Jane Flint is Professor Emerita of Molecular Biology at Princeton University. Dr. Flint's research focused on investigation of the mechanisms by which viral gene products modulate host pathways and antiviral defenses to allow efficient reproduction in normal human cells of adenoviruses, viruses that are used in such therapeutic applications as gene transfer and cancer treatment. Vincent R. Racaniello is Higgins Professor of Microbiology & Immunology at Columbia University Vagelos College of Physicians & Surgeons. Dr. Racaniello has been studying viruses for over 40 years, including polio- virus, rhinovirus, enteroviruses, hepatitis C virus, and Zika virus. He blogs about virus-es at virology.ws and is host of This Week in Virology. Glenn F. Rall is a Professor and the Chief Academic Officer at the Fox Chase Cancer Center, and is an Adjunct Professor in the Microbiology and Immunology departments at the University of Pennsylvania, as well as Thomas Jefferson, Drexel, and Temple Universities. Dr. Rall studies viral infections of the brain and the immune responses to those infections, with the goal of defining how viruses contribute to disease. Theodora Hatziioannou is a Research Associate Professor at Rockefeller University and is actively involved in teaching programs at Albert Einstein College of Medicine. Dr. Hatziioannou has worked on multiple viruses with a focus on retroviruses and the molecular mechanisms that govern virus tropism and on the improvement of animal models for human disease. Anna Marie Skalka is a Professor Emerita and former Senior Vice President for Basic Research at the Fox Chase Cancer Center. Dr. Skalka is internationally recognized for her contributions to the understanding of the biochemical mechanisms by which retroviruses replicate and insert their genetic material into the host genome, as well as her research into other molecular aspects of retrovirus biology.

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 Kaposi's 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