Elsevier S & T

HIV I: Molecular Biology and Pathogenesis: Clinical Applications: Molecular Biology and Pathogenesis: Clinical Applications

August, J. Thomas

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Table of contents
  • Contentsv
  • Contributorsxi
  • Preface written by Robin A. Weissxv
  • Chapter 1: Global Molecular Epidemiology of HIV: Understanding the Genesis of AIDS Pandemic1
  • I. Chapter Overview1
  • II. Introduction2
  • III. Genotype Classification of HIVs4
  • A. HIV Types (HIV-1 and HIV-2)4
  • B. Genotype Classification of HIV-1s4
  • C. HIV-2: Genotype Classification and Geographic Distribution7
  • IV. Global Distribution of HIV Genotypes9
  • A. Global HIV-1 Variability9
  • B. HIV-1 Variants in Asia9
  • C. Other HIV-1 Variants of Geographical Relevance10
  • D. Emergence og HIV-1 Recombinants Worldwide11
  • V. Methods for Identifying HIV Genetic Forms11
  • A. Phylogenetic Sequeuce Analysis11
  • B. Alternative Methods (Heteroduplex Mobility Assay and Serotyping)11
  • VI. Origin of HIVs and Genesis of HIV-1 Pandemic13
  • A. HIV/AIDS as a "Zoonosis"13
  • B. Dating the Origin of Pandemic HIV-1 Strains14
  • VII. Biological Significance of HIV-1 Variability and Recombination14
  • A. HIV-1 Subtypes and Disease Progression14
  • B. HIV-1 Dual Infection, Superinfection, and Recombination16
  • C. Biological Implications of Recombination17
  • VIII. Conclusions18
  • Acknowledgments18
  • References18
  • Chapter 2: Current Clinical Treatments of AIDSCover
  • I. Chapter Overview27
  • II. HIV Medications28
  • A. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors28
  • B. Nonnucleoside Reverse Transcriptase Inhibitors36
  • C. Protease Inhibitors41
  • III. HIV Treatment52
  • A. Initiation of Therapy53
  • B. Initial Regimen54
  • C. Long-Term Management59
  • D. Resistance60
  • E. Drugs in Development61
  • IV. Conclusion63
  • References63
  • Chapter 3: HIV-1-Specific Immune ResponseCover
  • I. Introduction75
  • II. Humoral HIV-1-Specific Response77
  • III. HIV-1-Specific T-Cell Responses78
  • A. Protective Role of HIV-1-Specific T-Cell Responses78
  • B. Kinetics of HIV-1-Specific T-Cell Responses in Primary Infection79
  • C. Phenotypic and Functional Profiles of HIV-1-Specific CD4 and CD8 T-Cell Responses80
  • D. Phenotype80
  • E. Function83
  • F. Specificity and Breadth of HIV-1-Specific T-Cell Responses86
  • References87
  • Chapter 4: Targeting HIV Attachment and Entry for TherapyCover
  • I. Chapter Overview93
  • II. Background94
  • III. Inhibition of Viral Attachment95
  • A. gp120 Inhibitors95
  • B. Targeting CD497
  • IV. Chemokine Receptors in HIV Infection98
  • V. Targeting Coreceptor Binding99
  • A. CXCR4 Inhibition99
  • B. Targeting CCR5 for HIV Therapy102
  • VI. Fusion Inhibitors107
  • A. Targeting gp41107
  • B. Inhibition of Membrane Fusion108
  • VII. Resistance to Inhibitors of Viral Entry109
  • VIII. Use Entry Inhibitors as Microbicides110
  • References111
  • Chapter 5: Inhibitors of HIV-1 Reverse TranscriptaseCover
  • I. Chapter Overview121
  • II. Introduction122
  • III. The Target123
  • A. Structure of HIV-1 RT124
  • B. Mechanism of HIV-1 RT DNA Polymerase Activity126
  • IV. Nucleoside RT Inhibitors127
  • A. Mechanisms of NRTI Inhibition127
  • B. NRTI Approved for Clinical Use129
  • C. Investigational NRTI132
  • D. HIV-1 Resistance to NRTIs133
  • V. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)140
  • A. Mechanisms of NNRTI Inhibition140
  • B. NNRTI Approved for Clinical Use143
  • C. Investigational NNRTI144
  • D. HIV-1 Resistance to NNRTIs146
  • E. Interactions Between NNRTI and NRTI Resistance Mutations148
  • F. Use of NNRTI as Microbicides149
  • VI. Other Inhibitors of HIV-1 RT150
  • A. Inhibitors of HIV-1 RT RNH151
  • B. Inhibitors of HIV-1 RT Dimerization153
  • C. Inhibitors of the Initiation of Reverse Transcription153
  • D. RT-Directed Mutagenic Inducers154
  • VII. Conclusion154
  • Acknowledgments155
  • References155
  • Chapter 6: Development of Protease Inhibitors and the Fight with Drug-Resistant HIV-1 VariantsCover
  • I. Chapter Overview169
  • II. Introduction170
  • III. Targeting Viral Protease170
  • A. Mechanism of Action of PIs170
  • B. Protease Structures and Substrate-Based Inhibitors172
  • C. Design of Symmetry-Based Inhibitors172
  • D. Structure-Based PIs174
  • IV. The Role of PIs and Challenges in HAART174
  • V. "Boosting": A Critical Modification of Clinical Efficacy of PIs175
  • VI. Viral Resistance to PIs176
  • A. Emergence of Drug Resistance to PIs176
  • B. Primary and Secondary Mutations178
  • C. Active site Mutants179
  • D. Nonactive Site Mutants179
  • E. Cleavage Site Mutants180
  • F. Noncleavage Site Mutants181
  • G. Insertions in Gag-Pol Polyproteins181
  • VII. PIs with Activity Against Drug-Resistant HIV-1182
  • A. Mutations That Allow Discrimination of PIs from Natural Substrates182
  • B. Development of Pls with Activity Against Drug-Resistant HIV184
  • C. Design Rationale of Darunavir184
  • D. HIV-1 Resistance to Darunavir186
  • E. Tipranavir and Darunavir188
  • VIII. Conclusions189
  • Acknowledgments191
  • References191
  • Chapter 7: HIV-1 Integrase Inhibitors: Update and PerspectivesCover
  • I. Chapter Overview199
  • II. Foreword200
  • III. Integration: A Crucial Step in the HIV Life Cycle200
  • A. HIV-1 IN Structure200
  • B. Chemistry of Retroviral Integration201
  • C. Integration Occurs Within a Large Macromolecular Complex202
  • IV. Approaches to Inhibit HIV Integration210
  • A. Small Molecule Inhibitors of HIV IN Enzymatic Activities210
  • B. Targeting the PIC216
  • V. Inhibitors in Clinical Trials216
  • VI. Inhibitors in Preclinical Development217
  • VII. Perspectives218
  • References219
  • Chapter 8: Topical Microbicides: A Promising Approach for Controlling the AIDS Pandemic via RetrovirCover
  • I. Chapter Overview229
  • II. The AIDS Pandemic and the Rationale for a Microbicide230
  • III. Topical Microbicides in Preclinical Development232
  • IV. Characteristics of an Ideal Microbicide237
  • V. The Retroviral Zinc Fingers of HIV-1 NCp7 as a Potential Microbicide Target238
  • VI. Characteristics of the SAMT Chemotype240
  • VII. Application of Thioesters for Microbicides244
  • VIII. Target Specificity of the SAMT NCp7 Inhibitors246
  • IX. Conclusions249
  • X. Addendum250
  • References251
  • Chapter 9: Viral Drug Resistance and FitnessCover
  • I. Chapter Overview257
  • II. Introduction258
  • A. Entry Inhibitors259
  • B. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors269
  • C. Non-Nucleoside Reverse Transcriptase Inhibitors274
  • D. Integrase Inhibitors276
  • E. Protease Inhibitors278
  • References283
  • Chapter 10: Gene Therapy to Induce Cellular Resistance to HIV-1 Infection: Lessons from Clinical TriCover
  • I. Chapter Overview297
  • II. Introduction: Do We Need HIV-1 Gene Therapy?298
  • III. Gene Therapy of HIV Infection: Lessons from Early Clinical Trials300
  • A. Clinical Trials Using Dominant Negative Forms of the HIV-1 Rev Protein302
  • B. Clinical Trials Using the RRE Decoy303
  • C. Clinical Trials Using Antisense RNAs304
  • D. Clinical Trials with Ribozymes304
  • IV. Gene Therapy of HIV Infection: Current Developments306
  • A. Gene Transfer to Hemapoietic Progenitors306
  • B. Gene Therapy Using Lentiviral Vectors309
  • C. RNA Interference as a Therapeutic Tool311
  • D. Targeting HIV-1 Internalization313
  • V. Gene Therapy for HIV Infection: Where Are We Heading?314
  • Acknowledgments317
  • References317
  • Chapter 11: Identification of Potential Drug Targets Using Genomics and Proteomics: A Systems ApproaCover
  • I. Chapter Overview327
  • II. Introduction328
  • III. Viral Targets329
  • A. Viral Genomics329
  • B. Current Therapies and Future Prospects330
  • IV. Cellular/Viral Protein-Protein Interactions331
  • A. Cellular Protein Interactions of Tat332
  • B. Cellular Protein Interactions of Nef337
  • C. Cellular Protein Interactions of Gag340
  • V. Viral-Induced Cellular Alterations343
  • A. Tat: Effects on Cellular Transcription343
  • B. Nef: Altering the Cell Surface348
  • C. Gag: Using Cellular Factors to Facilitate Budding350
  • VI. Other Approaches351
  • A. Virion Proteome351
  • B. Biomarkers352
  • C. RNA Interference353
  • VII. Conclusion354
  • Acknowledgments355
  • References355
  • Chapter 12: Rapid Disease Progression to AIDS due to Simian immunodeficiency virus Infection of MacaCover
  • I. Chapter Overview369
  • II. Introduction370
  • III. SIV Strain Diversity371
  • IV. Biology of SIV371
  • V. Pathogenesis of SIV in Macaques373
  • A. SIV-sm and SIV-mac Infection as Models for AIDS373
  • B. Variation in Disease Progression374
  • C. Acutely Lethal SIV-smPBj375
  • D. Clinical Correlates of Disease Progression376
  • VI. Unique Immunologic, Virological, and Pathological Features of Rapid Disease377
  • A. Immunologic Features378
  • B. Virological Features379
  • C. Pathological Features379
  • VII. Host Factors That Influence Disease Progression383
  • A. Macaque Species383
  • B. Host Immune Responses and Major Histocompatibility Complex383
  • VIII. Role of Virus Genotype/ Phenotype in Rapid Disease Progression384
  • A. Specific Genes Involved in Pathogenesis384
  • B. Evolution of SIV in RPs385
  • C. In Vivo Studies of the Role of Virus in Rapid Disease387
  • IX. Summary388
  • Acknowledgments389
  • References389
  • Chapter 13: Nonprimate Models of HIV-1 Infection and PathogenesisCover
  • I. Chapter Overview399
  • II. Introduction400
  • III. SCID-Hu Thy/Liv Mice401
  • IV. The hu-PBL-SCID Mouse405
  • V. NOD/LtSz-SCID Mice407
  • VI. Rag2-/- gammaC-/- and NOD-SCID gammaC-/- Mice408
  • VII. Humanized Immune Competent Mice and Rats409
  • VIII. HIV-1 Tg Mice410
  • IX. Rabbit Model of HIV Pathogenesis412
  • X. Conclusion413
  • References413
  • Chapter 14: Perspectives for a Protective HIV-1 VaccineCover
  • I. Chapter Overview423
  • II. Introduction424
  • A. Natural History of HIV-1 Infection424
  • B. Immune Response Elicited During HIV-1 Infection427
  • C. Requirements for an Effective HIV-1 Vaccine428
  • III. Current Strategies in Developing an HIV-1 Vaccine429
  • A. Live-Attenuated HIV429
  • B. Induction of Antibody-Mediated Immunity436
  • IV. Concluding Remarks441
  • References442
  • Chapter 15: Molecular Mechanisms of HIV-1 Vertical Transmission and Pathogenesis in InfantsCover
  • I. Chapter Overview453
  • II. Introduction454
  • III. Timing and Mechanism of HIV-1 Vertical Transmission456
  • IV. Factors Associated with HIV-1 Vertical Transmission458
  • V. HIV-1 Infection Diagnosis in Neonates and Infants460
  • VI. Prevention of HIV-1 Vertical Transmission460
  • VII. Characterization of HIV-1 Associated with Vertical Transmission462
  • VIII. Chemokine Receptors and HIV-1 Vertical Transmission464
  • IX. Molecular Properties of HIV-1 from Mother-Infant Pairs Associated with Vertical Transmission465
  • X. Characterization of Functional Domains of HIV-1 Genes Associated with Vertical Transmission470
  • XI. Properties of HIV-1 Associated with Lack of Vertical Transmission478
  • XII. Analysis of Immunologically Relevant Mutations in HIV-1 Isolates Associated with Vertical Trans481
  • XIII. Mechanisms of HIV-1 Pathogenesis and Disease Progression in Infants485
  • XIV. The Future491
  • Acknowledgments491
  • References492
  • Chapter 16: The Viral Etiology of AIDS-Associated MalignanciesCover
  • I. Chapter Overview509
  • II. Introduction510
  • III. Kaposi's Sarcoma512
  • A. Viral Etiology in KS513
  • B. KSHV Epidemiology515
  • C. Viral Oncogenesis516
  • IV. AIDS-Associated Lymphomas520
  • A. EBV, Its Latency, and Its Role in AIDS-Associated Lymphomas520
  • B. Latent Membrane Protein 1 (LMP-1)521
  • C. Latent Membrane Protein 2522
  • D. Epstein-Barr Nuclear Antigen 1 (EBNA-1)523
  • E. EBNA-2523
  • V. AIDS-Associated NHL524
  • A. Primary Central Nervous System Lymphoma525
  • B. Primary Effusion Lymphoma525
  • C. Systemic AIDS-Associated NHL526
  • VI. HPV-Associated Cancers527
  • A. Types of HPV-Induced Cancers527
  • VII. HPV„The Causative Agent529
  • A. Papillomavirus Genome Structure529
  • B. The HPV Life Cycle530
  • C. The HPV Capsid and the Vaccine532
  • D. Epidemiology of HPV and HIV/AIDS533
  • E. The Mechanism of HPV-Induced Transformation and Cancer Progression535
  • VIII. Conclusions538
  • Acknowledgments539
  • References539
  • Index559
  • Contents of Previous Volumes575
  • Color Plate Section594
Book details
  • Vendor Elsevier S & T
  • SKU 9780123736017
  • ISBN-13 9780080557229
  • Author August, J. Thomas
  • Edition 2nd
  • Category Medical
  • Subject Pharmacology

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Description eBook delivery & access Reviews
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