West Nile Encephalitis Virus Infection (eBook)

Preface 6
Contents 8
Contributors 17
1. Global Epidemiology of West Nile Virus 20
1 Introduction 20
2 West Nile Virus in Africa, Asia, and Europe 23
2.1 Africa 23
2.2 Middle East, Russia, Asia, and Australia 24
2.3 Europe 25
3 West Nile Virus in the Americas 26
3.1 United States 26
3.1.1 Mosquitoes and Vertebrates 26
3.1.2 Human Incidence and Distribution 27
3.2 Canada 30
3.3 Latin America and the Caribbean 30
4 Clinical Epidemiology 31
4.1 Risk Factors Associated with Human Disease 31
4.2 Transmission Modes 33
5 Summary 35
References 35
2 . West Nile Virus: Molecular Epidemiology and Diversity 43
1 Overview of WNV Genetic Diversity at a Global Scale 43
2 Molecular Epidemiology of WNV in the Americas 45
2.1 Evidence for a Single Point Introduction 45
2.2 Genetic Conservation and Diversification During Colonization 46
2.3 Insights into WNV Population Dynamics 48
2.4 Sampling Bias and Methodological Issues: Impact on Conclusions 49
2.5 Implications for WNV Pathogenesis 51
3 Ecology and Phylogeny: WNV Adaptation in the Western Hemisphere 52
3.1 General Considerations 52
3.2 Adaptation to Mosquito Hosts 54
3.3 Adaptation to Avian Hosts 54
4 Evolutionary Mechanisms in West Nile Virus 55
5 Summary and Future Studies 56
References 57
3 . Vector Biology and West Nile Virus 62
1 Introduction: Importance of Vector Biology in West Nile Virus Ecology 62
2 Transmission of West Nile Virus 63
2.1 Natural Transmission Cycle 63
2.2 Vector Competence and Vectorial Capacity 64
2.3 Mosquitoes Involved in Transmission of WNV 66
2.4 Other Potential Arthropod Vectors 68
2.5 Role of Vectors in Overwintering 68
3 Genetics and Molecular Biology of Virus–Mosquito Interactions 70
3.1 Influence of Mosquito Genetics on WNV Transmission 70
3.2 Key Interaction: Infection of and Dissemination from the Midgut 70
3.3 Transmission by Bite: Mosquito Salivary Proteins 71
3.4 Potential Barriers to Infection: Mosquito Defense Mechanisms 72
3.5 Pathogenesis in Mosquito Tissues 75
3.6 Role of Virus Genetics in Vector Interactions 76
4 Control of WNV Disease: Interruption of the Transmission Cycle 77
5 Conclusion 78
References 78
4. Clinical Manifestations of Neurological Disease 85
1 Introduction 85
2 Epidemiology and Risk Factors for WNV Neuroinvasive Disease 86
3 Clinical Manifestations 88
3.1 West Nile Meningitis 90
3.2 West Nile Encephalitis 93
3.3 West Nile Acute Flaccid Paralysis 97
3.4 Other Clinical Manifestations 99
4 Outcomes and Prognoses 100
5 Therapy of West Nile Virus Infection 102
References 106
5. Molecular Biology of West Nile Virus 112
1 Introduction 112
2 Virus Classification 113
3 Genome RNA 113
4 Virion Morphology and Proteins 114
5 WNV Replication Cycle 116
6 Viral Nonstructural Proteins 119
7 In Vitro Polymerase Assays 127
8 Conserved Viral RNA Terminal Structures and Sequences 128
8.1 Conserved Sequences 128
8.2 Secondary Structures 130
8.3 Tertiary Structures 131
9 Host Cell Proteins Interact with the WNV 3¢ Terminal SLs and Facilitate RNA Synthesis 131
9.1 Cellular Proteins Bind to the 3' (+) SL RNA 132
9.2 Cellular Proteins Bind to the 3' (–) SL 134
9.3 Virus Interactions with the Host Cell 136
9.4 Host Genetic Resistance to Flavivirus-Induced Disease 137
9.5 Virulence Determinants 138
10 Conclusions 139
References 139
6. Virulence of West Nile Virus in Different Animal Hosts 152
1 Introduction 152
2 Classification of West Nile Virus Strains: Antigenic and Nucleotide Sequence Diversity 153
3 WNV: Natural Hosts, Animal Models and Disease 155
3.1 WNV Disease in Humans 155
3.2 Nonhuman Primates 157
3.3 Avians 157
3.4 Equines 158
3.5 Chipmunks, Rabbits, and Tree Squirrels 159
3.6 Small Animal Models: Mice and Hamsters 159
4 Molecular Determinants of Natural Virulence Variations Between WNV Strains 160
4.1 Contribution of Individual Viral-Encoded Proteins to WNV Virulence 160
4.2 Comparative Studies of WNV Virulence in Mouse and Hamster Models 161
4.3 Emergence and Characterization of Attenuated WNV Variants in the Americas 162
4.4 Determinants of Virulence in Avians 163
5 Summary 164
References 164
7. Innate immune Response and Mechanisms of Interferon Antagonism Against West Nile Virus 169
1 Introduction 169
2 Recognition of WNV by Cellular Sensors: Activation of the First Wave of the Innate Immune Response 169
3 INF-alpha and IFN Stimulated Genes (ISGs) Are Essentialfor Survival of WNV Infections 173
4 Effectors of the IFN Response 174
5 Viral Antagonism of the IFN Response 176
6 What Is the Mechanism Responsible for this Inhibition of the IFN Response? 178
7 Implications for Natural Infections in Humans 178
References 179
8. Innate Immune Responses to West Nile Virus Infection 183
1 Introduction 183
2 Sensing WNV Infection: Role of Pattern-Recognition Receptors 184
2.1 Toll-Like Receptors 186
2.2 RNA Helicases 188
2.3 Nonconventional PRRs 189
3 Role of Innate Immune Cells in WNV Infection 189
3.1 Macrophages 189
3.2 Dendritic Cells 190
3.3 Gamma/DeltaT Cells 191
3.4 NK Cells 192
4 Cytokines Involved in Innate Responses to WNV Infection 193
4.1 Macrophage Migration Inhibitory Factor 193
4.2 IFN- Gamma 195
4.3 Other Inflammatory Cytokines 195
5 Concluding Remarks 196
References 197
9 . Mechanisms of Complement Regulation of Infection by Flaviviruses 202
1 Introduction 202
2 The Complement System 203
2.1 Complement Activation 204
2.1.1 Classical Pathway 205
2.1.2 Lectin Pathway 207
2.1.3 Alternative Pathway 207
2.1.4 Terminal Pathway 208
2.2 Complement Receptors Link Activation to Adaptive Immune Responses 209
2.3 Regulators of Complement Activation 211
3 Complement Regulation of Flavivirus Infection 212
3.1 Flavivirus Infection Activates Complement 213
3.2 Complement Augments Antibody-Mediated Neutralization of Flaviviruses 213
3.3 C1q Restricts Antibody-Dependent Enhancement of Flaviviruses 214
3.4 Complement C3 Enhances Flavivirus Infection via CR3 215
3.5 Complement Stimulates Adaptive Immunity to Flavivirus Infections 215
4 Immune Evasion of Complement by Flaviviruses 217
5 Concluding Remarks 218
References 218
10. Antibody-Mediated Neutralization of West Nile Virus: Factors that Govern Neutralization Potency 231
1 Introduction 231
2 Flavivirus Virion Structure 232
3 The Structure of the Envelope Protein and Epitopes Recognized by Neutralizing Antibodies 234
4 The Stoichiometry of Flavivirus Neutralization 237
4.1 Epitope Accessibility Governs the Neutralization Potency of Antibodies 237
4.2 The Stoichiometry of WNV Neutralization 239
5 Factors that Modulate Antibody Potency 240
5.1 Impact of Virion Maturation of Antibody-Mediated Neutralization 241
5.2 Complement Augments the Neutralization Potency of Antibodies 244
6 Mechanisms of Neutralization 244
7 Antibody Dependent Enhancement of Infection 246
7.1 The Stoichiometry of ADE 248
7.2 Mechanisms of ADE 248
8 Implications for Vaccine Development 249
References 250
11 . Structural Basis of Antibody Protection Against West Nile Virus 260
1 Introduction 260
2 Structure of West Nile Virus 261
2.1 The Viral Proteins 261
2.2 The Flavivirus Virion 263
2.3 Immature WNV Particles 264
3 Structural Basis of West Nile Virus Neutralization 265
3.1 WNV Antibody Neutralization 265
3.2 Structure of the E16 Fab–Domain III Complex 266
3.3 Structure of E16 Complexed with Virus 268
3.4 Implications for Function 269
4 Mechanisms of Action of Other Antibodies 271
4.1 Neutralization of Dengue Virus by 1A1D-2 271
5 Structural Insights into Antibody-Mediated Flavivirus Neutralization 272
References 273
12. Molecular Mechanisms of Flaviviral Membrane Fusion 276
1 Introduction 277
2 Overall Architecture of Flaviviral Membrane Fusion Proteins 278
3 Maturation and Priming of Fusion-Competent Virions 281
4 The Fusogenic Conformational Rearrangement 283
5 The Flaviviral Fusion Loop 284
6 Mechanism of Flaviviral Membrane Fusion 287
7 Strategies for Fusion Inhibition 290
References 293
13. CD4 + and CD8 + T-Cell Immune Responses in West Nile Virus Infection 298
1 Role of T Cells in Viral Infection: An Overview 298
2 WNV-Immune CD4 + and CD8 + T-Cell Responses, In Vitro 300
2.1 The CD4 + T-Cell Response 300
2.2 The CD8 + T-Cell Response 301
3 Role of CD4 T Cells in Recovery from WNV Infection 303
4 Role of CD8 + T Cells in Recovery from WNV Infection 305
5 Effector Mechanisms of WNV-Immune T Cells: Cytokines and Cytolytic Pathways 306
5.1 Cytokines 306
5.2 Cytotoxicity 307
6 T-Cell Trafficking into the CNS 310
7 T-Cell-Mediated CNS Pathology in WNV Infection 312
References 314
14. Enhanced Antigen Processing or Immune Evasion? West Nile Virus and the Induction of Immune Recognition Molecules 319
1 Introduction 320
2 Cell Surface Molecule Upregulation by West Nile Virus 321
2.1 West Nile Virus-Induced Cell Surface MHC Expression Is Functional 321
2.2 Type I Interferon and the Cell Cycle in the Responses to West Nile Virus 323
2.3 West Nile Virus-Induced Increase in ICAM-1 Expression 323
2.4 Increased Gene Transcription of WNV-Induced Immune Molecules Is Interferon Independent 324
3 Intracellular Responses to West Nile Virus 324
3.1 Increased Immune Molecule Expression Is Mediated by NF- k B 324
3.2 NF- k B Activation Is Independent of IFN and TNF 325
3.3 Involvement of Interferon Regulatory Factor-1 In WNV Responses 326
4 Decoy Hypothesis 326
4.1 Cell Surface Molecule Concentration and the Immunological Synapse 326
4.2 Recruitment of Low Affinity T Cells 327
4.3 Involvement of Cell Cycle: Divide and Conquer 329
4.4 Disease Resolution or Progression to Autoimmune Disease? 329
5 Mathematical Modelling of WNV Immune Responses 330
6 Modelling Impact of WNV-Induced MHC Increases In Vivo: Embryonic Infection 332
6.1 Immunological Silence and the Developing Embryo 332
6.2 Model of Embryonic Infection 333
6.3 Exogenous Infection in Pregnancy 334
7 Initiation of Immunity: Impact on Ag Presentation 335
7.1 Dendritic Cells and Virus Infection 335
7.2 The Langerhans Cell Response to West Nile Virus Infection 336
7.3 Novel Skin Model 338
7.4 Dendritic Cells in the CNS 340
8 Conclusions 342
References 343
15. Chemokines and Clearance of West Nile Virus Infection 350
1 Introduction 351
2 Chemokines and Viral Infections 352
2.1 Chemokines Participate in Innate and Adaptive Immune Responses During WNV Infection 354
2.2 WNV-Mediated Regulation of Chemokine Expression 356
2.3 Chemokines Shape Immune Responses to WNV Infection Within the CNS 358
3 Chemokine Studies in Human Cases of Flavivirus Encephalitis 361
4 Conclusions 362
References 363
16. Persistence of West Nile Virus Infection in Vertebrates 369
1 Introduction 369
2 WNV Persistent Infection in Nonhuman Primates 370
3 WNV Persistent Infection in Hamsters 371
4 Serial Passage of WNV in Hamster Urine 373
5 Genetic Changes Associated with Persistent Infection 375
6 Phenotypic Changes Associated with Persistent Infection 377
7 Evidence for Persistent Infection with Other Flaviviruses 380
8 Summary and Speculation 381
References 383
17. West Nile Virus Infection of the Central Nervous System 386
1 Introduction 386
2 Clinical Features of WNV Neuroinvasive Disease 387
2.1 WNV Meningitis 389
2.2 WNV Encephalitis 389
2.3 Acute Flaccid Paralysis 390
2.4 Laboratory Findings and Diagnosis 391
2.5 Prognosis and Outcome 391
2.6 Potential Therapies 392
3 Pathogenesis of WNV in the CNS 392
3.1 Neuropathology 392
3.2 Mechanisms of CNS Injury and Disease 394
4 WNV Entry into the CNS 395
5 CNS Immune Responses to WNV 397
5.1 Innate Immune Responses in the CNS 397
5.2 Adaptive Immune Responses in the CNS 398
6 Future Perspectives 400
References 400
18. The Human Antibody Response Against WNV 407
1 Introduction 407
2 Natural Infections in Humans 408
3 Serology 409
4 Antibody Repertoire Analysis 411
5 Epitope Mapping 413
6 Conclusion 417
References 418
19. Antibody Protection and Therapy for West Nile Virus Infections 423
1 Introduction 423
2 The Role of the E Protein in Antiflaviviral Immunity 424
3 Using Small Animal Models of Infection to Define Antibody-Mediated Protection and Therapy 425
4 Previous Use of Human Antibody for Prophylaxis and Therapy for Flaviviral Infections 426
5 MAbs as Human Therapeutics 427
6 Conclusion 428
References 428
20. Vaccine Development Against West Nile Virus 432
1 Background 433
2 Inactivated Vaccines 434
3 Recombinant Subunit Vaccines 434
4 Viral-Vectored WNV Vaccines 435
4.1 Canarypox Vector 435
4.2 Measles Virus Vector 436
4.3 Lentiviral Vector 436
4.4 Equine Herpesvirus Vector 437
5 Live Attenuated Vaccines 437
5.1 Attenuated WNV Isolates 438
5.2 Kunjin Virus 438
6 Chimeric Viruses 440
6.1 ChimeriVax-WN 442
6.2 WNV/DEN4 Chimera 443
6.3 DEN2/WNV Chimera 444
7 Conventional Non-infectious DNA Vaccines 445
8 Novel Nucleic Acid-Based Approaches for WNV Vaccine Development 447
8.1 Infectious Nucleic Acid Vaccines 447
8.2 Non-infectious, Replicating Vaccines 449
8.3 RNA-Based Capsid-Deleted Vaccines 449
8.4 VLP-Based Capsid-Deleted Vaccines 450
8.5 DNA-Based Capsid-Deleted Vaccine 450
8.6 Replicating DNA Vaccine Producing Single Round Infectious Particles 451
9 Conclusions and Future Directions 451
References 452
21. Novel Therapeutics Against West Nile Virus 457
1 Introduction 457
2 Strategies for the Identification of Novel Small Molecular Inhibitors 458
2.1 Rational Design 458
2.2 Biochemical Enzyme-Based Screening 460
2.3 Genetic Cell-Based Screening 461
3 Current WNV Inhibitors 464
3.1 Macromolecular Inhibitors 464
3.1.1 Antibody 464
3.1.2 Interferon 465
3.1.3 Small Peptides 465
3.1.4 Antisense Phosphorodiamidate Morpholino Oligomers 466
3.1.5 siRNA 466
3.2 Small Molecular Inhibitors 467
3.2.1 Inhibitors of Nucleoside Triphosphate Synthesis 467
3.2.2 NTPase/Helicase Inhibitors 468
3.2.3 Protease Inhibitors 468
3.2.4 Host Glucosidase Inhibitors 469
3.2.5 Other Small Molecular Inhibitors 470
4 New Antiviral Targets and Challenges on Antiviral Development 471
References 472
Index 479