Preface xvii
Acknowledgments xxi
About the Authors xxiii
Key of Repetitive Elements xxv
1 Infections of Populations: History and Epidemiology 2
Introduction to Viral Pathogenesis 3
A Brief History of Viral Pathogenesis 4
The Relationships among Microbes and the Diseases They Cause 4
The First Human Viruses Identified and the Role of Serendipity 5
New Methods Facilitate the Study of Viruses as Causes of Disease 7
Viral Epidemics in History 8
Epidemics Shaped History: the 1793 Yellow Fever Epidemic in Philadelphia 9
Tracking Epidemics by Sequencing: West Nile Virus Spread to the Western Hemisphere 10
Zoonotic Infections and Epidemics Caused by New Viruses 11
The Economic Toll of Viral Epidemics in Livestock 12
Population Density and World Travel Are Accelerators of Viral Transmission 12
Focus on Frontline Health Care: Ebolavirus in Africa 12
Emergence of a Birth Defect Associated with Infection: Zika Virus in Brazil 13
Epidemiology 14
Fundamental Concepts 14
Methods Used by Epidemiologists 17
Surveillance 17
Network Theory and Practical Applications 20
Parameters That Govern the Ability of a Virus to Infect a Population 20
Geography and Population Density 20
Climate 23
Perspectives 26
References 27
Study Questions 28
2 Barriers to Infection 30
Introduction 31
An Overview of Infection and Immunity 31
A Game of Chess Played by Masters 31
Initiating an Infection 33
Successful Infections Must Modulate or Bypass Host Defenses 34
Skin 34
Respiratory Tract 35
Alimentary Tract 38
Eyes 41
Urogenital Tract 42
Placenta 42
Viral Tropism 43
Accessibility of Viral Receptors 44
Other Host-Virus
Interactions That Regulate the Infectious Cycle 44
Spread throughout the Host 45
Hematogenous Spread 47
Neural Spread 50
Organ Invasion 51
Entry into Organs with Sinusoids 51
Entry into Organs That Lack Sinusoids 51
Organs with Dense Basement Membranes 53
Skin 53
Shedding of Virus Particles 54
Respiratory Secretions 54
Saliva 55
Feces 55
Blood 56
Urine 56
Semen 56
Milk 56
Skin Lesions 56
Tears 56
Perspectives 57
References 58
Study Questions 59
3 The Early Host Response: Cell Autonomous and Innate Immunity 60
Introduction 61
The First Critical Moments: How Do Individual Cells Detect a Virus Infection? 62
Cell Signaling Induced by Viral Entry Receptor Engagement 63
Receptor-Mediated Recognition of Microbe-Associated Molecular Patterns 64
Cell-Intrinsic Defenses 70
Apoptosis (Programmed Cell Death) 70
Programmed Necrosis (Necroptosis) 75
Autophagy 77
Epigenetic Silencing 77
Host Proteins That Restrict Virus Reproduction (Restriction Factors) 79
RNA Interference 83
CRISPR 83
The Continuum between Intrinsic and Innate Immunity 83
Secreted Mediators of the Innate Immune Response 83
Overview of Cytokine Functions 85
Interferons, Cytokines of Early Warning and Action 86
Chemokines 94
The Innate Immune Response 96
Monocytes, Macrophages, and Dendritic Cells 97
Complement 97
Natural Killer Cells 99
Other Innate Immune Cells Relevant to Viral Infections 101
Perspectives 103
References 104
Study Questions 106
4 Adaptive Immunity and Establishment of Memory 108
Introduction 109
Attributes of the Host Response 109
Speed 109
Diversity and Specificity 110
Memory 110
Self-Control 111
Lymphocyte Development, Diversity, and Activation 111
The Hematopoietic Stem Cell Lineage 111
The Two Arms of Adaptive Immunity 112
The Major Effectors of the Adaptive Response: B and T Cells 112
Diverse Receptors Impart Antigen Specificity to B and T Cells 118
Events at the Site of Infection Set the Stage for the Adaptive Response 120
Acquisition of Viral Proteins by Professional Antigen-Presenting Cells Enables Production of Proinflammatory Cytokines and Establishment of Inflammation 120
Activated Antigen-Presenting Cells Leave the Site of Infection and Migrate to Lymph Nodes 122
Antigen Processing and Presentation 125
Professional Antigen-Presenting Cells Induce Activation via Costimulation 125
Presentation of Antigens by Class I and Class II MHC Proteins 125
Lymphocyte Activation Triggers Massive Cell Proliferation 128
The CTL (Cell-Mediated) Response 130
CTLs Lyse Virus-Infected Cells 130
Control of CTL Proliferation 132
Control of Infection by CTLs without Killing 134
Rashes and Poxes 134
The Humoral (Antibody) Response 136
Antibodies Are Made by Plasma Cells 136
Types and Functions of Antibodies 137
Virus Neutralization by Antibodies 137
Antibody-Dependent Cell-Mediated Cytotoxicity: Specific Killing by Nonspecific Cells 140
Immunological Memory 140
Perspectives 142
References 143
Study Question Puzzle 145
5 Patterns and Pathogenesis 146
Introduction 147
Animal Models of Human Diseases 147
Patterns of Infection 151
Incubation Periods 151
Mathematics of Growth Correlate with Patterns of Infection 152
Acute Infections 152
Persistent Infections 155
Latent Infections 163
Abortive Infections 170
Transforming Infections 171
Viral Virulence 171
Measuring Viral Virulence 171
Approaches to Identify Viral Genes That Contribute to Virulence 171
Viral Virulence Genes 173
Pathogenesis 176
Infected Cell Lysis 176
Immunopathology 177
Immunosuppression Induced by Viral Infection 181
Oncogenesis 183
Molecular Mimicry 183
Perspectives 183
References 185
Study Question Puzzle 186
6 Cellular Transformation and Oncogenesis 188
Introduction 189
Properties of Transformed Cells 189
Control of Cell Proliferation 193
Oncogenic Viruses 197
Discovery of Oncogenic Viruses 197
Viral Genetic Information in Transformed Cells 200
The Origin and Nature of Viral Transforming Genes 205
Functions of Viral Transforming Proteins 206
Activation of Cellular Signal Transduction Pathways by Viral Transforming Proteins 206
Viral Signaling Molecules Acquired from the Cell 207
Alteration of the Production or Activity of Cellular Signal Transduction Proteins 209
Disruption of Cell Cycle Control Pathways by Viral Transforming Proteins 215
Abrogation of Restriction Point Control Exerted by the RB Protein 215
Production of Virus-Specific Cyclins 218
Inactivation of Cyclin-Dependent Kinase Inhibitors 218
Transformed Cells Increase in Size and Survive 218
Mechanisms That Permit Survival of Transformed Cells 219
Tumorigenesis Requires Additional Changes in the Properties of Transformed Cells 221
Inhibition of Immune Defenses 222
Other Mechanisms of Transformation and Oncogenesis by Human
Tumor Viruses 222
Nontransducing Oncogenic Retroviruses: Tumorigenesis with Very Long Latency 222
Oncogenesis by Hepatitis Viruses 223
Perspectives 225
References 226
Study Questions 228
7 Vaccines 230
Introduction 231
The Origins of Vaccination 231
Smallpox: a Historical Perspective 231
Worldwide Vaccination Programs Can Be Dramatically Effective 232
Vaccine Basics 237
Immunization Can Be Active or Passive 237
Active Vaccination Strategies Stimulate Immune Memory 238
The Fundamental Challenge 243
The Science and Art of Making Vaccines 243
Inactivated Virus Vaccines 244
Attenuated Virus Vaccines 247
Subunit Vaccines 250
Virus-Like Particles 252
Nucleic Acid Vaccines 253
Vaccine Technology: Delivery and Improving Antigenicity 254
Adjuvants Stimulate an Immune Response 254
Delivery and Formulation 254
Immunotherapy 255
The Ongoing Quest for an AIDS Vaccine 255
Perspectives 256
References 257
Study Question Puzzle 259
8 Antiviral Drugs 260
Introduction 261
A Brief History of Antiviral Drug Discovery 261
Discovering Antiviral Compounds 262
The Lexicon of Antiviral Discovery 262
Screening for Antiviral Compounds 264
Computational Approaches to Drug Discovery 266
The Difference between R and D 269
Drug Resistance 271
Examples of Antiviral Drugs 272
Inhibitors of Virus Attachment and Entry 272
Inhibitors of Viral Nucleic Acid Synthesis 275
Inhibition of Viral Polyprotein Processing and Assembly 282
Inhibition of Virus Particle Release 284
Expanding Targets for Antiviral Drug Development 284
Attachment and Entry Inhibitors 286
Nucleic Acid-Based Approaches 286
Proteases and Nucleic Acid Synthesis and Processing Enzymes 287
Virus Particle Assembly 287
Microbicides 287
Two Stories of Antiviral Success 287
Combination Therapy 288
Challenges Remaining 290
Perspectives 291
References 294
Study Questions 295
9 Therapeutic Viruses 296
Introduction 297
Phage Therapy 297
History 297
Some Advantages and Limitations of Phage Therapy 298
Applications in the Clinic and for Disease Prevention 299
Future Prospects 301
Oncolytic Animal Viruses 302
From Anecdotal Reports to Controlled Clinical Trials 302
Rational Design of Oncolytic Viruses 304
Two Clinically Approved Oncolytic Viruses 307
Future Directions 308
Gene Therapy 308
Introduction 308
Retroviral Vectors 309
Adenovirus-Associated Virus Vectors 316
Future Prospects 321
Vaccine Vectors 322
DNA Viruses 322
RNA Viruses 325
Perspectives 328
References 330
Study Questions 331
10 Virus Evolution 332
Virus Evolution 333
How Do Virus Populations Evolve? 333
Two General Virus Survival Strategies Can Be Distinguished 333
Large Numbers of Viral Progeny and Mutants Are Produced in Infected Cells 334
The Quasispecies Concept 335
Genetic Shift and Genetic Drift 338
Fundamental Properties of Viruses That Constrain Evolution 339
Two General Pathways for Virus Evolution 339
Evolution of Virulence 340
The Origin of Viruses 342
When and How Did They Arise? 342
Evolution of Contemporary Eukaryotic Viruses 342
Host-Virus Relationships Drive Evolution 348
DNA Virus-Host Relationships 348
RNA Virus-Host Relationships 350
The Host-Virus Arms Race 351
Lessons from Paleovirology 353
Endogenous Retroviruses 353
DNA Fossils Derived from Other RNA Viral Genomes 355
Endogenous Sequences from DNA Viruses 355
Short-versus Long-Term Rates of Viral Evolution 358
Perspectives 358
References 359
Study Questions 360
11 Emergence 362
The Spectrum of Host-Virus Interactions 363
Stable Interactions 363
The Evolving Host-Virus Interaction 364
The Dead-End Interaction 364
The Resistant Host 366
Encountering New Hosts: Humans Constantly Provide New Venues for Infection 368
Common Sources for Animal-to-Human Transmission 370
Viral Diseases That Illustrate the Drivers of Emergence 372
Poliomyelitis: Unexpected Consequences of Modern Sanitation 372
Introduction of Viruses into Naïve Populations 372
Hantavirus Pulmonary Syndrome: Changing Animal Populations 374
Severe Acute and Middle East Respiratory Syndromes (SARS and MERS): Zoonotic Coronavirus Infections 374
The Contribution to Emergence of Mutation, Recombination, or Reassortment 376
Canine Parvoviruses: Cat-to-Dog Host Range Switch by Two Amino Acid Changes 376
Influenza Epidemics and Pandemics: Escaping the Immune Response by Reassortment 376
New Technologies Uncover Previously Unrecognized Viruses 378
Hepatitis Viruses in the Human Blood Supply 378
A Revolution in Virus Discovery 380
Perceptions and Possibilities 381
Virus Names Can Be Misleading 382
All Viruses Are Important 382
Can We Predict the Next Viral Pandemic? 382
Preventing Emerging Virus Infections 383
Perspectives 384
References 384
Study Questions 385
12 Human Immunodeficiency Virus Type I Pathogenesis 386
Introduction 387
Worldwide Impact of AIDS 387
HIV-1 Is a Lentivirus 387
Discovery and Characterization 387
Distinctive Features of the HIV-1 Reproduction Cycle and the Functions of HIV-1 Proteins 390
The Viral Capsid Counters Intrinsic Defense Mechanisms 398
Entry and Transmission 400
Entry in the Cell 400
Entry into the Body 401
Transmission in Human Populations 402
The Course of Infection 403
The Acute Phase 403
The Asymptomatic Phase 406
The Symptomatic Phase and AIDS 406
Effects of HIV-1 on Other Tissues and Organs 406
Virus Reproduction 408
Dynamics in the Absence of Treatment 408
Dynamics of Virus Reproduction during Treatment 408
Latency 410
Immune Responses to HIV-1 411
Innate Response 411
Humoral Responses 411
HIV-1 and Cancer 412
Kaposis Sarcoma 412
B-Cell Lymphomas 413
Anogenital Carcinomas 413
Prospects for Treatment and Prevention 414
Antiviral Drugs 414
Confronting the Problems of Persistence and Latency 415
Gene Therapy Approaches 415
Immune System-Based Therapies 417
Antiviral Drug Prophylaxis 417
Perspectives 417
References 418
Study Questions 419
13 Unusual Infectious Agents 420
Introduction 421
Viroids 421
Replication 421
Sequence Diversity 424
Movement 424
Pathogenesis 425
Satellite Viruses and RNAs 425
Replication 426
Pathogenesis 426
Hepatitis Delta Virus 426
Prions and Transmissible Spongiform Encephalopathies 427
Scrapie 427
Physical Properties of the Scrapie Agent 429
Human TSEs 429
Hallmarks of TSE Pathogenesis 429
Prions and the prnp Gene 429
Prion Strains 434
Bovine Spongiform Encephalopathy 435
Chronic Wasting Disease 436
Treatment of Prion Diseases 437
Perspectives 438
References 439
Study Questions 439
Appendix Epidemiology and Pathogenesis of Selected Human Viruses 441
Glossary 471
Index 477
