Human Cytomegalovirus (eBook)

Preface 5
Contents 7
Contributors 9
Human Cytomegalovirus Genome 14
Introduction 15
Genome Organization and cis -Acting Elements 16
Clinical Isolates and Laboratory Strains 17
Protein-Coding ORFs 19
Genomic Organization: Evolution and Function 29
Perspectives 30
References 30
Human Cytomegalovirus microRNAs 34
Introduction 35
miRNA Biogenesis 36
Location and Conservation of HCMV miRNAs 40
HCMV miRNA Expression 44
Potential Function of HCMV miRNAs 47
Future Directions 48
References 48
Mutagenesis of the Cytomegalovirus Genome 54
Introduction 55
CMV Genetics in Cells 55
CMV Genetics in Bacteria 58
Genetic Analysis of Essential Genes 66
Concluding Remarks 70
References 70
Cytomegalovirus Cell Tropism 76
Target Cells of HCMV Infection 77
Pathogenetic Role of Selected Cell Types 81
Cell Biological Basis of HCMV Cell Tropism 86
Cell Tropism of Other Cytomegaloviruses 89
Impact of Cell Tropism Analyses 90
References 91
Virus Entry and Innate Immune Activation 98
Introduction to Virus Entry 99
Cellular Receptors Proposed for HCMV Entry 99
Envelope and Membrane Fusion 103
Introduction to Activation of Innate Immunity 104
Activation of Inflammatory Cytokines 104
Activation of Interferon Responses 106
Coordination of Entry Events and Innate Immune Activation Steps 107
Perspectives 109
References 109
Functions of Human Cytomegalovirus Tegument Proteins Prior to Immediate Early Gene Expression 114
Introduction 114
Tegument Proteins Known to Act at the Very Start of HCMV Infection 117
Delivery of the Genome to the Nucleus 118
Initiating Viral IE Gene Expression 120
Model for Postfusion, Preimmediate Early Events 123
Perspectives 124
References 125
Initiation of Cytomegalovirus Infection at ND10 130
Structural Observations in the First Hours After CMV Infection and Their Limits in Interpretative Value 131
Are ND10 Really the Start Sites of CMV Transcription? 134
Structural and Functional Aspects of IE1 135
IE1 Counteracts the Host Cell’s Silencing Mechanisms 136
Effect of ND10-Associated Proteins on CMV 138
Perspectives 141
References 142
Functional Roles of the Human Cytomegalovirus Essential IE86 Protein 146
Introduction 146
Mapping the Functional Domains of the IE86 Protein 148
Autoregulation of the MIE Promoter 152
Transcription from Viral and Cellular Promoters 153
Cell Cycle Progression 155
Perspectives 158
References 159
Nuts and Bolts of Human Cytomegalovirus Lytic DNA Replication 166
Introduction 167
Essential Region I: IE2-UL84 Responsive Promoter in oriLyt 168
Essential Region II: RNA/DNA Hybrid Structure 171
Viral-Encoded trans -Acting Factors Required for Lytic Replication 172
UL84 and IE2 174
Viral and Cellular Encoded UL84 Binding Partners 175
Summary and Perspectives 176
References 176
Interactions of Human Cytomegalovirus Proteins with the Nuclear Transport Machinery 180
Introduction 181
Nuclear Import and Export Pathways 182
Interaction of the Human Cytomegalovirus Protein pUL69 with the mRNA Export Factor UAP56 186
RNA Export by pUL69 189
Interaction of the HCMV pUL84 with Importin-a Proteins 191
Unconventional Interactions with the Nuclear Transport Machinery: Novel Targets for Antiviral Strategies? 192
References 193
Structure and Formation of the Cytomegalovirus Virion 200
Introduction 200
Formation of the Nucleocapsid 203
Tegumentation and Envelopment 209
Concluding Thoughts 212
References 212
Human Cytomegalovirus Modulation of Signal Transduction 218
Introduction 219
Signaling Overview 220
Biological Rationale for Modulation of Host Cell Signaling 225
Role of Signaling in Pathogenesis 228
Final Thoughts 228
References 229
Chemokines and Chemokine Receptors Encoded by Cytomegaloviruses 234
Introduction 235
Evolution of CMV vCK Genes 236
Chemokine Receptors Encoded by CMVs 240
Perspectives 250
References 250
Subversion of Cell Cycle Regulatory Pathways 256
The Host Cell Cycle 256
The Effect of HCMV on the Cell Cycle 259
Importance of Subversion of the Cell Cycle for the Viral Infection 261
Perspectives 269
References 270
Modulation of Host Cell Stress Responses by Human Cytomegalovirus 276
Introduction 277
Background: PI3K-Akt-TSC-mTOR Signaling 278
Background: The Complexes of mTOR Kinase and Their Activities 279
HCMV and the Activation of the PI3K-Akt-TSC-mTORC1 Pathway 281
The Effects of HCMV Downstream of Akt 284
HCMV Effects on the mTOR Complexes and Their Substrates 285
HCMV Effects on eIF4E and Mnk-1 286
Conclusions, Questions, Speculations 287
References 289
Control of Apoptosis by Human Cytomegalovirus 294
Introduction 295
vMIA Controls Mitochondria-Dependent Death 296
vICA Controls Caspase-8 300
IE1 491aa , IE2 579aa , and Akt-Dependent Pro-survival Pathways 300
UL38 Decreases Intrinsic Stress 301
M45 Is a Cell Type-Specific Survival Factor 302
m41, Late Infection, and the Golgi Apparatus 303
ß2.7 and Mitochondrial Respiratory Complex I 303
Summary and Perspectives 303
References 304
Aspects of Human Cytomegalovirus Latency and Reactivation 310
Introduction 311
Latency, Carriage and Reactivation of HCMV in the Cells of the Myeloid Lineage 311
Models of HCMV Latency Using Experimental Infection 313
Viral Gene Expression Associated with HCMV Latency 314
Key Aspects of HCMV Latency and Reactivation 315
Other Sites of HCMV Latency 321
Conclusion 322
References 322
Murine Model of Cytomegalovirus Latency and Reactivation 328
Introduction 329
Definitions and Caveats: The Difference Between Latency and Persistence 330
Latent Viral Genome Load Defining the Risk of Recurrence 333
Bidirectional Gene Pair Architecture of the Regulatory Major Immediate Early Locus 334
Stochastic Desilencing of the Major Immediate Early Locus During Latency 336
Extrinsic Signals Triggering Transcriptional Reactivation and Recurrence 336
Role of Viral Chromatin Remodeling 337
Dynamic Control of Latency at Immunological Checkpoints: The Immune Sensing Hypothesis 338
Concluding Thoughts and Perspectives 341
References 341
Cytomegalovirus Immune Evasion 346
The Type I Interferon System and Its Effects on CMV Replication 347
Interference with Antigen Presentation by Cytomegalovirus 350
Escaping the Natural Killer Cell Response 355
Perspectives 361
References 362
Cytomegalovirus Vaccine Development 374
Spectrum of HCMV Disease, Rationale for Vaccine, and Target Population 375
Evidence That Immunity Protects Against HCMV Infection and Disease 378
HCMV Vaccines in Clinical Trials 380
HCMV Vaccine Approaches in Preclinical Development 385
Perspectives 390
References 391
Cytomegalovirus Infection in the Human Placenta: Maternal Immunity and Developmentally Regulated Receptors on Trophoblasts Converge 396
Introduction 397
Spatially Distinct Infection in the Developing Placenta 397
Villous Cytotrophoblasts Express EGFRand Upregulate Integrin aV 399
Cell Column Cytotrophoblasts Induce Integrin 401
Expression 401
Replication in Differentiating/Invading Cytotrophoblasts 402
Infection Impairs Cell Functions Through Diverse Membrane Proximal Events 404
Implications for Congenital CMV Infection 405
References 406
Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing 410
Introduction 411
Tissue Repair and Angiogenic Factors Mediate TVS 411
Animal Models of CMV-Accelerated Graft Rejection 413
In Vitro Models of HCMV-Mediated Wound Healing and Angiogenesis 415
Conclusions 424
References 425
Manifestations of Human Cytomegalovirus Infection: Proposed Mechanisms of Acute and Chronic Disease 430
Introduction 431
Natural History of Acute CMV Infections in the Normal Host 434
Natural History of Acute CMV Infection in the Immunocompromised Host 439
Diseases Associated with Chronic Infection 455
References 462
Index 484