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 [...] 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