Cell Death During HIV Infection

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ISBN: 9780849328275 | 0849328276
Cover: Hardcover
Copyright: 11/29/2005

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In an effort to go beyond immune-based therapies, researchers are now considering the implications of apoptosis dysregulation during HIV-induced immunodeficiency. This work provides the first comprehensive compendium of the progress made in understanding the process of cell death related to HIV and the potential breakthroughs in treatment that offer much promise. Combining the work of more than two-dozen top researchers, this seminal volume provides clinicians and researchers with an excellent reference, while also serving as an incubator to stimulate future research. It explains the fundamental biology involved with apoptosis, explains its clinical impact in HIV, and examines the newest therapeutic approaches.

Section 1 Basic Concepts

Lentiviral Biology and Cell Death

(18)

Eric M. Poeschla

Introduction

(1)

Lentiviral Biology and Pathogenesis

(3)

The Origins of HIV-1 and the Emergence of Lentiviral Disease in Primates

(1)

Replication and Pathogenesis: A Comparative Lentiviral Perspective

(1)

Viral Life Cycle

(5)

Early Events

(2)

Uncoating and Transport to the Nucleus

(1)

Integration

(1)

Latency

(1)

Late Events

(1)

Conclusion

(1)

Acknowledgment

(1)

References

(10)

Regulation of Apoptosis

(14)

Maria Eugenia Guicciardi

Gregory J. Gores

Introduction

(1)

The Apoptotic Machinery

(5)

Caspases

(2)

Bcl-2 Family

(2)

Inhibitors of Apoptosis

(1)

Inhibitors of Apoptosis Proteins (IAPs)

(1)

FLICE/Caspase-8-Inhibitory Proteins (FLIPs)

(1)

Molecular Pathways of Apoptosis

(4)

The Mitochondrial Pathway (The Intrinsic Pathway)

(1)

The Death Receptor Pathway (The Extrinsic Pathway)

(3)

Summary and Conclusion

(1)

Acknowledgment

(1)

References

(4)

Approaches Used to Detect Apoptosis

(20)

Scott H. Kaufmann

Xue Wei Meng

Introduction

(2)

Morphological Assays of Apoptosis

(1)

Electron Microscopy

(1)

Light Microscopy

(1)

Fluorescence Microscopy after DNA Staining

(1)

Detection of DNA Fragmentation

(4)

Conventional Agarose Gel Electrophoresis

(1)

Extraction of Small Fragments

(1)

Flow Cytometry

(1)

Filtration Assays

(1)

Terminal Deoxyribonucleotidyl Transferase--Mediated dUTP Nick-End Labeling (TUNEL)

(1)

Comet Assay

(1)

Caspase Activation

(4)

Activity Assays

(1)

Cleavage of Procaspases and Substrates

(1)

Affinity Labeling

(1)

Immunodetection of Activated Caspases

(1)

Annexin V Staining

(1)

Flow Cytometry--Based Assays

(2)

Altered Cell Size

(1)

Loss of Mitochondrial Transmembrane Potential (ΔΨm)

(1)

Dye Uptake

(1)

Acknowledgments

(1)

References

(6)

Consequences of HIV Infection on Thymus Function and T Cell Development

(22)

Daniel B. Graham

David J. McKean

Introduction

(1)

Overview

(1)

T Cell Development in the Thymus

(1)

HIV Infection of Thymocyte Subsets

(2)

The Thymus as a Reservoir of HIV

(1)

Infection of Thymocytes

(1)

Infection of Thymic Stromal Cells

(1)

Thymic Architecture

(1)

Thymic Histology

(1)

Thymic Pathology during HIV Infection

(1)

The Aging Thymus

(1)

Early T Cell Ontogeny and Hematopoiesis

(1)

Thymopoiesis

(1)

Hematopoiesis

(1)

Thymic Selection and T Cell Maturation

(3)

Positive and Negative Selection

(1)

Tolerance to HIV

(1)

Thymocyte Signaling and Death Mechanisms

(2)

Thymic Microenvironment

(2)

Thymocyte--Stroma Cross Talk

(1)

Disruption of the Thymic Microenvironment

(2)

Indirect Effects of HIV on the Thymus

(1)

Thymic Output and T Cell Homeostasis

(2)

Attrition of T Cells

(1)

Thymic Output

(1)

Peripheral Expansion

(1)

Effects of Anti-HIV Therapy on the Thymus

(1)

HAART

(1)

Cytokines

(1)

Summary

(1)

References

(9)

Deadly Intentions: Apoptosis in the Peripheral Immune System

(18)

Michael J. Pinkoski

Introduction

(1)

A View to a Kill---General Mechanisms of Apoptosis

(3)

Outside Influences or an Inside Job---The Extrinsic and Intrinsic Pathways

(1)

All Revved Up with No Place to Grow---Activation--Induced Cell Death (AICD) and Peripheral Deletion

(3)

Murder by Proxy--Nonlymphoid Cells in Peripheral Lymphocyte Deletion

(1)

In the Company of Killers---Induction of Apoptosis by Cytotoxic Lymphocytes

(1)

Summary

(1)

References

(8)

Section 2 Mechanisms of HIV-Associated Cell Death

Viral Factors

Cell Death in HIV Infection: gp120

(14)

Stacey R. Vlahakis

Introduction

(1)

Structure and Expression of gp 120

(1)

Genetic Regulation of gp 120

(1)

gp120 Receptor Binding

(2)

CD4 Binding

(1)

Chemokine Receptor Binding

(1)

Host Immune Cell Infection with HIV

(1)

gp120-Induced Apoptosis in T Cells

(1)

Death Associated with gp120 Binding to CD4

100

(1)

Death Associated with gp120 Binding for CCR5

101

(1)

Death Associated with gp120 Binding to CXCR4

101

(1)

Therapeutic Agents Directed at gp120

102

(1)

gp120 Vaccines

103

(1)

Summary

103

(1)

References

104

(5)

Vpr

109

(18)

Julian J. Lum

Andrew D. Badley

Introduction

109

(1)

Viral Protein R (Vpr): Structure and Function in the Viral Life Cycle

109

(2)

Genomic Structure of Vpr in HIV-1

109

(1)

Amino Acid Sequence

110

(1)

Lessons from Yeast

110

(1)

Biology of Vpr

111

(3)

Nuclear Entry by Preintegration Complexes

111

(1)

Induction of Cell-Cycle Arrest

111

(1)

Molecular Targets of Vpr

112

(2)

Vpr Mediates Cell Death

114

(6)

Apoptotic vs. Necrotic Death

114

(3)

Vpr Polymorphisms

117

(1)

Novel Strategies to Inhibit Vpr Function

118

(2)

References

120

(7)

Interference of the Nef Protein of HIV-1 with Pro- and Antiapoptotic Pathways of T Cells

127

(16)

Andreas Baur

Introduction

127

(1)

Interaction of Nef with the Host T Cell

128

(3)

Nef Structure and Interaction with Cellular Proteins

128

(1)

Interaction of Nef with the Endocytosis Machinery

129

(1)

Interaction of Nef with Signaling Proteins of the T Cell Receptor (TCR) Environment

130

(1)

TCR Signals that Stimulate Anti- and Proapoptotic Pathways

131

(2)

Nef Signals that Stimulate Anti- and Proapoptotic Pathways

133

(3)

Survival Strategies of Viruses: Antiapoptosis and Immune Evasion

133

(1)

Interference of Nef with the Death Receptor/Extrinsic Pathway

134

(1)

Interference of Nef with the Mitochondria-Associated/Intrinsic Pathway

135

(1)

Nef and Immune Evasion of HIV

136

(1)

Proapoptotic Effects of Nef

137

(1)

Conclusion

138

(1)

References

138

(5)

HIV-1 Tat and Apoptotic Death

143

(12)

Sylviane Muller

Claude Desgranges

Introduction

143

(1)

HIV-1 Tat and Apoptosis

144

(3)

Modulating Apoptosis with Tat Antibodies

147

(1)

Concluding Remarks

148

(1)

Acknowledgments

148

(1)

References

148

(7)

HIV Protease (PR) and Cell Death

155

(16)

Zilin Nie

David R. McNamara

Andrew D. Badley

Protease (PR) in Virus Life Cycle and AIDS Pathogenesis

155

(1)

Effect of Protease Expression in Transgenic Models

156

(1)

HIV PR and Cell Death

156

(3)

Evidence of Cell Death Caused by HIV PR

156

(1)

Necrosis

156

(1)

Mechanism of the Cell Death Caused by HIV PR

157

(1)

Bcl-2

157

(1)

Procaspase-8

157

(2)

Initiation Factor of Translation eIF4GI and Other Cellular Proteins

159

(1)

Model for Apoptosis vs. Necrosis

159

(1)

Clinical Significance of the Cell Death Induced by PR

159

(1)

Discordance

159

(1)

Protease Inhibitor Resistance

160

(2)

Associations between Protease Mutations and Clinical or CD4 Outcome

162

(2)

In Vitro Effects of PR Mutations on Cell Killing

164

(1)

Conclusions

164

(1)

References

165

(6)

Immune Mechanisms

Immune Activation

171

(14)

Barbara N. Phenix

Savita Pahwa

Introduction

171

(1)

Markers of Immune Activation

172

(1)

Causes and Mechanisms of Immune Activation in HIV Infection

172

(1)

Consequences of Immune Activation

173

(2)

Death Receptor/Ligands and Intrinsic Apoptotic Machinery in HIV Infection

175

(2)

Modulation of HIV-Mediated Immune Activation, AICD, and Effect of Antiretroviral Therapy

177

(1)

Concluding Remarks

177

(1)

References

178

(7)

Impairment of HIV-Specific Immune Effector Cell Function

185

(22)

Demetre C. Dakalakis

Eric S. Rosenberg

Introduction

185

(1)

Viral Factors That Influence Level of Viremia

186

(1)

Host Genetic Factors That Influence Disease Progression

187

(2)

Chemokine Receptor Mutations

187

(1)

Human Leukocyte Antigen (HLA)

187

(2)

Gender

189

(1)

Immunologic Factors Impacting Disease Progression

189

(7)

Antibody Response

190

(1)

Cytotoxic T Lymphocytes

191

(1)

T Helper Cells

191

(2)

CD4+ T Cell Impairment

193

(1)

Apoptosis

194

(1)

HIV-Mediated Cell Killing (Cytopathic Death)

194

(1)

Syncytia Formation

195

(1)

Antibody-Dependent Cell-Mediated Cytotoxicity

196

(1)

Cytotoxic T Lymphocyte Directed CD4+ Lymphocyte Depletion

196

(1)

Other Mechanisms of CD4 Depletion and Viral Evasion

196

(1)

Conclusion

196

(1)

References

197

(10)

Infected vs. Uninfected Death

Mechanisms of HIV-Infected vs. Uninfected T Cell Killing

207

(22)

Jason F. Kreisberg

Gilad Doitsh

Warner C. Greene

Introduction

207

(2)

HIV Killing of Infected T Cells

209

(6)

Direct Killing by Apoptosis and Other Mechanisms

209

(1)

Cytopathicity of the HIV Envelope Protein Involves Both CD4 and the Chemokine Co-Receptors

209

(1)

Vpr Mediates Apoptosis by Directly Targeting the Mitochondria

210

(3)

Vpu Contributes to Apoptosis by Inhibiting the Antiapoptotic Effects of NF-kB

213

(1)

HIV Protease as a Mediator of Direct Cell Killing

214

(1)

Tat Increases the Sensitivity of Infected Cells to Apoptosis

214

(1)

Killing of Uninfected (Bystander) T Cells by HIV

215

(3)

CD4+ T Cell Apoptosis Mediated by Cell-Cell Interactions: Death Receptors

215

(1)

The HIV Accessory Genes Tat, Vpr, and Nef as Mediators of Bystander Cell Death

216

(1)

Accelerated T Cell Turnover: The Effects of HIV on the Thymus and Bone Marrow

216

(1)

The Role of Chemokine Receptors in HIV-Mediated Bystander Killing

217

(1)

Summary and Perspectives

218

(1)

References

218

(11)

Elevated Apoptosis of CD8+ T Lymphocytes during HIV-1 Infection

229

(24)

John Zaunders

Jerome Estaquier

Jacques Corbeil

CD8+ T Lymphocytes in HIV-1 Infection

230

(2)

Expansion and Contraction of CD8+ T Lymphocytes during Responses to Viral Infection

230

(1)

Role of TNF/TNFR Superfamily Members in Homeostasis of CD8+ T Lymphocytes

231

(1)

Role of Bcl-2 Family Members in CD8+ T Cell Apoptosis

231

(1)

Role of Common γ-Chain Cytokines in CD8+ T Cell Apoptosis

231

(1)

Role of IFN Type I in CD8+ T Cell Apoptosis

232

(1)

Role of Molecules Produced by Effector T Cells in CD8+ T Cell Apoptosis

232

(1)

Activation, Proliferation, and Apoptosis of CD8+ T Lymphocytes during HIV Infection

232

(2)

Dynamics of CD8+ T Lymphocytes in Chronic HIV-1 Infection

232

(1)

Dynamics of CD8+ T Lymphocytes in Nonpathogenic Chronic HIV-1 and SIV Infection

233

(1)

Dynamics of CD8+ T Lymphocytes in Primary HIV-1 Infection

233

(1)

Dysfunction of CD8+T Cells in HIV-1 Infection

234

(1)

Increased Rate of CD8+ T Cell Apoptosis in HIV-1 Infection

234

(4)

Elevated CD8+ T Cell Apoptosis In Vivo

234

(1)

Increased Rate of Spontaneous Apoptosis Ex Vivo

235

(1)

Apoptosis in Nonpathogenic HIV-1 and SIV Infections and after Haart

236

(1)

Role of CD95/CD95L Interactions in Elevated Apoptosis of CD8+ T Cells in HIV-1 Infection

236

(1)

Role of TNF/TNFR Interactions and Trail in Apoptosis of CD8+ T Lymphocytes in HIV-1 Infection

237

(1)

Role of AICD in Apoptosis of CD8+ T Lymphocytes in HIV-1 Infection

237

(1)

Role of HIV-1 Proteins in Elevated Apoptosis of CD8+ T Cells in HIV-1 Infection

237

(1)

Other HIV-Related Mechanisms

238

(1)

Summary

238

(1)

Acknowledgments

238

(1)

References

239

(14)

Autologous Cell-Mediated Killing

253

(18)

Georges Herbein

Introduction

253

(1)

Autologous Cell-Mediated Killing via Intercellular Contacts

254

(5)

Monocyte/Macrophage-Mediated T Cell Apoptosis

254

(1)

CD4+T Cell Apoptosis

254

(3)

CD8+T Cell Apoptosis

257

(1)

Dendritic Cell-Mediated T Cell Apoptosis

258

(1)

T Cell-Mediated Apoptosis

258

(1)

Autologous Cell-Mediated Killing via the Release of Soluble Factors

259

(1)

Cytotoxic HIV Proteins

259

(1)

Env

259

(1)

Nef, Tat, Vpr

260

(1)

Cytotoxic Factors

260

(1)

Autologous Cell-Mediated Killing Results in Immune Suppression

260

(2)

Immune Suppression

260

(1)

Reservoirs

261

(1)

Conclusion

262

(1)

Acknowledgments

262

(1)

References

263

(8)

Molecular Mechanisms of HIV-1 Syncytial Apoptosis

271

(8)

Christophe Lemaire

Jean-Luc Perfettini

Guido Kroemer

Catherine Brenner

Introduction

271

(1)

The Formation of Syncytia

272

(1)

Deregulation of Mitosis and Karyogamy

272

(1)

Cooperation of Dominant Transcription Factors

273

(2)

Mitochondrial and Caspase Activation

275

(1)

Concluding Remarks

276

(1)

Acknowledgments

277

(1)

References

277

(2)

Nonapoptotic HIV-Induced T Cell Death

279

(14)

Keiko Sakai

Matthew Smith-Raska

Michael J. Lenardo

Introduction

279

(1)

Cell Death Pathway during Acute HIV-1 Infection

280

(5)

Modes of Cell Death: Apoptosis vs. Nonapoptotic Cell Death

280

(4)

Molecular Mechanism of Nonapoptotic/Necrotic Cell Death

284

(1)

Mitochondrial Dysfunction

284

(1)

Cell-Cycle Arrest

285

(1)

Viral Mediators of Direct, Nonapoptotic Cell Death

285

(1)

Env

285

(1)

Viral Genome, Regulatory Proteins

285

(1)

Accessory Genes

285

(1)

Nef

285

(1)

Vpr

286

(1)

Vpu

286

(1)

Summary

286

(1)

Acknowledgment

286

(1)

References

287

(6)

Apoptosis in Organ Culture and Animal Models of HIV Disease

293

(26)

Shailesh K. Choudhary

David Camerini

Introduction

293

(1)

Apoptosis in HIV-1 Infected Organ Culture

294

(3)

Fetal Thymic Organ Culture (FTOC)

294

(2)

Secondary Lymphoid Tissue Organ Culture (LTOC)

296

(1)

Apoptosis in Animal Models of HIV-1 Disease

297

(6)

HIV-1-Infected SCID-hu Thy/Liv Mouse

297

(2)

HIV-1 Infected hu-PBL-SCID Mice

299

(1)

HIV-1-Infected Humanized Mice and Rats

300

(1)

HIV-1 Transgenic Mice

301

(1)

HIV-1-Infected Chimpanzees

302

(1)

SHIV-Infected Macaques

303

(1)

Summary and Future Perspectives

303

(1)

References

304

(15)

Section 3 Clinical Consequences of HIV-Induced Cell Death

T Cell Dynamics and the Role of Apoptosis in HIV Infection

319

(16)

Nienke Vrisekoop

Mette D. Hazenberg

Frank Miedema

Jose A.M. Borghans

Introduction

319

(1)

Inappropriate T Cell Apoptosis: Direct HIV-Induced Cytopathicity and CD4 Cross-Linking

320

(1)

T Cell Exhaustion Induced by Continuous High T Cell Turnover

321

(1)

Interference with Thymic Function

322

(2)

Appropriate T Cell Death: Chronic Immune Activation in HIV Pathogenesis

324

(3)

In Vivo Labeling Studies

325

(1)

HIV-Infected Individuals with Discordant Responses to Antiviral Therapy

325

(1)

HIV-2

326

(1)

SIV

326

(1)

Is Chronic Immune Activation Alone Enough to Induce CD4+T Cell Loss?

327

(1)

Why Are Only CD4+ and Not CD8+ T Cells Lost in HIV Infection?

327

(1)

Conclusion: An Integrated View

328

(1)

Acknowledgment

329

(1)

References

329

(6)

Alteration of the Apoptotic Pathways in the Thymus during HIV Infection

335

(20)

Luchino Y. Cohen

Marie-Lise Dion

Rafick-Pierre Sekaly

Introduction

335

(1)

The Apoptotic Machinery in Thymocytes

336

(1)

Role of Apoptosis in T Cell Development

337

(2)

Death by Neglect

337

(1)

Negative Selection

338

(1)

Impact of HIV Infection on Thymic Function

339

(2)

Alteration of Thymic Output after HIV Infection

339

(1)

Several Thymocyte Subsets Are Susceptible to HIV Infection

340

(1)

Modulation of Apoptosis in the Thymuses of Infected Individuals

341

(1)

Influence of HIV on Thymocyte Apoptosis Rate

341

(1)

Apoptosis in the Thymic Stroma

342

(1)

Mechanisms Involved in the Modulation of Apoptosis by HIV in the Thymus

342

(3)

Role of Cytokines in HIV-Mediated Perturbation of Thymocyte Apoptosis

342

(1)

Influence of IL-7 Levels

342

(1)

Role of TNF-α

343

(1)

Perturbation of Thymic Function by IFN-α

343

(1)

Influence of IL-10

344

(1)

Role of Glucocorticoids

344

(1)

Role of the CD95/Fas Pathway

344

(1)

Role of HIV Proteins in Thymic Apoptosis Modifications

345

(1)

Concluding Remarks

345

(1)

Acknowledgments

345

(1)

References

346

(9)

Correlations between Apoptosis and HIV Disease Progression

355

(26)

David H. Dockrell

Anne J. Tunbridge

Introduction

355

(1)

Rates of HIV Disease Progression

355

(1)

Viral and Host Factors That Influence Disease Progression

356

(2)

Evidence for an Influence of Apoptosis in Disease Progression in Lentivirus Infection

358

(1)

Links between Factors Implicated in Disease Progression and Apoptosis

359

(2)

Analysis of Apoptosis in Patient Cohorts with Defined Rates of Disease Progression

361

(2)

Impact of Antiretroviral Therapy on Levels of Lymphocyte Apoptosis

363

(6)

Discordant Responses to Antiretroviral Therapy

369

(1)

Conclusions

369

(1)

Acknowledgments

370

(1)

References

370

(11)

HIV-1 Infection and Cell Death in the Nervous System

381

(24)

Gareth Jones

Christopher Power

Neurological Dysfunction Associated with HIV-1 Infection

381

(2)

HIV-1 Gene Expression in the Nervous System

383

(1)

Neuronal Cell Death in HIV-1 Infection

383

(1)

Direct Effect of Viral Proteins

384

(2)

Soluble Factors from Macrophages/Microglia Exposed to HIV-1

386

(2)

Distinct HIV-1 Strains and Neurological Disease

388

(1)

Mechanisms of Neuronal Apoptosis

388

(3)

Extrinsic Pathway

388

(1)

Intrinsic Pathway

389

(2)

Future Perspectives: Implications for Therapy

391

(1)

References

392

(13)

Involvement of Apoptosis in Complications of HIV and Its Treatment

405

(16)

David Nolan

Introduction: Overview of Complications Associated with HIV Therapy

405

(1)

Complications of Therapy with Nucleoside Analogue Reverse Transcriptase Inhibitors

406

(8)

Mechanisms of Action: Therapeutic and Toxic Effects of NRTI Therapy

406

(4)

Zidovudine Myopathy: A Tale of Two Treatment Eras

410

(1)

Lipoatrophy: Pathological Fat Loss as a Mitochondrial Toxicity

410

(1)

Neuropathy: Contributions of Both HIV Disease and NRTI Therapy

411

(1)

``Lymphocyte Mitochondrial Toxicity'' and Didanosine Therapy: An Intersection of Therapeutic and Toxic Effects

412

(1)

Lactic Acidosis and Hyperlactatemia

413

(1)

Complications Associated with the Use of HIV Protease Inhibitors

414

(1)

Diarrhea Associated with Nelfinavir: A Common Pathway with Antiapoptotic Properties?

414

(1)

Ritonavir, Proteasomal Inhibition and Metabolic Complications

415

(1)

Conclusions

415

(1)

References

415

(6)

Apoptosis as a Pathogenic Mechanism of HIV-Associated Opportunistic Infections

421

(20)

Sara Warren

Xian-Ming Chen

Nicholas F. LaRusso

Andrew D. Badley

Introduction

422

(2)

Cryptosporidium

424

(3)

Epidemiology of Cryptosporidial Infection in Humans

424

(1)

Cryptosporidial Clinical Manifestations

424

(1)

Cryptosporidiosis and Epithelial Cell Apoptosis

425

(1)

C. parvum--Associated Epithelial Cell Apoptosis in Patients

425

(1)

C. parvum--Associated Epithelial Cell Apoptosis In Vitro

425

(1)

Mechanisms of C. parvum--Associated Epithelial Cell Apoptosis

425

(1)

Synergistic Effects of C. parvum Infection with HIV-1-Associated Soluble Factors to Induce Epithelial Cell Apoptosis

426

(1)

Diagnosis

427

(1)

Therapy

427

(1)

Epstein--Barr Virus

427

(5)

EBV Clinical Manifestations

428

(1)

Burkitt's Lymphoma

428

(1)

Lymphoproliferative Disorders

428

(1)

EBV Proteins That Modulate Apoptosis

429

(1)

LMP1

429

(1)

CTAR1

430

(1)

CTAR2

430

(1)

EBNA1

430

(1)

EBNA2

431

(1)

EBNA3, EBNA4, EBNA5, EBNA6

431

(1)

EBNA-LP

431

(1)

EBER

432

(1)

Diagnosis and Therapy

432

(1)

Conclusions

432

(1)

References

432

(9)

Section 4 Therapeutic Issues

Direct Effects of Anti-HIV Therapeutics on Apoptosis

441

(16)

David Schnepple

Andrew D. Badley

Introduction

441

(1)

Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

442

(4)

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

446

(1)

Protease Inhibitors (PIs)

446

(2)

Fusion Inhibitors

448

(2)

References

450

(7)

HIV-1 Reservoirs and Residual Viral Replication during Highly Active Antiretroviral Therapy

457

(18)

Roger J. Pomerantz

Giuseppe Nunnari

Introduction

457

(1)

HIV-1 Latency and Persistence

458

(1)

Cell-Associated and Cell-Free Virus during Haart

459

(3)

Residual HIV-1 Provirus In Vivo during Haart

459

(1)

Cell-Associated Virus

460

(1)

Cell-Free Virus

461

(1)

HIV-1 Sanctuaries and the Role of Blood-Tissue Barriers: Central Nervous System, Testes, and Retina

462

(1)

Male and Female Genital Tracts and HIV-1 Compartmentalization in the Haart Era

462

(1)

Treatment of Residual HIV-1 Disease: Purging Latent HIV-1 Cellular Reservoirs and the Requirement for Inducing Distinct Viral Archives from Latency

463

(4)

Stimulatory Therapy

463

(1)

Intensification Therapy

464

(1)

Immune-Based Approaches and Structured Treatment Interruptions (STIs)

465

(1)

Conclusion

466

(1)

Acknowledgments

467

(1)

References

467

(8)

Therapeutic Approaches to Modulation of Cell Death (non-HIV)

475

(30)

Dara Ditsworth

Rebecca L. Elstrom

Craig B. Thompson

Introduction

476

(2)

Cell Death by Murder

478

(3)

Death Receptor Pathways

478

(2)

Therapeutic Approaches

480

(1)

Inhibitor of Apoptosis Proteins (IAPs)

480

(1)

Inhibition of IAPs in Cancer Therapy

480

(1)

Activation of IAPs to Prevent Neuronal Loss

481

(1)

Caspases

481

(1)

Cell Death by Suicide

481

(9)

Bcl-2 Family

482

(1)

Induction of Cell Death with Bcl-2 Antisense or BH3-Mimetic Strategies

483

(1)

Prevention of Cell Death by Maintenance of Mitochondrial Membrane Integrity

483

(1)

p53 Status

483

(1)

Induction of Cell Death by Restoration of p53 Function

484

(1)

Induction of Cell Death by Activating Wild-Type p53

485

(1)

Survival Kinases

485

(1)

P13K/Akt/mTOR

485

(1)

P13K/Akt/mTOR Targeted Therapeutics

486

(1)

MAPK Signaling and BRAF

487

(1)

NF-κB Pathway

487

(1)

NF-κB-Targeted Therapeutics

488

(1)

Adenoviral Gene Therapy to Inhibit Multiple Kinases

488

(1)

Activation of Survival Kinase Cascades by Ligand Supplementation

488

(1)

Targeting Protein Degradation

489

(1)

General Inhibitors of Gene Silencing

489

(1)

ER Stress and Ca2+ Homeostasis

489

(1)

ER Stress in Neurodegenerative Disorders

490

(1)

Other Forms of Cell Death: Necrosis and Autophagy

490

(3)

Necrosis

490

(1)

Reactive Oxygen Species

490

(1)

ROS in Alzheimer's Disease

491

(1)

ROS in Ischemia-Reperfusion Injury

491

(1)

Protection against Reactive Oxygen Species

491

(1)

Cancer Therapeutics That Induce ROS and Cell Death

492

(1)

Modulation of PARP Activity in Necrotic Cell Death

492

(1)

Autophagy

492

(1)

Summary

493

(1)

References

493

(12)

Immunotherapy of HIV Disease

505

(18)

Franco Lori

Laurene M. Kelly

Andrea Cossarizza

Julianna Lisziewicz

Introduction

505

(1)

State-of-the-Art Haart Treatment

506

(1)

CD4 and CD8 T Lymphocytes during HIV-Induced Chronic Immune Activation

507

(1)

HIV-1-Induced Apoptosis

508

(2)

Antiretroviral Drugs and Apoptosis

509

(1)

Lymphocyte Dysfunction

510

(1)

Alternative HIV-1 Therapeutic Strategies

511

(5)

Cytokines

511

(1)

IL-2 and IL-15

511

(1)

IL-12

512

(1)

IL-7

512

(1)

Virostatics

513

(1)

Hydroxyurea

514

(1)

Mycophenolate Acid

515

(1)

Cyclosporin

516

(1)

Conclusion

516

(1)

References

516

(7)

Index

523

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Cell Death During HIV Infection

Summary

Table of Contents

Supplemental Materials