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Principles of Virology, the leading virology textbook in use, is an extremely valuable and highly informative presentation of virology at the interface of modern cell biology and immunology. This text utilizes a uniquely rational approach by highlighting common principles and processes across all viruses. Using a set of representative viruses to illustrate the breadth of viral complexity, students are able to under-stand viral reproduction and pathogenesis and are equipped with the necessary tools for future encounters with new or understudied viruses.

This fifth edition was updated to keep pace with the ever-changing field of virology. In addition to the beloved full-color illustrations, video interviews with leading scientists, movies, and links to exciting blogposts on relevant topics, this edition includes study questions and active learning puzzles in each chapter, as well as short descriptions regarding the key messages of references of special interest.

Volume I: Molecular Biology focuses on the molecular processes of viral reproduction, from entry through release. Volume II: Pathogenesis and Control addresses the interplay between viruses and their host organisms, on both the micro- and macroscale, including chapters on public health, the immune response, vaccines and other antiviral strategies, viral evolution, and a brand new chapter on the therapeutic uses of viruses. These two volumes can be used for separate courses or together in a single course. Each includes a unique appendix, glossary, and links to internet resources.

Principles of Virology, Fifth Edition, is ideal for teaching the strategies by which all viruses reproduce, spread within a host, and are maintained within populations. This edition carefully reflects the results of extensive vetting and feedback received from course instructors and students, making this renowned textbook even more appropriate for undergraduate and graduate courses in virology, microbiology, and infectious diseases.

Principles of Virology - Pathogenesis and Control, Fifth Edition Volume 2

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