Principles of Virology, Volume 2

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 Naive 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