Table of Contents
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Preface |
xiii |
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Acknowledgments |
xvii |
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1 |
Infection of a Susceptible Host |
2 |
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Introduction |
3 |
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A Brief History of Viral
Pathogenesis |
3 |
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Microbes as Infectious Agents |
3 |
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The First Human Viruses |
4 |
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The Golden Age of Viral
Pathogenesis |
5 |
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The New Millennium and Viral
Pathogenesis |
6 |
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Infection Basics |
6 |
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A Series of Unfortunate Events |
6 |
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Initiating an Infection |
6 |
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Viral Entry |
9 |
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Successful Infections Must
Modulate or Bypass Host Defenses |
14 |
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Viral Spread |
16 |
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Organ Invasion |
21 |
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Tropism |
23 |
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Perspectives |
26 |
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References |
26 |
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2 |
Infection of Populations |
28 |
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Introduction |
29 |
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Principles of Viral Pathogenesis |
29 |
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Statistics |
30 |
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Epidemiology |
31 |
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Shedding of Virions |
34 |
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Transmission of Viral Infection |
36 |
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Geography and Season |
37 |
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Viral Virulence |
40 |
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Host Susceptibility to Viral
Disease |
48 |
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Other Determinants of
Susceptibility |
48 |
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Perspectives |
50 |
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References |
51 |
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3 |
Virus Offense Meets Host Defense: Early Actions |
52 |
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Introduction |
53 |
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Primary Physical and Chemical
Defenses |
54 |
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The First Critical Moments of
Infection |
54 |
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Intrinsic Cellular Defenses |
55 |
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How Do Individual Cells Detect
Foreign Invaders? |
55 |
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Receptor-Mediated Recognition of
Pathogen-Associated Molecules |
55 |
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Cytokines, the Primary Output of
Intrinsic Cell Defense |
59 |
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Interferons, Cytokines of Early Warning and
Action |
61 |
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Apoptosis (Programmed Cell Death) |
72 |
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The Hostile Cytoplasm: Other
Intrinsic Defenses |
78 |
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Autophagy |
78 |
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Epigenetic Silencing |
78 |
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RNA Silencing |
78 |
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Cytosine Deamination
(Apobec,
[Apolipoprotein
B Editing Complex) |
79 |
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Trim (Tripartite Interaction
Motif) Proteins |
79 |
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Perspectives |
80 |
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References |
82 |
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4 |
Immune Defenses |
86 |
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Introduction |
87 |
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Innate and Adaptive Immune
Defenses |
87 |
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The Innate Immune Response |
89 |
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General Features |
89 |
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Sentinel Cells |
89 |
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Natural Killer Cells |
91 |
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Complement |
93 |
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The Inflammatory Response |
97 |
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The Adaptive Immune Response |
99 |
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General Features |
99 |
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Cells of the Adaptive Immune
System |
101 |
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Adaptive Immunity: the Action of
Lymphocytes That Carry Distinct Antigen Receptors |
102 |
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Antigen Presentation and
Activation of Immune Cells |
107 |
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The Cell-Mediated Adaptive
Response |
110 |
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The Antibody Response |
116 |
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The Immune System and the Brain |
120 |
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Immunopathology: Too Much of a Good Thing |
121 |
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Immunopathological Lesions |
121 |
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Viral Infection-Induced Immunosuppression |
124 |
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Systemic: Inflammatory Response
Syndrome |
124 |
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Autoimmune Diseases |
124 |
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Heterologous T-Cell Immunity |
125 |
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Superantigens “Short-Circuit” the Immune
System |
126 |
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Mechanisms Mediated by Free
Radicals |
127 |
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Perspectives |
127 |
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References |
131 |
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5 |
Patterns of Infection |
134 |
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Introduction |
135 |
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Life Cycles and Host Defenses |
135 |
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Mathematics of Growth Correlate
with Patterns of Infection |
136 |
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Acute Infections |
138 |
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Definition and Requirements |
138 |
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Acute Infections Tend To Be
Efficiently Contained and Cleared |
138 |
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Antigenic Variation Provides a
Selective Advantage in Acute Infections |
140 |
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Acute Infections Present Common
Public Health Problems |
141 |
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Persistent Infections |
142 |
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Definition and Requirements |
142 |
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An Ineffective Intrinsic or
Innate Immune Response Can Promote a Persistent Infection |
143 |
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Modulation of the Adaptive
Immune Response Perpetuates a Persistent Infection |
143 |
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Persistent Infections May Be
Established in Tissues with Reduced Immune Surveillance |
147 |
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Persistent Infections May Occur
When Cells of the Immune System Arc Infected |
147 |
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Two Viruses That Cause
Persistent Infections |
148 |
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Measles Virus |
148 |
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Lymphocytic Choriomeningitis
Virus |
149 |
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Latent Infections |
150 |
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General Properties |
150 |
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Herpes Simplex Virus |
150 |
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Epstein-Barr Virus |
156 |
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Slow Infections: Sigurdsson’s
Legacy |
160 |
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Abortive Infections |
160 |
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Transforming Infections |
161 |
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Perspectives |
161 |
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References |
162 |
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6 |
Human Immunodeficiency Virus Pathogenesis |
164 |
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Introduction |
165 |
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Worldwide Scope of the Problem |
165 |
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HIV is a Lentivirus |
166 |
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Discovery and Characterization |
166 |
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Distinctive Features of the HIV
Replication Cycle and the Roles of Auxiliary Proteins |
169 |
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Cellular Targets |
176 |
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Routes of Transmission |
177 |
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Sources of Virus Infection |
177 |
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Modes of Transmission |
177 |
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Mechanics of Spread |
179 |
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The Course of Infection |
180 |
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Patterns of Virus Appearance and
Immune Cell Indicators of Infection |
180 |
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Variability of Response to
Infection |
181 |
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Origins of Cellular Immune
Dysfunction |
182 |
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CD4+ T Lymphocytes |
182 |
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Cytotoxic T Lymphocytes |
182 |
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Monocytes and Macrophages |
182 |
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B Cells |
183 |
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Natural Killer Cells |
183 |
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Autoimmunity |
183 |
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Immune Responses to HXV |
184 |
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Humoral Responses |
184 |
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The Cellular Immune Response |
186 |
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Summary: the Critical Balance |
186 |
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Dynamics of HTV-1 Replication in
AIDS Patients |
186 |
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Effects of HIV on Different
Tissues and Organ Systems |
188 |
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Lymphoid Organs |
188 |
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The Nervous System |
188 |
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The Gastrointestinal System |
190 |
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Other Organ Systems |
190 |
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HIV and Cancer |
191 |
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Kaposi’s Sarcoma |
191 |
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B-Cell Lymphomas |
193 |
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Anogenital Carcinomas |
194 |
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Prospects for Treatment and
Prevention |
194 |
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Antiviral Drugs and Therapies |
194 |
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Highly Active Antiretroviral
Therapy |
194 |
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Prophylactic Vaccine Development
To Prevent Infection |
195 |
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Perspectives |
196 |
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References |
197 |
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7 |
Transformation and Oncogenesis |
200 |
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Introduction |
201 |
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Properties of Transformed Cells |
202 |
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Control of Cell Proliferation |
204 |
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Oncogenic Viruses |
207 |
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Discovery of Oncogenic
Viruses |
208 |
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Viral Genetic Information in
Transformed Cells |
212 |
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The Origin and Nature of Viral
Transforming Genes |
217 |
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Functions of Viral Transforming
Proteins |
218 |
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Activation of Cellular Signal
Transduction Pathways by Viral Oncogene Products |
221 |
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Viral Mimics of Cellular
Signaling Molecules |
221 |
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Alteration of the Production or
Activity of Cellular Signal Transduction Proteins |
224 |
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Disruption of Cell Cycle Control
Pathways by Viral Oncogene Products |
230 |
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Abrogation of Restriction Point
Control Exerted by the Rb Protein |
230 |
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Production of Virus-Specific Cyclins |
233 |
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Inactivation of Cyciin-Dependent
Kinase
Inhibitors |
233 |
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Transformed Cells Must Also Grow
and Survive |
234 |
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Integration of Mitogenic
and Growth-Promoting Signals |
234 |
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Mechanisms That Permit Survival
of Transformed Cells |
234 |
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Tumorigenesis Requires Additional Changes in
the Properties of Transformed Cells |
239 |
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Inhibition of Immune Defenses |
240 |
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Other Mechanisms of
Transformation and Oncogenesis by Human Tumor
Viruses |
241 |
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Nontransducing, Complex Oncogenic
Retroviruses: Tumorigenesis with Very Long Latency |
241 |
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Oncogenesis by Hepatitis Viruses |
242 |
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Perspectives |
246 |
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References |
247 |
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8 |
Vaccines |
250 |
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Introduction |
251 |
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The Historical Origins of
Vaccination |
251 |
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Smallpox: a Historical
Perspective |
251 |
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Large-Scale Vaccination Programs
Can Be Dramatically Effective |
253 |
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Vaccine Basics |
256 |
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Immunization Can Be Active or
Passive |
256 |
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Active Vaccines Stimulate Immune
Memory |
256 |
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The Fundamental Challenge |
260 |
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The Science and Art of Making
Vaccines |
261 |
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Basic Approaches |
261 |
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Vaccine Technology |
271 |
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Most Killed and Subunit Vaccines
Rely on Adjuvants
To Stimulate an Immune Response |
271 |
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Delivery |
272 |
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Immunotherapy |
273 |
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The Quest for an AIDS Vaccine |
274 |
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Formidable Challenges |
274 |
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The Central Issues |
275 |
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Perspectives |
275 |
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References |
276 |
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9 |
Antiviral Drugs |
278 |
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Introduction |
279 |
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Paradox? So Much Knowledge, So
Pew Antivirals |
279 |
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Historical Perspective |
281 |
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Discovering Antiviral Compounds |
281 |
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The New Lexicon of Antiviral
Discovery |
281 |
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Screening for Antiviral Compounds |
282 |
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Designer Antivirals
and Computer-Based Searching |
285 |
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The Difference between “R” and
“D” |
287 |
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Examples of Some Approved
Antiviral Drugs |
289 |
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The Search for New Antiviral
Targets |
293 |
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Antiviral Gene Therapy and Transdomioant
Inhibitors |
295 |
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Resistance to Antiviral Drugs |
298 |
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Human Immunodeficiency Virus and
AIDS |
299 |
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Examples of Anti-HIV Drugs |
299 |
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The Combined Problems of
Treating a Persistent Infection and Emergence of Drug Resistance |
303 |
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Combination Therapy |
305 |
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Strategic Treatment Interruption |
307 |
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Challenges and Lessons Learned |
307 |
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Perspectives |
307 |
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References |
308 |
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10 |
Evolution and Emergence |
310 |
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Virus Evolution |
311 |
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The Classic Theory of
Host-Parasite Interactions |
311 |
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How Do Viral Populations Evolve? |
312 |
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The Origin of Viruses |
321 |
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The Fundamental Properties of
Viruses Constrain and Drive Evolution |
330 |
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Emerging Viruses |
333 |
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The Spectrum of Host-Virus
Interactions |
333 |
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Encountering New Hosts:
Fundamental Problems in Ecology |
339 |
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Expanding Viral Niches:
Snapshots of Selected Emerging Viruses |
341 |
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345 |
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Some Emergent Viruses Arc Truly
Novel |
349 |
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A Revolution in Diagnostic
Virology |
350 |
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Perceptions and Possibilities |
350 |
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Infectious Agents and Public
Perceptions |
350 |
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What Next? |
351 |
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Perspectives |
353 |
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References |
354 |
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Appendix A |
Diseases, Epidemiology, and Disease Mechanisms of
Selected Animal Viruses Discussed in this Book |
357 |
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Appendix B |
Unusual Infectious Agents |
385 |
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Glossary |
393 |
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Index |
399 |
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