Оглавление
Jane Flint. Principles of Virology
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
VOLUME I Molecular Biology. PRINCIPLES OF. Virology
About the Instructor Companion Website
Preface
What’s New
Principles Taught in Two Distinct, but Integrated Volumes
Volume I: The Science of Virology and the Molecular Biology of Viruses
Volume II: Pathogenesis, Control, and Evolution
Acknowledgments
About the Authors
Key of Repetitive Elements
PART I The Science of Virology
1 Foundations
LINKS FOR CHAPTER 1
Luria’s Credo
Viruses Defined
Why We Study Viruses. Viruses Are Everywhere
PRINCIPLES Foundations
Viruses Infect All Living Things
BOX 1.1. BACKGROUND. Some astounding numbers
BOX 1.2. DISCUSSION. The first animal virus discovered remains a scourge today
Viruses Can Cause Human Disease
Viruses Can Be Beneficial
Viruses “R” Us
Viruses Can Cross Species Boundaries
Viruses Are Unique Tools To Study Biology
Virus Prehistory
Viral Infections in Antiquity
The First Vaccines
Microorganisms as Pathogenic Agents
BOX 1.3. DISCUSSION. Origin of vaccinia virus
Discovery of Viruses
BOX 1.4. DISCUSSION. New methods amend Koch’s principles
The Defining Properties of Viruses
The Structural Simplicity of Virus Particles
The Intracellular Parasitism of Viruses. Organisms as Hosts
Lessons from Bacteriophages
Animal Cells as Hosts
BOX 1.5. EXPERIMENTS. The Hershey-Chase experiment
BOX 1.6. BACKGROUND. Properties of lysogeny shared with animal viruses. Lytic versus Lysogenic Response to Infection
Propagation as a Prophage
Insertional Mutagenesis
Gene Repression and Induction
Transduction of Host Genes
BOX 1.7. TERMINOLOGY. The episome
BOX 1.8. DISCUSSION. Are viruses living entities? What can/can’t they do?
Cataloging Animal Viruses
The Classical System
BOX 1.9. TERMINOLOGY. Complexities of viral nomenclature
Classification by Genome Type: the Baltimore System
BOX 1.10. DISCUSSION. Giant viruses discovered in amoebae
A Common Strategy for Viral Propagation
Perspectives
REFERENCES. Books
STUDY QUESTIONS
2 The Infectious Cycle
LINKS FOR CHAPTER 2
Introduction
The Infectious Cycle
The Cell
PRINCIPLES The infectious cycle
Entering Cells
Viral RNA Synthesis
Viral Protein Synthesis
Viral Genome Replication
Assembly of Progeny Virus Particles
Viral Pathogenesis
BOX 2.1. EXPERIMENTS. In vitro assembly of tobacco mosaic virus
Overcoming Host Defenses
Cultivation of Viruses. Cell Culture. Types of Cell Culture
BOX 2.2. BACKGROUND. The cells of Henrietta Lacks
BOX 2.3. EXPERIMENTS. Zika virus blocks the neuronal road
Evidence of Viral Reproduction in Cultured Cells
BOX 2.4. TERMINOLOGY. In vitro and in vivo
Embryonated Eggs
Laboratory Animals
Assay of Viruses
Measurement of Infectious Units
Plaque Assay
Fluorescent-Focus Assay
BOX 2.5. METHODS. Calculating virus titer from the plaque assay
Infectious-Centers Assay
Transformation Assay
End-Point Dilution Assay
Efficiency of Plating
BOX 2.6. METHODS. End-point dilution assays
Measurement of Virus Particles
Electron Microscopy
Hemagglutination
Centrifugation
Measurement of Viral Enzyme Activity
Serological Methods
BOX 2.7. DISCUSSION. Neutralization antigenic sites
Fluorescent Proteins
Fluorescence Microscopy
Detection of Viral Nucleic Acids
BOX 2.8. EXPERIMENTS. Viral RNA is not infectious virus
BOX 2.9. EXPERIMENTS. Pathogen de-discovery
Viral Reproduction: the Burst Concept
The One-Step Growth Cycle
BOX 2.10. METHODS. How to read a phylogenetic tree
One-Step Growth Analysis: a Valuable Tool for Studying Animal Viruses
BOX 2.11. DISCUSSION. Multiplicity of infection (MOI)
Global Analysis
DNA Microarrays
Mass Spectrometry
Protein-Protein Interactions
Single-Cell Virology
BOX 2.12. WARNING. Determining a role for cellular proteins in viral reproduction can be quite difficult
Perspectives
REFERENCES. Books
Review Articles
Papers of Special Interest
STUDY QUESTIONS
PART II Molecular Biology
3 Genomes and Genetics
LINKS FOR CHAPTER 3
Introduction
Genome Principles and the Baltimore System
Structure and Complexity of Viral Genomes
PRINCIPLES Genomes and Genetics
BOX 3.1. BACKGROUND. What information is encoded in a viral genome?
BOX 3.2. TERMINOLOGY. Important conventions: plus (+) and minus (–) strands
DNA Genomes
Double-Stranded DNA (dsDNA) (Fig. 3.2)
Gapped DNA (Fig. 3.3)
Single-Stranded DNA (ssDNA) (Fig. 3.4)
RNA Genomes
dsRNA (Fig. 3.5)
BOX 3.3. BACKGROUND. RNA synthesis in cells
(+) Strand RNA (Fig. 3.6)
(+) Strand RNA with a DNA Intermediate (Fig. 3.7)
(–) Strand RNA (Fig. 3.8)
What Do Viral Genomes Look Like?
Coding Strategies
What Can Viral Sequences Tell Us?
The “Big and Small” of Viral Genomes: Does Size Matter?
BOX 3.4. EXPERIMENTS. Planaria and mollusks yield the biggest RNA genomes
The Origin of Viral Genomes
Genetic Analysis of Viruses
BOX 3.5. EXPERIMENTS. Origin of segmented RNA virus genomes
Classical Genetic Methods. Mapping Mutations
Functional Analysis
BOX 3.6. METHODS. Spontaneous and induced mutations
BOX 3.7. TERMINOLOGY. What is wild type?
Engineering Mutations into Viral Genomes. Infectious DNA Clones
BOX 3.8. TERMINOLOGY. DNA-mediated transformation and transfection
BOX 3.9. METHODS. Synthesis of infectious horsepox virus from chemically synthesized DNA
Types of Mutation
Introducing Mutations into the Viral Genome
Reversion Analysis
BOX 3.10. TERMINOLOGY. Operations on nucleic acids and proteins
BOX 3.11. DISCUSSION. Is the observed phenotype due to the mutation?
RNA Interference (RNAi)
Targeted Gene Editing with CRISPR-Cas9
Haploid Cell Screening
Engineering Viral Genomes: Viral Vectors
DNA Virus Vectors
RNA Virus Vectors
Perspectives
REFERENCES. Review Articles
Papers of Special Interest
STUDY QUESTIONS
4 Structure
LINKS FOR CHAPTER 4
Introduction
Functions of the Virion
PRINCIPLES Structure
Nomenclature
Methods for Studying Virus Structure
BOX 4.1. METHODS. The development of cryo-electron microscopy, a revolution in structural biology
Building a Protective Coat
Helical Structures
BOX 4.2. METHODS. Nanoconstruction with virus particles
Capsids with Icosahedral Symmetry. General Principles
BOX 4.3. BACKGROUND. The triangulation number, T, and how it is determined
BOX 4.4. EXPERIMENTS. Viral chain mail: not the electronic kind
Structurally Simple Capsids
BOX 4.5. DISCUSSION. Remarkable architectural relationships among viruses with double-stranded DNA genomes
Structurally Sophisticated Capsids
BOX 4.6. EXPERIMENTS. A fullerene cone model of the human immunodeficiency virus type 1 capsid
Other Capsid Architectures
Packaging the Nucleic Acid Genome
Direct Contact of the Genome with a Protein Shell
Packaging by Specialized Viral Proteins
Packaging by Cellular Proteins
BOX 4.7. EXPERIMENTS. A high-resolution view of an encapsidated viral genome
Viruses with Envelopes
Viral Envelope Components
Envelope Glycoproteins
BOX 4.8. DISCUSSION. A viral membrane directly surrounding the genome
Other Envelope Proteins
Simple Enveloped Viruses: Direct Contact of External Proteins with the Capsid or Nucleocapsid
Enveloped Viruses with an Additional Protein Layer
Large Viruses with Multiple Structural Elements
BOX 4.9. DISCUSSION. A virus particle with different structures in different hosts
Particles with Helical or Icosahedral Parts. Bacteriophage T4
BOX 4.10. DISCUSSION. The extreme pleomorphism of influenza A virus, a genetically determined trait of unknown function
Herpesviruses
Mimiviruses
Alternative Architectures
Poxviruses
Pithoviruses
Other Components of Virions
Enzymes
Other Viral Proteins
Cellular Macromolecules
Mechanical Properties of Virus Particles. Investigation of Mechanical Properties of Virus Particles
Stabilization and Destabilization of Virus Particles
Perspectives
REFERENCES. Reviews
Papers of Special Interest
Websites
STUDY QUESTIONS
5 Attachment and Entry
LINKS FOR CHAPTER 5
Introduction
Attachment of Virus Particles to Cells. General Principles
PRINCIPLES Attachment and entry
BOX 5.1. TERMINOLOGY. Is it a receptor or a coreceptor?
Identification of Receptors for Virus Particles
Virus-Receptor Interactions
Nonenveloped Virus Receptor Binding
Alternative Attachment Strategies
Transmembrane Glycoproteins of Enveloped Viruses Mediate Attachment and Entry
Cell Surface Lectins and Spread of Infection
Entry into Cells
Virus-Induced Signaling via Cell Receptors
Routes of Entry
Membrane Fusion
Class I Fusion Proteins
Alternative Fusion Triggers
BOX 5.2. BACKGROUND. Unusual triggers of retroviral fusion proteins
The Membrane Fusion Process
Class II Fusion Proteins
BOX 5.3. EXPERIMENTS. Membrane fusion proceeds through a hemifusion intermediate
BOX 5.4. DISCUSSION. Sex and the fusion protein
Class III Fusion Proteins
Intracellular Trafficking and Uncoating
Movement of Viral and Subviral Particles within Cells
Uncoating of Enveloped Virus Particles. Release of Viral Ribonucleoprotein
Uncoating by Ribosomes in the Cytoplasm
Uncoating of Nonenveloped Viruses. Disrupting the Endosomal Membrane
Forming a Pore in the Endosomal Membrane
Disrupting the Lysosomal Membrane
Import of Viral Genomes into the Nucleus
The Nuclear Pore Complex
Nuclear Localization Signals
Nuclear Import of RNA Genomes
BOX 5.5. BACKGROUND. Transport through the nuclear pore
Nuclear Import of DNA Genomes
Import of Retroviral Genomes
BOX 5.6. DISCUSSION. The bacteriophage DNA injection machine
Perspectives
REFERENCES. Books
Reviews
Papers of Special Interest
STUDY QUESTIONS
6 Synthesis of RNA from RNA Templates
LINKS FOR CHAPTER 6
Introduction
The Nature of the RNA Template. Secondary Structures in Viral RNA
PRINCIPLES Synthesis of RNA from RNA templates
BOX 6.1. TERMINOLOGY. What should we call RNA polymerases and the processes they catalyze?
Naked or Nucleocapsid RNA
The RNA Synthesis Machinery. Identification of RNA-Dependent RNA Polymerases
Three-Dimensional Structures of RNA-Dependent RNA Polymerases
BOX 6.2. BACKGROUND. Two-metal mechanism of catalysis by polymerases
Mechanisms of RNA Synthesis. Initiation
De Novo Initiation
Primer-Dependent Initiation
Capping
Elongation
Functions of Additional Polymerase Domains
RNA Polymerase Oligomerization
Template Specificity
Unwinding the RNA Template
Role of Cellular Proteins
Paradigms for Viral RNA Synthesis
(+) Strand RNA
Synthesis of Nested Subgenomic mRNAs
(−) Strand RNA
BOX 6.3. EXPERIMENTS. Mapping gene order by UV irradiation
Ambisense RNA
Double-Stranded RNA
Unique Mechanisms of mRNA and Genome Synthesis of Hepatitis Delta Virus
BOX 6.4. EXPERIMENTS. Release of mRNA from rotavirus particles
BOX 6.5. BACKGROUND. Ribozymes
Do Ribosomes and RNA Polymerases Collide?
Origins of Diversity in RNA Virus Genomes. Misincorporation of Nucleotides
Segment Reassortment and RNA Recombination
RNA Editing
BOX 6.6. DISCUSSION. RNA recombination leading to the production of pathogenic viruses
Perspectives
REFERENCES. Reviews
Papers of Special Interest
STUDY QUESTIONS
7 Synthesis of RNA from DNA Templates
LINKS FOR CHAPTER 7
Introduction
Properties of Cellular RNA Polymerases That Transcribe Viral DNA. Eukaryotes Have Three Transcriptional Systems
PRINCIPLES Synthesis of RNA from DNA templates
Cellular RNA Polymerases II and III Transcribe Viral Templates
Some Viral Genomes Must Be Converted to Templates Suitable for Transcription
Transcription by RNA Polymerase II
BOX 7.1. EXPERIMENTS. Mapping of a human adenovirus type 2 initiation site and accurate transcription in vitro
Regulation of RNA Polymerase II Transcription
Recognition of Local and Distant Regulatory Sequences
The Simian Virus 40 Enhancer: a Model for Viral and Cellular Enhancers
BOX 7.2. TERMINOLOGY. The idiosyncratic nomenclature for sequence-specific DNA-binding proteins that regulate transcription
BOX 7.3. DISCUSSION. Host cell metabolism can regulate viral enhancers
Common Properties of Proteins That Regulate Transcription
BOX 7.4. EXPERIMENTS. Mechanisms of enhancer action
Transcription of Viral DNA Templates by the Cellular Machinery Alone
Viral Proteins That Govern Transcription of DNA Templates. Patterns of Regulation
BOX 7.5. EXPERIMENTS. Epigenetic silencing of integrated proviral DNAs
The Human Immunodeficiency Virus Type 1 Tat Protein Autoregulates Transcription
Cellular Proteins Recognize the HIV-1 LTR
The Tat Protein Regulates Transcription by Unique Mechanisms
BOX 7.6. WARNING. Caution: transient-expression assays do not reproduce conditions within virus-infected cells
The Transcriptional Cascades of DNA Viruses. Common Strategies Are Executed by Virus-Specific Mechanisms
Examples of Viral Proteins That Stimulate Transcription
BOX 7.7. EXPERIMENTS. In vivo functions of the VP16 acidic activation domain
Coordination of Transcription of Late Genes with Viral DNA Synthesis
BOX 7.8. DISCUSSION. Some potential advantages of temporal regulation of viral gene expression
Entry into One of Two Alternative Transcriptional Programs
BOX 7.9. EXPERIMENTS. Coupling productive transcription of herpes simplex virus late genes to establishment of viral replication forks
BOX 7.10. DISCUSSION. Two bacteriophage lambda repressors govern the outcome of infection
Transcription of Viral Genes by RNA Polymerase III
BOX 7.11. EXPERIMENTS. Partial reversal of repressive histone modification during reactivation of herpes simplex virus type 1 (HSV-1) from latency
The VA-RNA I Promoter
Inhibition of the Cellular Transcriptional Machinery
Unusual Functions of Cellular Transcription Components in Virus-Infected Cells
Viral DNA-Dependent RNA Polymerases
Perspectives
REFERENCES. Reviews
Papers of Special Interest
STUDY QUESTIONS
8 Processing
LINKS FOR CHAPTER 8
Introduction
PRINCIPLES Processing
Covalent Modification during Viral Pre-mRNA Processing. Capping the 5′ Ends of Viral mRNA
Synthesis of Viral 5′ Cap Structures by Cellular Enzymes
BOX 8.1. TRAILBLAZER. Identification of 5′ cap structures on viral mRNAs
Synthesis of Viral 5′ Cap Structures by Viral Enzymes
Acquisition of Viral 5′ Cap Structures from Cellular RNAs
Synthesis of 3′ Poly(A) Segments of Viral mRNA
Polyadenylation of Viral Pre-mRNA by Cellular Enzymes
BOX 8.2. TRAILBLAZER. Identification of poly(A) sequences on viral mRNAs
Polyadenylation of Viral Pre-mRNAs by Viral Enzymes
Internal Methylation of Adenosine Residues. Discovery of Internal Methylation
Stimulation of Viral mRNA Production and Translation
Inhibition of Virus Reproduction
Splicing of Viral Pre-mRNA. Discovery of Splicing
BOX 8.3. TRAILBLAZER. Discovery of the spliced structure of adenoviral major late mRNAs
Mechanism of Splicing
Alternative Splicing
Regulated Processing of Viral Pre-mRNA
BOX 8.4. DISCUSSION. Catalysis of pre-mRNA splicing by RNA
Cellular Differentiation Regulates Production of Papillomaviral Late Pre-mRNAs
Production of Spliced and Unspliced RNAs Essential for Virus Reproduction
Temporal Regulation of Synthesis of Adenoviral Major Late mRNAs
Editing of Viral mRNAs
Editing during mRNA Synthesis
Editing following mRNA Synthesis
BOX 8.5. EXPERIMENTS. RNA editing regulates the cytotoxicity of Ebola viruses
Export of RNAs from the Nucleus
The Cellular Export Machinery
Export of Viral mRNA
The Human Immunodeficiency Virus Type 1 Rev Protein Directs Export of Intron-Containing mRNAs
RNA Signals Can Mediate Export of intron-containing Viral mRNAs by Cellular Proteins
Export of Unspliced Viral mRNAs
BOX 8.6. METHODS. Increasing expression of transgenes in mammalian cells using the woodchuck hepatitis virus posttranscriptional regulatory element
Posttranscriptional Regulation of Viral or Cellular Gene Expression by Viral Proteins
Temporal Control of Viral Gene Expression. Regulation of Alternative Splicing and Polyadenylation by Viral Proteins
BOX 8.7. EXPERIMENTS. A single adenoviral protein controls the early-to-late switch in major late RNA processing
Regulation of mRNA Export
Viral Proteins Can Inhibit Cellular mRNA Production
Inhibition of Polyadenylation and Splicing
Inhibition of Cellular mRNA Export
Regulation of Turnover of Viral and Cellular mRNAs in the Cytoplasm. Intrinsic Turnover
Regulation of mRNA Stability by Viral Proteins
mRNA Stabilization Can Facilitate Transformation
Nonsense-Mediated mRNA Decay
BOX 8.8. DISCUSSION. Coopting a cellular mechanism of RNA degradation leads to viral pathogenesis
BOX 8.9. DISCUSSION. No longer an oddity of herpesviruses: splicing-related noncoding RNAs
Noncoding RNAs
Small Interfering RNAs and Micro-RNAs. Discovery and Synthesis
Cellular miRNAs in Virus-Infected Cells
Viral Micro-RNAs
BOX 8.10. DISCUSSION. A cellular miRNA that protects the hepatitis C virus genome from degradation and promotes its replication
Viral Gene Products That Block RNA Interference
Long Noncoding RNAs
Cellular lncRNAs in Infected Cells
Cellular lncRNAs That Modulate Virus Reproduction
Viral lncRNAs
Circular RNAs
Perspectives
BOX 8.11. EXPERIMENTS. An unusual viral circular RNA, both coding and linked to oncogenesis
REFERENCES. Reviews
Papers of Special Interest
STUDY QUESTIONS
9 Replication of DNA Genomes
LINKS FOR CHAPTER 9
Introduction
PRINCIPLES Replication of DNA genomes
DNA Synthesis by the Cellular Replication Machinery
Eukaryotic Replicons. General Features
BOX 9.1. EXPERIMENTS. Discoveries of primer-independent DNA polymerases: another dogma overturned
BOX 9.2. BACKGROUND. The two mechanisms of synthesis of double-stranded viral DNA molecules
Origins of Cellular Replication
Cellular Replication Proteins. Eukaryotic DNA Polymerases
Other Proteins Required for DNA Synthesis in Mammalian Cells
Mechanisms of Viral DNA Synthesis
Lessons from Simian Virus 40. The Origin of SV40 DNA Replication
Mechanism of SV40 DNA Synthesis
BOX 9.3. EXPERIMENTS. Mapping of the simian virus 40 origin of replication
Replication of Other Viral DNA Genomes
Synthesis of Viral RNA Primers by Cellular or Viral Enzymes
Priming via DNA: Specialized Structures in Viral Genomes
BOX 9.4. EXPERIMENTS. Unwinding of the simian virus 40 origin leads to spooling of DNA
Protein Priming
Properties of Viral Replication Origins
Number of Origins
Viral Replication Origins Share Common Features
BOX 9.5. BACKGROUND. Rolling-circle replication
Recognition of Viral Replication Origins
Properties of Simian Virus 40 LT
Viral Origin Recognition Proteins Share Several Properties
BOX 9.6. EXPERIMENTS. The mechanism by which simian virus 40 LT unwinds and translocates along DNA
Viral DNA Synthesis Machines
Resolution and Processing of Viral Replication Products
Exponential Accumulation of Viral Genomes
Viral Proteins Can Induce Synthesis of Cellular Replication Proteins
Functional Inactivation of the RB Protein
Synthesis of Viral Replication Machines and Accessory Enzymes
Viral DNA Replication Independent of Cellular Proteins
Delayed Synthesis of Structural Proteins Prevents Premature Packaging of DNA Templates
Inhibition of Cellular DNA Synthesis
Synthesis of Viral DNA in Specialized Intracellular Compartments
BOX 9.7. DISCUSSION. Are viral replication foci a universal feature of cells infected by DNA viruses?
Limited Replication of Viral DNA Genomes
Integrated Parvoviral DNA Can Be Replicated as Part of the Cellular Genome
BOX 9.8. BACKGROUND. Ubiquitinylation of proteins
Different Viral Origins Regulate Replication of Epstein-Barr Virus
BOX 9.9. DISCUSSION. Integration into host cell telomeres as a mechanism of herpesvirus latency?
Limited and Amplifying Replication from a Single Origin: the Papillomaviruses
BOX 9.10. EXPERIMENTS. Distinguishing once-per-cell-cycle from random replication of human papillomavirus DNA
Origins of Genetic Diversity in DNA Viruses. Fidelity of Replication by Viral DNA Polymerases. Proofreading Mechanisms
Proofreading by Viral DNA Polymerases
Modulation of the DNA Damage Response
Inhibition of DNA Damage Responses
Differential Impacts on DNA Damage Response Pathways
DNA Damage Responses Essential for Virus Reproduction
Recombination of Viral Genomes. General Mechanisms of Recombination
Origin-Independent, Recombination-Dependent Replication
Viral Genome Recombination
BOX 9.11. DISCUSSION. Replication and recombination/repair are two sides of the same coin: earliest insights from bacteriophage λ
Perspectives
REFERENCES. Reviews
Papers of Special Interest
STUDY QUESTIONS
10 Reverse Transcription and Integration
LINKS FOR CHAPTER 10
Retroviral Reverse Transcription. Discovery
Impact
PRINCIPLES Reverse transcription and integration
BOX 10.1. TRAILBLAZER. Bacteriophage lambda, a paradigm for the joining of retroviral and host DNAs
The Process of Reverse Transcription
Essential Components
BOX 10.2. TERMINOLOGY. Conventions for designating sequences in nucleic acids
BOX 10.3. DISCUSSION. tRNA mimicry and the primer-binding site of human immunodeficiency virus type 1 (HIV-1) genomic RNA
Distinct Steps in Reverse Transcription
BOX 10.4. WARNING
General Properties and Structure of Retroviral Reverse Transcriptases. Domain Structure and Variable Subunit Organization
Catalytic Properties
Structure of RT
Other Examples of Reverse Transcription
BOX 10.5. DISCUSSION. Reverse transcriptase can reverse direction
BOX 10.6. BACKGROUND. Present-day establishment of endogenous retroviruses—a race against time?
Retroviral DNA Integration
The Pathway of Integration: Integrase-Catalyzed Steps
BOX 10.7. BACKGROUND. Model in vitro reactions elucidate catalytic mechanisms of retroviral integrase
Multiple Parameters Govern Selection of Host DNA Target Sites
Other Host Proteins May Affect Integration
Integrase Structure and Mechanism. IN Proteins Are Composed of Three Structural Domains
A Multimeric Form of IN Is Required for Catalysis
Characterization of Intasomes
Hepadnaviral Reverse Transcription. A DNA Virus with Reverse Transcriptase
BOX 10.8. DISCUSSION. A retrovirus with a DNA genome?
Reverse Transcription in the Hepadnaviral Infectious Cycle
The Process of Hepadnaviral Reverse Transcription. Essential Components
Critical Steps in Reverse Transcription
BOX 10.9. DISCUSSION. A single P-protein molecule does it all?
Perspectives
REFERENCES. Books
Landmark Publications and Papers of Special Interest
Hepadnaviral Reverse Transcription
STUDY QUESTIONS
11 Protein Synthesis
LINKS FOR CHAPTER 11
Introduction
Mechanisms of Eukaryotic Protein Synthesis. General Structure of Eukaryotic mRNA
PRINCIPLES Protein synthesis
BOX 11.1. TRAILBLAZER. Viral components of the translational machinery
The Translation Machinery. Ribosomes
tRNAs
Translation Proteins
Initiation
5′-End-Dependent Initiation
5′-End-Independent Initiation
BOX 11.2. TRAILBLAZER. Discovery of the IRES
BOX 11.3. BACKGROUND. Use of the IRES in expression vectors
BOX 11.4. METHODS. Translation in vitro: the reticulocyte lysate and wheat germ extract
Elongation and Termination
The Diversity of Viral Translation Strategies
Polyprotein Synthesis
Leaky Scanning
BOX 11.5. EXPERIMENTS. Raiders of the lost ORF
Reinitiation
StopGo Translation
Suppression of Termination
Ribosomal Frameshifting
Bicistronic mRNAs
Regulation of Translation during Viral Infection
Inhibition of Translation Initiation after Viral Infection. Phosphorylation of eIF2α
Viral Regulation of PKR
Beneficial Effects of eIF2α Phosphorylation on Viral Reproduction
Regulation of eIF4F
Cleavage of eIF4G
Modulation of eIF4E Activity by Phosphorylation
Modulation of eIF4E Activity by Binding Proteins
Modulation of eIF4E by miRNA
A Viral Protein That Replaces eIF4F
A Viral Cap-Binding Protein
Regulation of Poly(A)-Binding Protein Activity
Regulation of eIF3
Interfering with RNA
Modification of Ribosomal Proteins
N6-Methyladenosine Modification of RNA
Stress-Associated RNA Granules
Perspectives
REFERENCES. Review Articles
Papers of Special Interest
STUDY QUESTIONS
12 Intracellular Trafficking
LINKS FOR CHAPTER 12
Introduction
PRINCIPLES Intracellular trafficking
BOX 12.1. DISCUSSION. Getting from point A to point B in heavy traffic
Assembly within the Nucleus
BOX 12.2. BACKGROUND. Cytoskeletal proteins also facilitate virus reproduction in bacteria
BOX 12.3. DISCUSSION. A separation of convenience: transport and assembly of components of virus particles
Import of Viral Proteins for Assembly
Assembly at the Plasma Membrane
BOX 12.4. DISCUSSION. Does host cell architecture shape virus structure?
Transport of Viral Membrane Proteins to the Plasma Membrane
Translocation of Viral Membrane Proteins into the Endoplasmic Reticulum
Reactions within the ER
BOX 12.5. EXPERIMENTS. Viruses with a sweet tooth: autonomous glycosylation of viral proteins
BOX 12.6. DISCUSSION. The evolving sugar “shield” of human immunodeficiency virus type 1
BOX 12.7. DISCUSSION. Overcoming the cellular compartmentalization of oxidation-reduction potential
Vesicular Transport to the Cell Surface
BOX 12.8. TRAILBLAZER. A viral glycoprotein exploited to identify the ER retrotranslocation machinery
BOX 12.9. EXPERIMENTS. Characterizing ER-to-Golgi transport using a temperature-sensitive viral protein
Sorting of Viral Proteins in Polarized Cells
Epithelial Cells
Neurons
Disruption of the Secretory Pathway in Virus-Infected Cells. Inhibition of Transport of Cellular Proteins
Drastic Effects on Compartments of the Secretory Pathway
Induction or Inhibition of the Unfolded Protein Response
Signal Sequence-Independent Transport of Viral Proteins to the Plasma Membrane
Lipid-plus-Protein Signals
Protein Sequence Signals
Interactions with Internal Cellular Membranes
Localization of Viral Proteins to Compartments of the Secretory Pathway
Localization of Viral Proteins to the Nuclear Membrane
Transport of Viral Genomes to Assembly Sites
Transport of Genomic and Pregenomic RNA from the Nucleus to the Cytoplasm
Transport of Genomes from the Cytoplasm to the Plasma Membrane
Perspectives
REFERENCES. Reviews
Papers of Special Interest
STUDY QUESTIONS
13 Assembly, Release, and Maturation
LINKS FOR CHAPTER 13
Introduction
Methods of Studying Virus Assembly and Egress
PRINCIPLES Assembly, release, and maturation
Structural Studies of Virus Particles
Visualization of Assembly and Exit by Microscopy
Biochemical and Genetic Analyses of Assembly Intermediates
BOX 13.1. BACKGROUND. Late steps in T4 assembly
BOX 13.2. METHODS. Assembly of herpes simplex virus 1 nucleocapsids in a simplified system
Methods Based on Recombinant DNA Technology
Assembly of Protein Shells
Formation of Structural Units
Assembly from Individual Proteins
Assembly from Polyproteins
Participation of Cellular and Viral Chaperones
Capsid and Nucleocapsid Assembly
Intermediates in Assembly
BOX 13.3. DISCUSSION. A continuous-assembly mechanism for some large DNA viruses?
Self-Assembly and Assisted Assembly Reactions
Viral and Cellular Components That Regulate Self-Assembly
Viral Scaffolding Proteins: Chaperones for Assembly
Selective Packaging of the Viral Genome and Other Components of Virus Particles. Concerted or Sequential Assembly
BOX 13.4. EXPERIMENTS. Visualization of structural transitions during assembly of DNA viruses
Recognition and Packaging of the Nucleic Acid Genome
Nucleic Acid Packaging Signals
BOX 13.5. DISCUSSION. Sequential or concerted assembly of adenovirus particles?
BOX 13.6. DISCUSSION. Viral terminase motors: powerful nanomachines for pushing DNA into capsids
BOX 13.7. EXPERIMENTS. Dimerization-induced conformational change and encapsidation of the human immunodeficiency virus type 1 genome
Packaging of Segmented Genomes
BOX 13.8. BACKGROUND. Packaging a headful of viral DNA
Incorporation of Enzymes and Other Nonstructural Proteins
Acquisition of an Envelope
Sequential Assembly of Internal Components and Budding from a Cellular Membrane
Coordination of the Assembly of Internal Structures with Acquisition of the Envelope
Release of Virus Particles
Assembly and Budding at the Plasma Membrane
ESCRT-Dependent Budding
ESCRT-Independent Budding
Nonstructural Proteins Can Facilitate Release
Assembly at Internal Membranes: the Problem of Exocytosis. Cytoplasmic Compartments of the Secretory Pathway
Envelopment by a Virus-Specific Mechanism
Intranuclear Assembly
BOX 13.9. EXPERIMENTS. Repulsion of virus particles from infected cells accelerates vaccinia virus spread
Release of Nonenveloped Virus Particles
Maturation of Progeny Virus Particles. Proteolytic Processing of Structural Proteins
BOX 13.10. BACKGROUND. A bacteriophage paradigm for lysis of host cells
Cleavage of Polyproteins
Cleavage of Precursor Proteins
Other Maturation Reactions
BOX 13.11. EXPERIMENTS. A notable example of virus maturation: extracellular assembly of specific structures
Cell-to-Cell Spread
BOX 13.12. BACKGROUND. Extracellular and cell-to-cell spread
BOX 13.13. DISCUSSION. Intercellular transport by plant virus movement proteins
Perspectives
REFERENCES. Reviews
Papers of Special Interest
STUDY QUESTIONS
14 The Infected Cell
LINKS FOR CHAPTER 14
Introduction
Signal Transduction. Signaling Pathways
PRINCIPLES The infected cell
BOX 14.1. TERMINOLOGY. How to interpret illustration of signal transduction cascades in this text
Signaling in Virus-Infected Cells
Activation of Common Signaling Pathways
Infection with a Particular Virus Modulates Multiple Signal Transduction Pathways
BOX 14.2. DISCUSSION. Outcomes of virus infection governed by AKT and mTOR signaling
Gene Expression
Inhibition of Cellular Gene Expression
BOX 14.3. DISCUSSION. A virus infection-induced feedback loop linking mRNA turnover to transcription
BOX 14.4. BACKGROUND. Multiple parameters govern the steady-state concentration of a cellular mRNA
Differential Regulation of Cellular Gene Expression
BOX 14.5. DISCUSSION. Insights into virus-host interactions from RNA profiling studies
BOX 14.6. DISCUSSION. Rewiring host cell networks: viral hub proteins
Metabolism
Methods To Study Metabolism
Glucose Metabolism
BOX 14.7. EXPERIMENTS. Members of the same virus family can exert different effects on metabolism: glycolysis in cells infected by two human herpesviruses
Virus Infection Can Alter the Rate of Glycolysis by Several Mechanisms
Virus Infection Can Redirect the Utilization of Glycolytic Intermediates and Products
BOX 14.8. EXPERIMENTS. Relocation of an ATP-generating enzyme to support viral genome replication
Human Disease Associated with Virus-Induced Alterations in Glucose Metabolism
The Citric Acid Cycle
Enhanced Replenishment of the Citric Acid Cycle by Metabolism of Glutamine
Electron Transport and Oxidative Phosphorylation
BOX 14.9. EXPERIMENTS. Vaccinia virus infection stimulates both synthesis and degradation of long-chain fatty acids
Lipid Metabolism
Regulation of Fatty Acid Oxidation in Virus-Infected Cells
Infection by Several Enveloped Viruses Stimulates Fatty Acid Synthesis
BOX 14.10. DISCUSSION. Dengue virus infection induces autophagy to mobilize fatty acids for energy generation
Reprogramming of Lipid Metabolism in Cells Infected by Nonenveloped Picornaviruses
Remodeling of Cellular Organelles
BOX 14.11. DISCUSSION. Does infection by human adenovirus type 36 contribute to obesity in humans?
The Nucleus
BOX 14.12. EXPERIMENTS. Counting the number of herpesviral genomes that can be expressed and replicated
The Cytoplasm
Cytoplasmic Viral Factories
BOX 14.13. EXPERIMENTS. Examining remodeling of organelles in virus-infected cells
Replication and Assembly Platforms
Other Cytoplasmic Organelles
Perspectives
REFERENCES. Review Articles
Papers of Special Interest
STUDY QUESTIONS
APPENDIX Structure, Genome Organization, and Infectious Cycles of Viruses Featured in This Book. Adenoviruses. Family Adenoviridae
Arenaviruses. Family Arenaviridae
Coronaviruses. Family Coronaviridae
Filoviruses. Family Filoviridae
Flaviviruses. Family Flaviviridae
Hepadnaviruses. Family Hepadnaviridae
Herpesviruses. Family Herpesviridae
Orthomyxoviruses. Family Orthomyxoviridae
Paramyxoviruses. Family Paramyxoviridae
Parvoviruses. Family Parvoviridae
Picornaviruses. Family Picornaviridae
Polyomaviruses. Family Polyomaviridae
Poxviruses. Family Poxviridae
Reoviruses. Family Reoviridae
Retroviruses. Family Retroviridae
Rhabdoviruses. Family Rhabdoviridae
Togaviruses. Family Togaviridae
Glossary
Index. A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z
VOLUME II Pathogenesis and Control. PRINCIPLES OF. Virology
About the Instructor Companion Website
Preface
What’s New
Principles Taught in Two Distinct, but Integrated Volumes
Volume I: The Science of Virology and the Molecular Biology of Viruses
Volume II: Pathogenesis, Control, and Evolution
Acknowledgments
About the Authors
Key of Repetitive Elements
1 Infections of Populations: History and Epidemiology
LINKS FOR CHAPTER 1
Introduction to Viral Pathogenesis
PRINCIPLES Introduction to viral pathogenesis
A Brief History of Viral Pathogenesis. The Relationships among Microbes and the Diseases They Cause
BOX 1.1. DISCUSSION. Why viruses may not fulfill Koch’s postulates
The First Human Viruses Identified and the Role of Serendipity
BOX 1.2. BACKGROUND. Mosquito control measures
New Methods Facilitate the Study of Viruses as Causes of Disease
Viral Epidemics in History
BOX 1.3. METHODS. Nanopore sequencing
Epidemics Shaped History: the 1793 Yellow Fever Epidemic in Philadelphia
Tracking Epidemics by Sequencing: West Nile Virus Spread to the Western Hemisphere
Zoonotic Infections and Epidemics Caused by “New” Viruses
The Economic Toll of Viral Epidemics in Livestock
Population Density and World Travel Are Accelerators of Viral Transmission
Focus on Frontline Health Care: Ebolavirus in Africa
Emergence of a Birth Defect Associated with Infection: Zika Virus in Brazil
Epidemiology
Fundamental Concepts. Incidence versus Prevalence
BOX 1.4. DISCUSSION. Video games model infectious-disease epidemics
Prospective and Retrospective Studies
BOX 1.5. TERMINOLOGY. Morbidity, mortality, incidence, and case fatality
Mortality, Morbidity, and Case Fatality Ratios
R-naught (R0)
Methods Used by Epidemiologists
Surveillance
BOX 1.6. METHODS. The use of statistics in virology
BOX 1.7. BACKGROUND. Descriptive epidemiology and the discovery of human immunodeficiency virus
BOX 1.8. METHODS
Network Theory and Practical Applications
Parameters That Govern the Ability of a Virus to Infect a Population
Geography and Population Density
BOX 1.9. DISCUSSION. A virus on the move
Climate
BOX 1.10. EXPERIMENTS. Temperature influences the transmission of influenza virus
BOX 1.11. BACKGROUND
BOX 1.12. DISCUSSION. Plant virus epidemiology
Perspectives
BOX 1.13. DISCUSSION. This moment in time: the SARS-CoV-2 pandemic
REFERENCES. Books
Review Articles
Papers of Special Interest
STUDY QUESTIONS
2 Barriers to Infection
LINKS FOR CHAPTER 2
Introduction
An Overview of Infection and Immunity. A Game of Chess Played by Masters
PRINCIPLES Barriers to infection
BOX 2.1. TERMINOLOGY. Is it evasion or modulation?
Initiating an Infection
Successful Infections Must Modulate or Bypass Host Defenses
Skin
Respiratory Tract
BOX 2.2. EXPERIMENTS. Dermal damage increases immunity and host survival
BOX 2.3. DISCUSSION. In praise of mucus
Alimentary Tract
BOX 2.4. EXPERIMENTS. Olfactory neurons: front-line sentinels
BOX 2.5. EXPERIMENTS. Commensal bacteria aid virus infections in the gastrointestinal tract
Eyes
Urogenital Tract
Placenta
Viral Tropism
BOX 2.6. DISCUSSION. Is intuition a host defense?
Accessibility of Viral Receptors
Other Host-Virus Interactions That Regulate the Infectious Cycle
BOX 2.7. DISCUSSION. A mechanism for expanding the tropism of influenza virus is revealed by analyzing infections that occurred in 1940
Spread throughout the Host
BOX 2.8. DISCUSSION. Gender differences in infection and disease
Hematogenous Spread
BOX 2.9. TERMINOLOGY. The viruses in your blood
Neural Spread
BOX 2.10. TERMINOLOGY. Infection of the nervous system: definitions and distinctions
Organ Invasion
Entry into Organs with Sinusoids
Entry into Organs That Lack Sinusoids
BOX 2.11. TERMINOLOGY. Which direction: anterograde or retrograde?
Organs with Dense Basement Membranes
Skin
Shedding of Virus Particles
Respiratory Secretions
Saliva
Feces
BOX 2.12. DISCUSSION. A ferret model of influenza virus infection ignites irrational fears
Blood
Urine
Semen
Milk
Skin Lesions
Tears
Perspectives
BOX 2.13. DISCUSSION. Chicken pox parties
REFERENCES. Books
Review Articles
Papers of Special Interest
STUDY QUESTIONS
3 The Early Host Response: Cell-Autonomous and Innate Immunity
LINKS FOR CHAPTER 3
Introduction
PRINCIPLES The early host response: cell-autonomous and innate immunity
BOX 3.1. WARNING. Everything is intertwined
The First Critical Moments: How Do Individual Cells Detect a Virus Infection?
BOX 3.2. TERMINOLOGY. Intrinsic or innate?
Cell Signaling Induced by Viral Entry Receptor Engagement
Receptor-Mediated Recognition of Microbe-Associated Molecular Patterns
Toll-Like Receptors (TLRs)
BOX 3.3. TRAILBLAZER. Toll receptors: the fruit fly connection
BOX 3.4. BACKGROUND. Plants produce proteins that are both “detectors” and “alarms”
RIG-I-Like Receptors (RLRs)
Cytoplasmic DNA Sensors
Viral proteins antagonize pattern recognition receptors
BOX 3.5. EXPERIMENTS. A viral DNA sensor moonlights as a sensor for the RNA virus influenza A virus
Cell-Intrinsic Defenses
Apoptosis (Programmed Cell Death)
BOX 3.6. DISCUSSION. A new function for oncoproteins of DNA tumor viruses
BOX 3.7. TERMINOLOGY. What to do with the second “p”?
Apoptosis Is a Defense against Viral Infection
Viral Gene Products That Modulate Apoptosis
Apoptosis Is Monitored by Sentinel Cells
Programmed Necrosis (Necroptosis)
Autophagy
Epigenetic Silencing
Host Proteins That Restrict Virus Reproduction (Restriction Factors)
Targeting Viral Genomes
BOX 3.8. EXPERIMENTS. Epigenetic silencing of unintegrated retroviral DNA
Deaminases
Targeting Genome Synthesis
Targeting Trafficking of Viral Components
Targeting Release of Virus Particles
Targeting Everything: TRIM, a Family of Divergent Antiviral Proteins
RNA Interference
CRISPRs
The Continuum between Intrinsic and Innate Immunity
Secreted Mediators of the Innate Immune Response
BOX 3.9. BACKGROUND. Ancient mechanisms of immunity
Overview of Cytokine Functions
BOX 3.10. EXPERIMENTS. O-linked sugars as very early warning signals
Interferons, Cytokines of Early Warning and Action
BOX 3.11. TERMINOLOGY. Infiltration and inflammation
BOX 3.12. TRAILBLAZER. The interferon system is crucial for antiviral defense
Type I IFN Synthesis
BOX 3.13. DISCUSSION. A gut feeling about a new interferon type
BOX 3.14. DISCUSSION. Switching IFN-β transcription on and off
IFN Signaling
IFN Produces an Antiviral State
Some IFN-Induced Gene Products and Their Antiviral Actions
RNase L and 2′ -5′ -oligo(A) Synthetases
Regulators of the IFN Response
Viral Gene Products That Counter the IFN Response
Chemokines
The Innate Immune Response
Monocytes, Macrophages, and Dendritic Cells
Complement
The Complement Cascade
BOX 3.15. DISCUSSION. The complement system has four major biological functions
“Natural Antibody” Protects against Infection
Regulation of the Complement Cascade
Natural Killer Cells
NK-Cell Recognition of Infected Cells: Detection of “Missing Self” or “Altered Self” Signals
MHC Class I Receptors on NK Cells Produce Inhibitory Signals
Viral Proteins Modulate NK-Cell Actions
NK-Cell Memory
Other Innate Immune Cells Relevant to Viral Infections
Neutrophils
γδ Cells
Innate Lymphoid Cells
Perspectives
REFERENCES. Books
Reviews
Classic Papers
Selected Papers
STUDY QUESTIONS
4 Adaptive Immunity and the Establishment of Memory
LINKS FOR CHAPTER 4
Introduction
Attributes of the Host Response. Speed
PRINCIPLES Adaptive immunity and the establishment of memory
Diversity and Specificity
Memory
BOX 4.1. TERMINOLOGY. Pathogens, antigens, and epitopes
Self-Control
Lymphocyte Development, Diversity, and Activation
The Hematopoietic Stem Cell Lineage
BOX 4.2. TERMINOLOGY. Leukocytes and lymphocytes
The Two Arms of Adaptive Immunity
The Major Effectors of the Adaptive Response: B and T Cells
B Cells
T Cells
BOX 4.3. METHODS. Flow cytometry
Box 4.4. DISCUSSION. The well-protected thymus
Diverse Receptors Impart Antigen Specificity to B and T Cells
BOX 4.5. DISCUSSION. Convergent evolution of host proteins that bind to viral epitopes
Events at the Site of Infection Set the Stage for the Adaptive Response
Acquisition of Viral Proteins by Professional Antigen-Presenting Cells Enables Production of Proinflammatory Cytokines and Establishment of Inflammation
The Inflammasome and Cytokine Release
Inflammation
Activated Antigen-Presenting Cells Leave the Site of Infection and Migrate to Lymph Nodes
BOX 4.6. BACKGROUND. Infection of the sentinels: dysfunctional immune modulation
Antigen Processing and Presentation. Professional Antigen-Presenting Cells Induce Activation via Costimulation
Presentation of Antigens by Class I and Class II MHC Proteins
Cytotoxic T Cells Recognize Infected Cells by Engaging MHC Class I Receptors
BOX 4.7. TRAILBLAZER. Virology provides Nobel Prize-winning insight: MHC restriction
Th Cells Recognize Professional Antigen-Presenting Cells by Engaging MHC Class II Receptors
Lymphocyte Activation Triggers Massive Cell Proliferation
BOX 4.8. DISCUSSION. Influence of MHC alleles on human partnership and sexual satisfaction
The CTL (Cell-Mediated) Response
CTLs Lyse Virus-Infected Cells
Control of CTL Proliferation
BOX 4.9. BACKGROUND. Interferon γ signaling
BOX 4.10. METHODS. Measuring the antiviral cellular immune response
Control of Infection by CTLs without Killing
Rashes and Poxes
BOX 4.11. DISCUSSION. The immune system within the brain
The Humoral (Antibody) Response. Antibodies Are Made by Plasma Cells
Types and Functions of Antibodies
Virus Neutralization by Antibodies
Antibody-Dependent Cell-Mediated Cytotoxicity: Specific Killing by Nonspecific Cells
Immunological Memory
Perspectives
REFERENCES. Books
Reviews
Classic Papers
Selected Papers
STUDY QUESTION PUZZLE
5 Patterns and Pathogenesis
LINKS FOR CHAPTER 5
Introduction
Animal Models of Human Diseases
PRINCIPLES Patterns and pathogenesis
BOX 5.1. BACKGROUND. A 2,500-year-old smallpox case study
BOX 5.2. WARNING. Of mice and cells
BOX 5.3. METHODS. Genetically engineered mouse models for studying viral pathogenesis
BOX 5.4. WARNING. The dangers of inbreeding
Patterns of Infection
Incubation Periods
Mathematics of Growth Correlate with Patterns of Infection
Acute Infections
BOX 5.5. METHODS. Mathematical approaches to understanding viral population dynamics
BOX 5.6. DISCUSSION. Norovirus: the “two-bucket virus”
BOX 5.7. DISCUSSION. Poliovirus escape antibodies
Acute Infections Pose Common Public Health Problems
Persistent Infections
Multiple Cellular Mechanisms Promote Viral Persistence
Modulation of the Adaptive Immune Response Can Perpetuate a Persistent Infection
Persistent Infections May Be Established in Tissues with Reduced Immune Surveillance
Persistent Infections May Be Established in Cells of the Immune System
Examples of Viruses That Cause Persistent Infections
BOX 5.8. TERMINOLOGY
Latent Infections
Herpes Simplex Virus
BOX 5.9. DISCUSSION. The hygiene hypothesis: why people vary in their response to herpes simplex virus infection
BOX 5.10. DISCUSSION
Epstein-Barr Virus
BOX 5.11. DISCUSSION. Epstein-Barr virus, depression, and pregnancy
Abortive Infections
Transforming Infections
Viral Virulence
Measuring Viral Virulence
BOX 5.12. TERMINOLOGY. Measures of viral virulence
Approaches To Identify Viral Genes That Contribute to Virulence
BOX 5.13. EXPERIMENTS. Viral virulence is dependent on multiple parameters
Viral Virulence Genes
BOX 5.14. TERMINOLOGY. Four classes of viral virulence genes
Gene Products That Alter Virus Reproduction
BOX 5.15. EXPERIMENTS. Inadvertent creation of a more virulent poxvirus
Noncoding Sequences That Affect Virus Reproduction
Gene Products That Modify Host Defense Mechanisms
Gene Products That Enable the Virus To Spread in the Host
BOX 5.16. DISCUSSION
Pathogenesis
Infected Cell Lysis
Immunopathology
Immunopathological Lesions
Superantigens “Short-Circuit” the Immune System
Damage Mediated by Free Radicals
Immunosuppression Induced by Viral Infection
Oncogenesis
Molecular Mimicry
Perspectives
BOX 5.17. EXPERIMENTS. Viral infections promote or protect against autoimmune disease
REFERENCES. Books
Reviews
Papers of Special Interest
STUDY QUESTIONS
6 Cellular Transformation and Oncogenesis
LINKS FOR CHAPTER 6
Introduction
Properties of Transformed Cells. Cellular Transformation
PRINCIPLES Cellular transformation and oncogenesis
BOX 6.1. TERMINOLOGY. Some cancer terms
BOX 6.2. BACKGROUND. Genetic alterations associated with the development of cancer
BOX 6.3. BACKGROUND. Telomeres, telomerase, and cellular immortality
Properties That Distinguish Transformed from Normal Cells
Control of Cell Proliferation. Sensing the Environment
Integration of Mitogenic and Growth-Promoting Signals
Regulation of the Cell Cycle
The Cell Cycle Engine
Oncogenic Viruses
Discovery of Oncogenic Viruses. Retroviruses
BOX 6.4. EXPERIMENTS. A cancer virus with genomic features of both papillomaviruses and polyomaviruses
Oncogenic DNA Viruses
BOX 6.5. DISCUSSION. Walleye dermal sarcoma virus, a retrovirus with a unique transmission cycle
Recent Identification of Oncogenic Viruses
Common Properties of Oncogenic Viruses
Viral Genetic Information in Transformed Cells. State of Viral DNA
BOX 6.6. DISCUSSION. A polyomavirus that contributes to development of Merkel cell carcinoma in humans
Identification and Properties of Viral Transforming Genes
BOX 6.7. TRAILBLAZER. Identification of the transforming proteins of simian virus 40
BOX 6.8. TRAILBLAZER. Preparation of the first oncogene probe
The Origin and Nature of Viral Transforming Genes
Functions of Viral Transforming Proteins
Activation of Cellular Signal Transduction Pathways by Viral Transforming Proteins
Viral Signaling Molecules Acquired from the Cell. The Transduced Cellular Genes of Acutely Transforming Retroviruses
Viral Homologs of Cellular Genes
Alteration of the Production or Activity of Cellular Signal Transduction Proteins. Insertional Activation by Nontransducing Retroviruses
Viral Proteins That Alter Cellular Signaling Pathways
BOX 6.9. DISCUSSION. Transformation by remote control?
Alteration of the Activities of Cellular Signal Transduction Molecules
Disruption of Cell Cycle Control Pathways by Viral Transforming Proteins
Abrogation of Restriction Point Control Exerted by the RB Protein. The Restriction Point in Mammalian Cells
Viral Proteins Prevent Negative Regulation by RB and Related Proteins
Production of Virus-Specific Cyclins
Inactivation of Cyclin-Dependent Kinase Inhibitors
Transformed Cells Increase in Size and Survive
Mechanisms That Permit Survival of Transformed Cells
Viral Inhibitors of the Apoptotic Cascade
Integration of Inhibition of Apoptosis with Stimulation of Proliferation
Inactivation of the Cellular Tumor Suppressor p53
Tumorigenesis Requires Additional Changes in the Properties of Transformed Cells
Inhibition of Immune Defenses
Other Mechanisms of Transformation and Oncogenesis by Human Tumor Viruses
Nontransducing Oncogenic Retroviruses: Tumorigenesis with Very Long Latency
Oncogenesis by Hepatitis Viruses. Hepatitis B Virus
Hepatitis C Virus
Perspectives
REFERENCES. Chapters in Books
Review Articles
Papers of Special Interest
STUDY QUESTIONS
7 Vaccines
LINKS FOR CHAPTER 7
Introduction
The Origins of Vaccination. Smallpox: a Historical Perspective
PRINCIPLES Vaccines
Worldwide Vaccination Programs Can Be Dramatically Effective
Box 7.1. BACKGROUND. Whither the milkmaid?
Eradicating a Viral Disease: Is It Possible?
BOX 7.2. BACKGROUND. The current U.S. smallpox vaccine
BOX 7.3. DISCUSSION. Should laboratory stocks of smallpox virus be destroyed?
BOX 7.4. TRAILBLAZER. Rinderpest virus: the other eradicated virus
National Programs for Eradication of Agriculturally Important Viral Diseases Differ Substantially from Global Programs
BOX 7.5. DISCUSSION. The poliomyelitis eradication effort: should vaccine eradication be next?
Vaccine Basics. Immunization Can Be Active or Passive
Active Vaccination Strategies Stimulate Immune Memory
BOX 7.6. EXPERIMENTS. A historical example that underscores the principle of long-lasting immune memory
Protection from Infection or Protection from Disease?
Vaccines Must Be Safe, Efficacious, and Practical
BOX 7.7. DISCUSSION. The public’s view of risk-taking is a changing landscape
BOX 7.8. DISCUSSION. National vaccine programs depend on public acceptance of their value
BOX 7.9. METHODS. Development of new delivery vehicles for vaccines
The Fundamental Challenge
The Science and Art of Making Vaccines
BOX 7.10. DISCUSSION. Delivering vaccines to people in hard-to-reach locations
BOX 7.11. TERMINOLOGY. Live and let die
Inactivated Virus Vaccines
BOX 7.12. WARNING. Amplification of influenza virus in eggs leads to mutations that limit antigenicity
Attenuated Virus Vaccines
BOX 7.13. BACKGROUND. Shingles vaccines
BOX 7.14. DISCUSSION. Vaccine adverse event reporting
Subunit Vaccines
BOX 7.15. DISCUSSION. Plant-based vaccines
BOX 7.16. DISCUSSION. Accidental infections “in the wild”
Virus-Like Particles
BOX 7.17. TRAILBLAZER. Development of the first anticancer vaccine
Nucleic Acid Vaccines
BOX 7.18. DISCUSSION. Should men be encouraged to get the human papillomavirus vaccine?
Vaccine Technology: Delivery and Improving Antigenicity. Adjuvants Stimulate an Immune Response
Delivery and Formulation
Immunotherapy
The Ongoing Quest for an AIDS Vaccine
Perspectives
REFERENCES. Books
Historical Papers and Books
Reviews
Selected Papers
STUDY QUESTION PUZZLE
8 Antiviral Drugs
LINKS FOR CHAPTER 8
Introduction
A Brief History of Antiviral Drug Discovery
PRINCIPLES Antiviral drugs
Discovering Antiviral Compounds
The Lexicon of Antiviral Discovery
Screening for Antiviral Compounds. Viral targets
Host targets
Mechanism-Based Screens
Cell-Based Screens
High-Throughput Screens
Sources of Chemical Compounds Used in Screening
Computational Approaches to Drug Discovery. Structure-Assisted Drug Design
Genome Sequencing and Other Advances Expose New Targets for Antiviral Drugs
In Silico Drug Discovery via Virtual Screening
BOX 8.1. EXPERIMENTS. An allosteric antiviral by in silico design
The Difference between “R” and “D” Antiviral Drugs Are Expensive To Discover, Develop, and Bring to the Market
BOX 8.2. DISCUSSION. New drugs, new mechanisms—no interest?
BOX 8.3. TERMINOLOGY. Clinical trials
Antiviral Drugs Must Be Safe
Drug Formulation and Delivery
Drug Resistance
Examples of Antiviral Drugs
Inhibitors of Virus Attachment and Entry
BOX 8.4. TERMINOLOGY. What’s in a name?
Maraviroc (Selzentry), Human Immunodeficiency Virus Type 1 Attachment Inhibitor
Enfuvirtide (Fuzeon), Human Immunodeficiency Virus Type 1 Fusion Inhibitor
Amantadine (Symmetrel), Inhibitor of Influenza A Virus Uncoating
Inhibitors of Viral Nucleic Acid Synthesis
Herpesvirus DNA Polymerase Inhibitors
Cidofovir (Vistide), a Broad-Spectrum Antiviral
Azidothymidine (Retrovir), Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor
Lamivudine (Epivir), Hepatitis B Virus Reverse Transcriptase Inhibitor
Ribavirin (Virazole), an Inhibitor of RNA Viruses
Inhibitors of Hepatitis C Virus RNA Polymerase
Nonnucleoside Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase
Foscarnet (Foscavir), Nonnucleoside Inhibitor of Herpesvirus DNA Synthesis
Baloxavir Marboxil (Xofluza), Inhibitor of Influenza Virus mRNA Synthesis
Inhibitors of Hepatitis C Virus NS5A Protein
Inhibitors of Human Immunodeficiency Virus Type 1 Integrase
Inhibition of Viral Polyprotein Processing and Assembly
Human Immunodeficiency Virus Type 1 Protease Inhibitors
Inhibitors of Hepatitis C Virus Protease
Inhibition of Virus Particle Release. Influenza Virus Neuraminidase Inhibitors
Expanding Targets for Antiviral Drug Development
BOX 8.5. EXPERIMENTS. Inhibitors of influenza virus neuraminidase: development and impact
Attachment and Entry Inhibitors
Nucleic Acid-Based Approaches
Proteases and Nucleic Acid Synthesis and Processing Enzymes
Virus Particle Assembly
Microbicides
Two Stories of Antiviral Success
Combination Therapy
BOX 8.6. EXPERIMENTS. Highly specific, designed inhibitors may have unpredicted activities
Challenges Remaining
Perspectives
BOX 8.7. DISCUSSION. What price drugs?
REFERENCES. Books
Reviews
Papers of Special Interest
Websites
STUDY QUESTIONS
9 Therapeutic Viruses
LINKS FOR CHAPTER 9
Introduction
Phage Therapy. History
PRINCIPLES Therapeutic viruses
Some Advantages and Limitations of Phage Therapy
Applications in the Clinic and for Disease Prevention
BOX 9.1. DISCUSSION. Phage therapy rescues dying patient
Future Prospects
Oncolytic Animal Viruses. From Anecdotal Reports to Controlled Clinical Trials
BOX 9.2. WARNING. Before standardization of clinical trials: some early studies of human viruses to treat cancer in humans
BOX 9.3. DISCUSSION. Multiple mechanisms might contribute to the tumor cell-selective reproduction of ONYX-015 and similar viruses
Rational Design of Oncolytic Viruses
Tumor Cell-Selective Reproduction
Strategies for Increasing Cell Lysis
Promoting Antitumor Immune Responses
BOX 9.4. DISCUSSION. An Achilles’ heel of cancer cells
Two Clinically Approved Oncolytic Viruses. Oncorine
BOX 9.5. BACKGROUND. Corporate struggles and the failure to develop ONYX-015 in the United States
Talimogene Laherparepvec
Future Directions
Gene Therapy. Introduction
Retroviral Vectors. Beneficial Features for Gene Therapy
BOX 9.6. WARNING. Fatality in a gene therapy trial
Overcoming the Limitations of First-Generation Vectors
BOX 9.7. WARNING. Inadvertent insertional activation of a cellular gene during gene transfer
Examples of Clinical Success
CAR T Cells for Cancer Immunotherapy
Other Applications of Retroviral Vectors
Adenovirus-Associated Virus Vectors
Developing and Improving AAV Vectors
Clinical Trials
BOX 9.8. EXPERIMENTS. Reconstruction of an ancestral adenovirus-associated virus
Other Applications of AAV Vectors
Future Prospects
Vaccine Vectors
DNA Viruses. Adenovirus Vectors
Poxvirus Vectors
Adenovirus-Associated Virus Vectors
RNA Viruses. Vesicular Stomatitis Virus Vectors
Flaviviruses and Alphaviruses
Newcastle Disease Virus Vectors
Perspectives
REFERENCES. Review Articles
Papers of Special Interest
Blog Posts
STUDY QUESTIONS
10 Virus Evolution
LINKS FOR CHAPTER 10
Virus Evolution
How Do Virus Populations Evolve?
Two General Virus Survival Strategies Can Be Distinguished
PRINCIPLES Evolution
Large Numbers of Viral Progeny and Mutants Are Produced in Infected Cells
RNA Virus Evolution
DNA Virus Evolution
The Quasispecies Concept
Sequence Conservation in Changing Genomes
The Error Threshold
Genetic Bottlenecks
Genetic Shift and Genetic Drift
Exchange of Genetic Information
BOX 10.1. EXPERIMENT. Does Muller’s ratchet ever occur in nature?
Fundamental Properties of Viruses That Constrain Evolution
Two General Pathways for Virus Evolution
BOX 10.2. BACKGROUND. Reassortment of influenza virus genome segments
Evolution of Virulence
BOX 10.3. BACKGROUND. Evolution by nonhomologous recombination and horizontal gene transfer
BOX 10.4. DISCUSSION. An unexpected constraint on evolution: selection for transmission and survival within a host
The Origin of Viruses. When and How Did They Arise?
Evolution of Contemporary Eukaryotic Viruses
RNA Viruses
The Protovirus Hypothesis for Retroviruses and Relatives
DNA Virus Origins
BOX 10.5. BACKGROUND. Discovery of virus giants: the largest known viral particles and genomes
Host-Virus Relationships Drive Evolution
DNA Virus–Host Relationships. Papillomaviruses and Polyomaviruses
Herpesviruses
RNA Virus-Host Relationships
(–) Strand RNA Viruses
(+) Strand RNA Viruses
The Host–Virus “Arms Race”
BOX 10.6. EXPERIMENTS. A classic experiment in virus evolution: deliberate release of rabbitpox virus in Australia
BOX 10.7. EXPERIMENTS. Host-virus arms race and the transferrin receptor
Lessons from Paleovirology
Endogenous Retroviruses
BOX 10.8. EXPERIMENTS. Retrovirus lineage traced to the Paleozoic Era
DNA Fossils Derived from Other RNA Viral Genomes
Endogenous Sequences from DNA Viruses
BOX 10.9. BACKGROUND. Retroviral Env proteins and evolution of the placenta
Short- versus Long-Term Rates of Viral Evolution
Perspectives
BOX 10.10. BACKGROUND. The world’s supply of human immunodeficiency virus genomes provides remarkable opportunity for selection
REFERENCES
Review Articles
Papers of Special Interest
STUDY QUESTIONS
11 Emergence
LINKS FOR CHAPTER 11
The Spectrum of Host-Virus Interactions
Stable Interactions
PRINCIPLES Emergence
The Evolving Host-Virus Interaction
The Dead-End Interaction
The Resistant Host
BOX 11.1. DISCUSSION. An evolving virus infection: the West Nile virus outbreak
Encountering New Hosts: Humans Constantly Provide New Venues for Infection
Common Sources for Animal-to-Human Transmission
BOX 11.2. DISCUSSION. Why do bats harbor so many viruses?
Viral Diseases That Illustrate the Drivers of Emergence. Poliomyelitis: Unexpected Consequences of Modern Sanitation
Introduction of Viruses into Naïve Populations
BOX 11.3. DISCUSSION. Enterovirus D68, a reemerging pathogen associated with childhood paralysis
Hantavirus Pulmonary Syndrome: Changing Animal Populations
Severe Acute and Middle East Respiratory Syndromes (SARS and MERS): Zoonotic Coronavirus Infections
BOX 11.4. DISCUSSION. Zika virus: new patterns of disease?
The Contribution to Emergence of Mutation, Recombination, or Reassortment
Canine Parvoviruses: Cat-to-Dog Host Range Switch by Two Amino Acid Changes
Influenza Epidemics and Pandemics: Escaping the Immune Response by Reassortment
New Technologies Uncover Previously Unrecognized Viruses
Hepatitis Viruses in the Human Blood Supply
BOX 11.5. DISCUSSION. Avian influenza viruses: scientific and societal implications of transmissibility experiments using animal models
A Revolution in Virus Discovery
BOX 11.6. BACKGROUND. Discovery of hepatitis C virus, a triumph of persistence
Perceptions and Possibilities
Virus Names Can Be Misleading
All Viruses Are Important
Can We Predict the Next Viral Pandemic?
BOX 11.7. DISCUSSION. Viral infections as agents of war and terror
Preventing Emerging Virus Infections
Perspectives
REFERENCES. Books
Review Articles
Papers of Special Interest
STUDY QUESTIONS
12 Human Immunodeficiency Virus Type 1 Pathogenesis
LINKS FOR CHAPTER 12
Introduction. Worldwide Impact of AIDS
HIV-1 Is a Lentivirus. Discovery and Characterization
PRINCIPLES HIV-1 pathogenesis
BOX 12.1. DISCUSSION. Lessons from the discovery of the AIDS virus
Distinctive Features of the HIV-1 Reproductive Cycle and the Functions of HIV-1 Proteins
BOX 12.2. TRAILBLAZER. The earliest records of HIV-1 infection
The Regulatory Proteins Tat and Rev
The Accessory Proteins
BOX 12.3. BACKGROUND. Evolution of tetherin antagonism
The Viral Capsid Counters Intrinsic Defense Mechanisms
BOX 12.4. BACKGROUND. Virus tropism and animal models for HIV-1
Entry and Transmission. Entry into the Cell
Entry into the Body
Transmission in Human Populations
The Course of Infection
The Acute Phase
The Asymptomatic Phase
The Symptomatic Phase and AIDS
Effects of HIV-1 on Other Tissues and Organs
Effects of HIV-1 Infection on the Nervous System
Virus Reproduction. Dynamics in the Absence of Treatment
Dynamics of Virus Reproduction during Treatment
Latency
Immune Responses to HIV-1. Innate Response
Humoral Responses
HIV-1 and Cancer
Kaposi′s Sarcoma
B-Cell Lymphomas
Anogenital Carcinomas
Prospects for Treatment and Prevention. Antiviral Drugs
BOX 12.5. BACKGROUND. The Berlin patient
Confronting the Problems of Persistence and Latency
Gene Therapy Approaches
BOX 12.6. DISCUSSION. CCR5 is the target in the first CRISPR-Cas-edited human embryos
Immune System-Based Therapies
Antiviral Drug Prophylaxis. Preexposure Prophylaxis (PrEP)
Postexposure Prophylaxis (PEP)
Perspectives
REFERENCES. Books
Reviews
Research Articles of Historical Interest
Highlights
Websites
STUDY QUESTIONS
13 Unusual Infectious Agents
LINKS FOR CHAPTER 13
Introduction
Viroids
Replication
PRINCIPLES Unusual infectious agents
BOX 13.1. DISCUSSION. Why do viroids infect only plants?
BOX 13.2. DISCUSSION. Viroids and mutation rates
Sequence Diversity
Movement
Pathogenesis
Satellite Viruses and RNAs
Replication
Pathogenesis
Hepatitis Delta Virus
Prions and Transmissible Spongiform Encephalopathies
Scrapie
BOX 13.3. EXPERIMENTS. Hepatitis delta-like viruses in birds and snakes
Physical Properties of the Scrapie Agent
Human TSEs
Hallmarks of TSE Pathogenesis
Prions and the prnp Gene
BOX 13.4. EXPERIMENTS. Detection of Creutzfeldt-Jakob prions in nasal brushings and urine
Prion Strains
BOX 13.5. EXPERIMENTS. Structure of an infectious prion
Bovine Spongiform Encephalopathy
Chronic Wasting Disease
BOX 13.6. EXPERIMENTS. Prions in plants
Treatment of Prion Diseases
Perspectives
REFERENCES. Reviews
Papers of Special Interest
STUDY QUESTIONS
APPENDIX Epidemiology and Pathogenesis of Selected Human Viruses
Adenoviruses
Arenaviruses
Bunyaviruses
Caliciviruses
Coronaviruses
Filoviruses
Flaviviruses
Flaviviruses
Flaviviruses
Hepadnaviruses
Herpesviruses
Herpesviruses
Herpesviruses
Orthomyxoviruses
Papillomaviruses
Paramyxoviruses
Paramyxoviruses
Picornaviruses
Picornaviruses
Picornaviruses
Polyomaviruses
Poxviruses
Reoviruses
Reoviruses
Retroviruses
Retroviruses
Rhabdoviruses
Togaviruses
Togaviruses
Glossary
Index
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