Volume II: Pathogenesis and Control
1. Infection of a Susceptible Host
Introduction
A Brief History of Viral Pathogenesis
Microbes as Infectious Agents
The First Human Viruses
The Golden Age of Viral Pathogenesis
The New Millennium and Viral Pathogenesis
Infection Basics
A Series of Unfortunate Events
Initiating an Infection
Viral Entry
Successful Infections Must Evade Host Defenses
Viral Spread
Organ Invasion
Tropism
Perspectives
References
2. Infection of Populations
Introduction
Principles of Viral Pathogenesis
Statistics
Epidemiology
Shedding of Virions
Transmission of Viral Infection
Geography and Season
Viral Virulence
Host Susceptibility to Viral Disease
Other Determinants of Susceptibility
Perspectives
References
3. Virus Offense Meets Host Defense: Early Actions
The Host Defense against Viral Infections
Primary Physical and Chemical Defenses
The First Critical Moments of Infection
Intrinsic Cellular Defenses
Receptor-Mediated Recognition of Pathogen-Associated Molecules
Cytokines, the Primary Output of Intrinsic Cell Defense
Interferons, Cytokines of Early Warning and Action
Apoptosis (Programmed Cell Death)
The Hostile Cytoplasm: Other Intrinsic Defenses
Autophagy
Epigenetic Silencing
RNA Silencing
Cytosine Deamination (Apobec, Apolipoprotein B Editing Complex)
Trim Proteins (Tripartite Interaction Motif)
Perspectives
References
4. Immune Defenses
Introduction
Innate and Adaptive Immune Defenses
The Innate Immune Response
General Features
Sentinel Cells
Natural Killer Cells
Complement
The Inflammatory Response
The Adaptive Immune Response
General Features
Cells of the Adaptive Immune System
Adaptive Immunity: the Action of Lymphocytes That Carry Distinct Antigen Receptors
Antigen Presentation and Activation of Immune Cells
The Cell-Mediated Adaptive Response
The Antibody Response
The Immune System and the Brain
Immunopathology: Too Much of a Good Thing
Immunopathological Lesions
Viral Infection-Induced Immunosuppression
Systemic Inflammatory Response Syndrome
Autoimmune Diseases
Heterologous T-Cell Immunity
Superantigens “Short-Circuit” the Immune System
Mechanisms Mediated by Free Radicals
Perspectives
References
5. Patterns of Infection
Introduction
Life Cycles and Host Defenses
Mathematics of Growth Correlate with Patterns of Infection
Acute Infections
Definition and Requirements
Acute Infections Tend To Be Efficiently Contained and Cleared
Antigenic Variation Provides a Selective Advantage in Acute Infections
Common Public Health Problems
Persistent Infections
Definition and Requirements
An Ineffective Intrinsic or Innate Immune Response Can Promote a Persistent Infection
Modulation of the Adaptive Immune Response Perpetuates a Persistent Infection
Persistent Infections May Be Established in Tissues with Reduced Immune Surveillance
Persistent Infections May Occur When Cells of the Immune System Are Infected
Two Viruses That Cause Persistent Infections
Measles Virus
Lymphocytic Choriomeningitis Virus
Latent Infections
General Properties
Herpes Simplex Virus
Epstein-Barr Virus
Slow Infections: Sigurdsson’s Legacy
Abortive Infections
Transforming Infections
Perspectives
References
6. Human Immunodeficiency Virus Pathogenesis
Introduction
Worldwide Scope of the Problem
HIV is a Lentivirus
Discovery and Characterization
Distinctive Features of the HIV Replication Cycle and the Roles of Auxiliary Proteins
Cellular Targets
Routes of Transmission
Sources of Virus Infection
Modes of Transmission
Mechanics of Spread
The Course of Infection
Patterns of Virus Appearance and Immune Cell Indicators of Infection
Variability of Response to Infection
Origins of Cellular Immune Dysfunction
CD4+ T Lymphocytes
Cytotoxic T Lymphocytes
Monocytes and Macrophages
B Cells
Natural Killer Cells
Autoimmunity
Immune Responses to HIV
Humoral Responses
The Cellular Immune Response
Summary: the Critical Balance
Dynamics of HIV-1 Replication in AIDS Patients
Effects of HIV on Different Tissues and Organ Systems
Lymphoid Organs
The Nervous System
The Gastrointestinal System
Other Organ Systems
HIV and Cancer
Kaposi’s Sarcoma
B-Cell Lymphomas
Anogenital Carcinomas
Propects for Treatment and Prevention
Antiviral Drugs and Therapies
Highly Active Antiretroviral Therapy
Prophylactic Vaccine Development To Prevent Infection
Perspectives
References
7. Transformation and Oncogenesis
Introduction
Properties of Transformed Cells
Control of Cell Proliferation
Oncogenic Viruses
Discovery of Oncogenic Viruses
Viral Genetic Information in Transformed Cells
The Origin and Nature of Viral Transforming Genes
Functions of Viral Transforming Proteins
Transformation by Activation of Cellular Signal Transduction Pathways
Viral Mimics of Cellular Signaling Molecules
Alteration of the Production or Activity of Cellular Signal Transduction Proteins
Transformation via Cell Cycle Control Pathways
Abrogation of Restriction Point Control Exerted by the Rb Protein
Production of Virus-Specific Cyclins
Inactivation of Cyclin-Dependent Kinase Inhibitors
Transformed Cells Must Also Grow and Survive
Viral Inhibitor of the Apoptotic Cascade
Integration of Inhibition of Apoptosis with Stimulation of Proliferation
Inactivation of the Cellular Tumor Suppressor p53
Other Mechanisms of Transformation and Oncogenesis
Nontransducing, Complex Oncogenic Retroviruses: Tumorigenesis with Very Long Latency
Oncogenesis by Hepatitis Viruses
Perspectives
References
8. Vaccines
Introduction
The Historical Origins of Vaccination
Smallpox: a Historical Perspective
Large-Scale Vaccination Programs Can Be Dramatically Effective
Vaccine Basics
Immunization Can Be Active or Passive
Active Vaccines Stimulate Immune Memory
The Fundamental Challenge
The Science and Art of Making Vaccines
Basic Approaches
New Vaccine Technology
Adjuvants
Delivery
Immunotherapy
The Quest for an AIDS Vaccine
Perspectives
References
9. Antiviral Drugs
Introduction
Paradox: So Much Knowledge, So Few Antivirals
Historical Perspective
Discovering Antiviral Compounds
Screening for Antiviral Compounds
Designer Antivirals and Computer-Based Searching
The Difference between “R” and “D”
Examples of Some Approved Antiviral Drugs
The Search for New Antiviral Targets
Antiviral Gene Therapy and Transdominant Inhibitors
Resistance to Antiviral Drugs
Human Immunodeficiency Virus and AIDS
Examples of Antiviral Drugs
The Combined Problems of Treating a Persistent Infection and Emergence of Drug Resistance
Combination Therapy
Strategic Treatment Interruption
Challenges and Lessons Learned
Perspectives
References
10. Evolution and Emergence
Virus Evolution
The Classic Theory of Host-Parasite Interactions
How Do Viral Populations Evolve?
The Origin of Viruses
The Fundamental Properties of Viruses Constrain and Drive Evolution
Emerging Viruses
The Spectrum of Host-Virus Interactions
Encountering New Hosts: Fundamental Problems in Ecology
Expanding Viral Niches: Snapshots of Selected Emerging Viruses
Host Range Can Be Expanded by Mutation or Recombination
Some Emergent Viruses Are Truly Novel
A Paradigm Shift in Diagnostic Virology
Perceptions and Possibilities
Infectious Agents and Public Perceptions
What Next?
Perspectives
References
Appendix A: Diseases, Epidemiology, and Disease Mechanisms of Selected Animal Viruses Discussed in This Book
Appendix B: Unusual Infectious Agents
Glossary
Index