Chemokine Receptors and NeuroAIDS (eBook)

About the Editor: Olimpia Meucci, MD, PhD is a Professor of Pharmacology and Physiology & Microbiology and Immunology at Drexel University College of Medicine in Philadelphia, PA. Since her seminal discovery about the regulation of neuronal signaling by chemokines, her research has primarily focused on the physio-pathological roles of this important class of neuroimmune modulators in the central nervous system and their involvement in neuroAIDS. These studies have significantly contributed to current understanding of the cellular and molecular mechanisms of HIV-related neuropathology including the interaction of the chemokine system with drug of abuse, namely opiates, which continues to be a major area of investigation in the Meucci lab.

Meucci_FM_O.pdf 1
Anchor 1 5
Anchor 2 7
Anchor 3 10
Meucci_Ch01_O.pdf 14
Chapter 1 14
Introduction 14
Meucci_Ch02_O.pdf 16
Chapter 2 17
HIV Neuroinvasion: Early Events, Late Manifestations 17
2.1 .Clinical Manifestations and Epidemiology of HIV Infection of the Nervous System 17
2.2 .Biology of HIV Infection and Invasion of the Brain 19
2.3 .HIV Neuropathogenesis: Human and Primate Studies 21
2.4 .Mechanisms of HIV-Induced Neurodegeneration: Neurotoxicity of HIV Proteins 24
2.5 .Mechanisms of HIV-Induced Neurodegeneration: Roles for Chemokines and Chemokine Receptors 26
2.6 .Mechanisms of HIV-Induced Neurodegeneration: Roles for Excitotoxins and N-Methyl-.d.-Aspartate Receptors 28
2.7 .Other Links Between Chemokines and Excitotoxic Injury: Glutamate Release 30
2.8 .Therapeutic Considerations 31
References 32
Meucci_Ch03_O.pdf 44
Chapter 3 44
HIV Co-receptors: The Brain Perspective 44
.Chemokines as Co-receptors for HIV Infection 44
3.1.1 .CD4 44
3.1.2 .Discovery of Chemokine Receptors as “Second Receptors” for HIV-1 Infection 44
3.2 .Chemokines and Chemokine Receptors as Determinants of HIV-1 Infection and Disease 45
3.2.1 .Chemokines and Chemokine Receptors in HIV-1 Transmission 45
3.2.2 .Chemokines and Chemokine Receptors and HIV-1 Disease Progression 46
3.2.3 .Chemokines and Response to HAART Therapy 47
3.2.4 .Chemokines as a Double-Edged Sword in HIV-1 Infection 48
3.3 .Chemokines and Chemokine Receptors in HIV-1-Associated CNS Disease 48
3.3.1 .Direct Mechanisms of Neuronal Injury and Apoptosis 49
3.3.2 .Indirect Mechanisms of Neuronal Injury and Apoptosis 51
3.3.2.1 .Monocyte/Macrophage Recruitment 51
3.3.2.2 .Impaired Astrocyte Function and Chemokine Expression 52
3.4 .Chemokines/Chemokine Receptor Pathways as Survival Pathways for Monocyte/Macrophage Reservoirs of HIV Infection 53
3.5 .Chemokines/Chemokine Receptor Based Therapeutics: Trials and Tribulations 54
References 55
Meucci_Ch04_O.pdf 62
Chapter 4 62
HIV Infection and the PNS 62
4.1 .Introduction 62
4.2 .General Principles in HIV Neurological Disease 62
4.3 .Recognizing Peripheral Nervous System Involvement in HIV 63
4.4 .Prevalence and Risk Factors of HIV-Associated Peripheral Neuropathy 66
4.5 .Distal Symmetric Polyneuropathy 67
4.6 .Antiretroviral Toxic Neuropathy 68
4.7 .Neuropathies Associated With HIV Seroconversion 69
4.8 .Inflammatory Demyelinating Polyradiculoneuropathies 69
4.9 .Mononeuropathy Multiplex 70
4.10 .Progressive Polyradiculopathy 71
4.11 .Diffuse Infiltrative Lymphocytosis Syndrome 72
4.12 .Autonomic Neuropathy 73
4.13 .Neuropathies Associated with Immune Reconstitution 73
4.14 .Motor Neuron Disease 74
4.15 .Pathology of HIV-Associated Peripheral Neuropathy 74
4.16 .The Role of Chemokine Receptors in HIV Neuropathogenesis 78
4.17 .Direct and Indirect Mechanisms of Neurotoxicity 79
4.18 .Pathology of Antiretroviral Toxic Neuropathy 82
4.19 .The Role of Chemokine Receptors in Neuropathic Pain 84
4.20 .Models of HIV-Associated Peripheral Neuropathy 85
4.21 .Treatment of HIV-Associated Peripheral Neuropathy 87
4.22 .Conclusion 88
References 88
Meucci_Ch05_O.pdf 97
Chapter 5 97
HIV Latency and Reactivation: Role in Neuropathogenesis 97
5.1 .Introduction 97
5.2 .Types of Latency and Major Cellular Reservoirs 97
5.2.1 .Pre-integration Latency 98
5.2.2 .Post-integration Latency and the Resting CD4+ T Cell 100
5.2.3 .Monocyte–Macrophage Latency 103
5.2.4 .Cells of the CNS 106
5.2.5 .Dendritic Cells 107
5.2.6 .Bone Marrow Cell Populations 108
5.2.7 .Other Potential Minor Reservoirs 109
5.3 .Maintenance of Latency 109
5.3.1 .Chromatin Determinants 110
5.3.2 .Availability of Cellular Transcription Factors 113
5.3.3 .Availability of Viral Proteins 113
5.4 .RNA Interference 115
5.5 .Neuropathogenesis and Reseeding from Reservoirs 115
5.6 .Concluding Remarks 117
References 118
Meucci_Ch06_O.pdf 129
Chapter 6 129
HIV Coreceptors and Their Roles in Leukocyte Trafficking During Neuroinflammatory Diseases 129
6.1 .Overview 129
6.2 .Leukocyte Trafficking into the CNS 130
6.3 .NeuroAIDS 133
6.3.1 .Human Studies 134
6.3.2 .Macaque Model 135
6.4 .CNS Autoimmunity 135
6.4.1 .CXCL12 and CXCR4 136
6.4.2 .CCR5 and Its Ligands 138
6.5 .West Nile Virus Encephalitis 142
6.5.1 .CXCL12 and CXCR4 142
6.5.2 .CCR5 143
6.6 .Conclusions 145
References 146
Meucci_Ch07_O.pdf 157
Chapter 7 158
Chemokine Proteolytic Processing in HIV Infection: Neurotoxic and Neuroimmune Consequences 158
7.1 .Introduction 158
7.2 .Chemokine Proteolysis Overview 159
7.3 .Chemokine Proteolysis Altering HIV Binding to Its Coreceptors 162
7.3.1 .HIV-Induced Proteases 162
7.3.1.1 .MMPs 163
7.3.1.2 .CD26/DPP IV 164
7.3.1.3 .Cathepsins 165
7.3.2 .Regulation of Anti-HIV Properties of Chemokines by Limited Proteolysis 165
7.4 .Role of Chemokine Proteolysis in HIV Neuropathogenesis: CXCL12 and MMPs 166
7.4.1 .MMP-Mediated CXCL12 Processing in the Brain Associated with HIV Infection 166
7.4.1.1 .CXCL12 Cleavage by MMPs 166
7.4.1.2 .MMP Processing of CXCL12 is Associated with a Shift of Receptor Affinity from CXCR4 to CXCR3 168
7.4.2 .Pathogenic Effects of MMP-Processed CXCL12 on Neurons 170
7.4.2.1 .Perturbation of Neuronal Membrane Physiology 170
7.4.2.2 .Neurotoxicity of the MMP-Processed CXCL12 170
7.4.3 .Immunogenic Properties of MMP-Processed CXCL12 on Glial Cells 171
7.4.4 .MMP-Processed CXCL12 Effects in an In Vivo Model 172
7.4.5 .Evolutionary Advantages for the Virus 173
7.5 .Concluding Remarks 174
References 175
Meucci_Ch08_O.pdf 182
Chapter 8 182
Chemokines and Chemokine Receptors in the Brain 182
8.1 .Introduction 182
8.2 .Expression of Chemokines and Their Receptors in the CNS 182
8.2.1 .Chemokine Receptor Expression in the CNS 182
8.2.1.1 .CCR Family 183
8.2.1.2 .CXCR Family 183
8.2.1.3 .CX3CR1 186
8.2.2 .Chemokine Expression in the CNS 187
8.2.2.1 .CC Chemokines 187
8.2.2.2 .CXC Chemokines 187
8.2.2.3 .CX3CL1 188
8.3 .Role of Chemokines in Regulating CNS Activity 188
8.4 .Neuromodulatory Action of Chemokines 190
8.4.1 .Effect on Neurotransmission 190
8.4.2 .Involvement of Chemokines in Nociception 191
8.5 .Conclusions and Perspectives 194
References 194
Meucci_Ch09_O.pdf 199
Chapter 9 199
Chemokine Signaling in the Nervous System and Its Role in Development and Neuropathology 199
9.1 .Introduction 199
9.2 .Chemokines and the Development of the Nervous System 200
9.3 .The Role of Chemokines in the Control of Adult Neurogenesis 207
9.4 .Chemokine Signaling in Pathological Pain States 213
9.5 .Conclusions 221
References 221
Meucci_Ch10_O.pdf 229
Chapter 10 229
Modulation of Neuronal Cell Cycle Proteins by Chemokine Receptors and Its Role in the Survival of Postmitotic Neurons 229
10.1 .Introduction 229
10.2 .General Structure of Chemokines and Their Receptors 229
10.3 .Receptor Dynamics 230
10.3.1 .Receptor Oligomerization 230
10.3.2 .Ligand Receptor Binding 232
10.3.2.1 .CXCR4 232
10.3.2.2 .CCR5 232
10.3.2.3 .CCR2 233
10.3.2.4 .CXCR3 234
10.3.3 .Regulation of Signaling 234
10.3.3.1 .CXCR4 234
10.3.3.2 .CCR5 235
10.3.3.3 .CCR2 236
10.3.3.4 .CXCR3 236
10.4 .Physiological Roles of Chemokine Receptor Signaling in Nervous System 237
10.4.1 .Roles of CXCR4 During CNS Development 237
10.4.2 .Roles of CXCR4 in Mature CNS 239
10.5 .Role of CCR5 and CXCR4 in AIDS Neuropathogenesis 239
10.5.1 .Chemokine Receptor Activation by HIV Envelope Protein gp120 240
10.5.2 .HIV Envelope gp120 – Mediated SignalingPathways in CNS 241
10.5.3 .Role of Cell Cycle Proteins in Chemokine Receptor-Mediated Neuronal Survival 243
10.5.4 .A Comparison Between CXCL12 and gp120 Signaling 245
10.6 .Role of CXCR3 and CCR2 in NeuroAIDS 246
10.6.1 .CXCR3 246
10.6.2 .CCR2 247
10.7 .Conclusions 247
References 248
Meucci_Ch11_O.pdf 260
Chapter 11 260
Chemokines and Primary Brain Tumors 260
11.1 .The Prognostic Significance of CXCL12 and CXCR4 Expression in Brain Tumors 260
11.2 .CXCR4 Activity Stimulates Brain Tumor Growth Through Diverse Mechanisms 263
11.2.1 .CXCR4 and Brain Tumor Stem Cells 263
11.2.2 .CXCL12 Stimulates Brain Tumor Cell Proliferation and Survival 265
11.3 .CXCL12 Functions as a Migratory/Invasive Factor for Brain Tumor Cells 268
11.4 .CXCR4 and Angiogenesis 269
11.5 .Therapeutic Targeting of Chemokine Pathways 270
11.6 .Other Chemokines Contribute to Brain Tumor Biology 271
11.7 .Conclusions and Future Directions 272
References 273
Meucci_Ch12_O.pdf 278
Chapter 12 278
Chemokines as Neuromodulators: Regulation of Glutamatergic Transmission by CXCR4-Mediated Glutamate Release From Astrocytes 278
12.1 .The CXCL12/CXCR4 Signaling Pathway In the Central Nervous System (CNS) 278
12.1.1 .The Expression of CXCL12/CXCR4 System In the CNS 278
12.1.2 .The Effect of CXCR4-Mediated Signaling Pathway on Neuronal Activity and Neurotransmitter Release 280
12.1.3 .Activation of CXCR4 Induces Release of Chemical Transmitters (Gliotransmitters) from Glial Cells 282
12.2 .Regulated Exocytosis of Glutamate from Astrocytes can Modulate Synaptic Transmission 284
12.2.1 .Mechanisms of Gliotransmitters Release: Evidence on CXCR4-Mediated Glutamate Exocytosis from Astrocytes 284
12.2.2 .Localized Calcium Microdomains Control Exocytosis of Glutamate in Astrocytes 288
12.2.3 .Glutamate Exocytosis from Astrocytes Induces Synaptic Modulation 291
12.3 .The Calcium-Dependent Glutamate Release From Astrocytes is Deregulated in Pathological Conditions With an Inflammatory C 292
12.3.1 .The Case of HIV-Associated Dementia 293
12.3.2 .The Case of Alzheimer’s Disease 295
References 297
Meucci_Ch13_O.pdf 308
Chapter 13 308
Role of CX3CL1 in Synaptic Activity and Neuroprotection 308
13.1 .Introduction 308
13.1.1 .CX3CL1/CX3CR1 Pair: Structure and Signalling 308
13.1.2 .Distribution in the Nervous System 309
13.2 .CX3CL1 Functions in Physiological and Pathological Conditions 310
13.2.1 .CX3CL1 and Synaptic Activity 310
13.2.2 .CX3CL1 and Pain Modulation 312
13.2.3 .CX3CL1 and Neuroprotection 314
13.2.3.1 .HIV Infection 315
13.2.3.2 .Glutamate Excitotoxicity and Models of Brain Ischemia 315
13.2.3.3 .Modulatory Effects on Neuronal Precursors 317
13.2.3.4 .Neuroinflammation and Neurodegeneration Models 317
13.3 .CX3CL1 as Mediators of Intercellular Communication in the Nervous System 318
References 319
Meucci_Ch14_O.pdf 324
Chapter 14 325
Interaction Between Opioid and Chemokine Receptors in Immune Cells: Implications for HIV Infection 325
14.1 .Introduction 325
14.2 .Regulation of Chemokine Expression by Opioids 327
14.3 .Regulation of Chemokine Receptor Expression by Opioids 330
14.4 .Cross-talk Between Opioid and Chemokine Receptors 333
14.4.1 .Certain Chemokine Receptors Cross-Desensitize Opioid Receptors 333
14.4.2 .Opioid Receptors Cross-Desensitize Chemokine Receptors 335
14.4.3 .Molecular Mechanism of Heterologous Desensitization between Opioid and Chemokine Receptors 336
14.4.4 .Implications for HIV Infection 336
14.5 .Conclusions 337
References 338
Meucci_Ch15_O.pdf 342
Chapter 15 342
Chronic Morphine’s Role on Innate Immunity, Bacterial Susceptibility and Implications in Wound Healing 342
15.1 .Introduction 342
15.2 .Wound Healing and Innate Immunity 342
15.2.1 .Pro-inflammatory Response 342
15.2.2 .Pro-angoigenic Response 344
15.3 .Opioids 345
15.3.1 .Endogenous Opioids 346
15.3.2 .Exogenous Opioids 346
15.3.3 .Opioid Antagonists 347
15.4 .Opioids and Innate Immunity 347
15.4.1 .Morphine and Immunosuppression 347
15.4.2 .Morphine and Neutrophils 347
15.4.3 .Morphine and Macrophages 348
15.4.4 .Morphine and Wound Healing 349
15.5 .HIV and Innate Immunity 350
15.5.1 .HIV and Macrophages: The Trojan Horse 350
15.5.2 .HIV and the Host Innate Immunity Response 351
15.5.3 .Opioids, HIV and Wound Healing 351
15.6 .Proposed Model 352
15.7 .Summary 353
References 353
Meucci_Ch16_O.pdf 358
Chapter 16 358
Opioids, Astroglial Chemokines, Microglial Reactivity, and Neuronal Injury in HIV-1 Encephalitis 358
16.1 .Introduction 358
16.1.1 .The Endogenous Opioid System 358
16.2 .Opioid–Chemokine Interactions 359
16.2.1 .Chemokine Ligands and Receptors 359
16.2.2 .Pain/Nociception 359
16.3 .NeuroAIDS 360
16.3.1 .Glia are the Principal Targets of HIV in the CNS 360
16.4 .Opiate–Immune Interactions in the Brain are Unique 361
16.5 .Microglia 363
16.5.1 .Opioids and Microglia 363
16.5.2 .Neuron-Microglia Chemokine Signaling 365
16.6 .Astroglia 365
16.6.1 .Astroglia and HIV-1 366
16.7 .Opioids, HIV, and Astroglial-derived Chemokines 367
References 370
Meucci_Ch17_O.pdf 383
Chapter 17 383
Regulation of Neuronal Chemokine Receptor CXCR4 by .m.-Opioid Agonists and Its Involvement in NeuroAIDS 383
17.1 .CXCR4 and Opioid Receptors in the CNS: Distribution, Signaling, and Involvement in Neuropathology 383
17.2 .Heterologous Desensitization of G-protein-Coupled Chemokine Receptors 385
17.3 .Cross-talk Between Opioid and Chemokine Receptors 387
17.4 .Opioid–Chemokine Interaction in HIV Neuropathology 392
17.5 .Concluding Remarks 394
References 395
Meucci_BM1_O.pdf 402
Anchor 1 402
Anchor 2 403
Meucci_Index_O.pdf 404