinical Trials with Ribozymes 322
IV. Gene Therapy of HIV Infection: Current Developments 324
A. Gene Transfer to Hemapoietic Progenitors 324
B. Gene Therapy Using Lentiviral Vectors 327
C. RNA Interference as a Therapeutic Tool 329
D. Targeting HIV-1 Internalization 331
V. Gene Therapy for HIV Infection: Where Are We Heading? 332
Acknowledgments 335
References 335
Chapter 11: Identification of Potential Drug Targets Using Genomics and Proteomics: A Systems Approach 345
I. Chapter Overview 345
II. Introduction 346
III. Viral Targets 347
A. Viral Genomics 347
B. Current Therapies and Future Prospects 348
IV. Cellular/Viral Protein-Protein Interactions 349
A. Cellular Protein Interactions of Tat 350
B. Cellular Protein Interactions of Nef 355
C. Cellular Protein Interactions of Gag 358
V. Viral-Induced Cellular Alterations 361
A. Tat: Effects on Cellular Transcription 361
B. Nef: Altering the Cell Surface 366
C. Gag: Using Cellular Factors to Facilitate Budding 368
VI. Other Approaches 369
A. Virion Proteome 369
B. Biomarkers 370
C. RNA Interference 371
VII. Conclusion 372
Acknowledgments 373
References 373
Chapter 12: Rapid Disease Progression to AIDS due to Simian immunodeficiency virus Infection of Macaques: Host and Viral Factors 387
I. Chapter Overview 387
II. Introduction 388
III. SIV Strain Diversity 389
IV. Biology of SIV 389
V. Pathogenesis of SIV in Macaques 391
A. SIV-sm and SIV-mac Infection as Models for AIDS 391
B. Variation in Disease Progression 392
C. Acutely Lethal SIV-smPBj 393
D. Clinical Correlates of Disease Progression 394
VI. Unique Immunologic, Virological, and Pathological Features of Rapid Disease 395
A. Immunologic Features 396
B. Virological Features 397
C. Pathological Features 397
VII. Host Factors That Influence Disease Progression 401
A. Macaque Species 401
B. Host Immune Responses and Major Histocompatibility Complex 401
VIII. Role of Virus Genotype/ Phenotype in Rapid Disease Progression 402
A. Specific Genes Involved in Pathogenesis 402
B. Evolution of SIV in RPs 403
C. In Vivo Studies of the Role of Virus in Rapid Disease 405
IX. Summary 406
Acknowledgments 407
References 407
Chapter 13: Nonprimate Models of HIV-1 Infection and Pathogenesis 417
I. Chapter Overview 417
II. Introduction 418
III. SCID-Hu Thy/Liv Mice 419
IV. The hu-PBL-SCID Mouse 423
V. NOD/LtSz-SCID Mice 425
VI. Rag2-/- gammaC-/- and NOD-SCID gammaC-/- Mice 426
VII. Humanized Immune Competent Mice and Rats 427
VIII. HIV-1 Tg Mice 428
IX. Rabbit Model of HIV Pathogenesis 430
X. Conclusion 431
References 431
Chapter 14: Perspectives for a Protective HIV-1 Vaccine 441
I. Chapter Overview 441
II. Introduction 442
A. Natural History of HIV-1 Infection 442
B. Immune Response Elicited During HIV-1 Infection 445
C. Requirements for an Effective HIV-1 Vaccine 446
III. Current Strategies in Developing an HIV-1 Vaccine 447
A. Live-Attenuated HIV 447
B. Induction of Antibody-Mediated Immunity 454
IV. Concluding Remarks 459
References 460
Chapter 15: Molecular Mechanisms of HIV-1 Vertical Transmission and Pathogenesis in Infants 471
I. Chapter Overview 471
II. Introduction 472
III. Timing and Mechanism of HIV-1 Vertical Transmission 474
IV. Factors Associated with HIV-1 Vertical Transmission 476
V. HIV-1 Infection Diagnosis in Neonates and Infants 478
VI. Prevention of HIV-1 Vertical Transmission 478
VII. Characterization of HIV-1 Associated with Vertical Transmission 480
VIII. Chemokine Receptors and HIV-1 Vertical Transmission 482
IX. Molecular Properties of HIV-1 from Mother-Infant Pairs Associated with Vertical Transmission 483
X. Characterization of Functional Domains of HIV-1 Genes Associated with Vertical Transmission 488
XI. Properties of HIV-1 Associated with Lack of Vertical Transmission 496
XII. Analysis of Immunologically Relevant Mutations in HIV-1 Isolates Associated with Vertical Transmission 499
XIII. Mechanisms of HIV-1 Pathogenesis and Disease Progression in Infants 503
XIV. The Future 509
Acknowledgments 509
References 510
Chapter 16: The Viral Etiology of AIDS-Associated Malignancies 527
I. Chapter Overview 527
II. Introduction 528
III. Kaposi's Sarcoma 530
A. Viral Etiology in KS 531
B. KSHV Epidemiology 533
C. Viral Oncogenesis 534
IV. AIDS-Associated Lymphomas 538
A. EBV, Its Latency, and Its Role in AIDS-Associated Lymphomas 538
B. Latent Membrane Protein 1 (LMP-1) 539
C. Latent Membrane Protein 2 540
D. Epstein-Barr Nuclear Antigen 1 (EBNA-1) 541
E. EBNA-2 541
V. AIDS-Associated NHL 542
A. Primary Central Nervous System Lymphoma 543
B. Primary Effusion Lymphoma 543
C. Systemic AIDS-Associated NHL 544
VI. HPV-Associated Cancers 545
A. Types of HPV-Induced Cancers 545
VII. HPV—The Causative Agent 547
A. Papillomavirus Genome Structure 547
B. The HPV Life Cycle 548
C. The HPV Capsid and the Vaccine 550
D. Epidemiology of HPV and HIV/AIDS 551
E. The Mechanism of HPV-Induced Transformation and Cancer Progression 553
VIII. Conclusions 556
Acknowledgments 557
References 557
Index 577
Contents of Previous Volumes 593
Color Plate Section 612

Erscheint lt. Verlag 14.12.2007
Mitarbeit Herausgeber (Serie): J. Thomas August, Ferid Murad
Sprache englisch
Themenwelt Sachbuch/Ratgeber
Medizin / Pharmazie Allgemeines / Lexika
Medizin / Pharmazie Medizinische Fachgebiete Pharmakologie / Pharmakotherapie
Studium Querschnittsbereiche Infektiologie / Immunologie
Naturwissenschaften Biologie Mikrobiologie / Immunologie
Technik
ISBN-10 0-08-055722-8 / 0080557228
ISBN-13 978-0-08-055722-9 / 9780080557229
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