Jane Flint is Professor Emerita of Molecular Biology at Princeton University. Dr. Flint's research focused on investigation of the mechanisms by which viral gene products modulate host pathways and antiviral defenses to allow efficient reproduction in normal human cells of adenoviruses, viruses that are used in such therapeutic applications as gene transfer and cancer treatment.

Vincent R. Racaniello is Higgins Professor of Microbiology & Immunology at Columbia University Vagelos College of Physicians & Surgeons. Dr. Racaniello has been studying viruses for over 40 years, including polio- virus, rhinovirus, enteroviruses, hepatitis C virus, and Zika virus. He blogs about virus-es at virology.ws and is host of This Week in Virology.

Glenn F. Rall is a Professor and the Chief Academic Officer at the Fox Chase Cancer Center, and is an Adjunct Professor in the Microbiology and Immunology departments at the University of Pennsylvania, as well as Thomas Jefferson, Drexel, and Temple Universities. Dr. Rall studies viral infections of the brain and the immune responses to those infections, with the goal of defining how viruses contribute to disease.

Theodora Hatziioannou is a Research Associate Professor at Rockefeller University and is actively involved in teaching programs at Albert Einstein College of Medicine. Dr. Hatziioannou has worked on multiple viruses with a focus on retroviruses and the molecular mechanisms that govern virus tropism and on the improvement of animal models for human disease.

Anna Marie Skalka is a Professor Emerita and former Senior Vice President for Basic Research at the Fox Chase Cancer Center. Dr. Skalka is internationally recognized for her contributions to the understanding of the biochemical mechanisms by which retroviruses replicate and insert their genetic material into the host genome, as well as her research into other molecular aspects of retrovirus biology.

Volume 1

Preface

Acknowledgments

About the Authors

PART I: The Science of Virology

1 Foundations

Luria's Credo

Viruses Defined

Why We Study Viruses

Viruses Are Everywhere

Viruses Infect All Living Things

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

Discovery of Viruses

The Defining Properties of Viruses

The Structural Simplicity of Virus Particles

The Intracellular Parasitism of Viruses

Cataloging Animal Viruses

The Classical System

Classification by Genome Type: the Baltimore System

A Common Strategy for Viral Propagation

Perspectives

References

Study Questions

2 The Infectious Cycle

Introduction

The Infectious Cycle

The Cell

Entering Cells

Viral RNA Synthesis

Viral Protein Synthesis

Viral Genome Replication

Assembly of Progeny Virus Particles

Viral Pathogenesis

Overcoming Host Defenses

Cultivation of Viruses

Cell Culture

Embryonated Eggs

Laboratory Animals

Assay of Viruses

Measurement of Infectious Units

Efficiency of Plating

Measurement of Virus Particles

Viral Reproduction: the Burst Concept

The One-Step Growth Cycle

One-Step Growth Analysis: a Valuable Tool for Studying Animal Viruses

Global Analysis

DNA Microarrays

Mass Spectrometry

Protein-Protein Interactions

Single-Cell Virology

Perspectives

References

Study Questions

PART II: Molecular Biology

3 Genomes and Genetics

Introduction

Genome Principles and the Baltimore System

Structure and Complexity of Viral Genomes

DNA Genomes

RNA Genomes

What Do Viral Genomes Look Like?

Coding Strategies

What Can Viral Sequences Tell Us?

The "Big and Small" of Viral Genomes: Does Size Matter?

The Origin of Viral Genomes

Genetic Analysis of Viruses

Classical Genetic Methods

Engineering Mutations into Viral Genomes

Engineering Viral Genomes: Viral Vectors

Perspectives

References

Study Questions

4 Structure

Introduction

Functions of the Virion

Nomenclature

Methods for Studying Virus Structure

Building a Protective Coat

Helical Structures

Capsids with Icosahedral Symmetry

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

Viruses with Envelopes

Viral Envelope Components

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 Particles with Helical or Icosahedral Parts Alternative Architectures

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

Study Questions

5 Attachment and Entry

Introduction

Attachment of Virus Particles to Cells

General Principles

Identification of Receptors for Virus Particles

Virus-Receptor Interactions

Entry into Cells

Virus-induced Signaling via Cell Receptors

Routes of entry

Membrane Fusion

Intracellular Trafficking and Uncoating

Movement of Viral and Subviral Particles within Cells

Uncoating of enveloped viruses

Uncoating of non-enveloped viruses

Import of Viral Genomes into the Nucleus

The Nuclear Pore Complex

Nuclear Localization Signals

Import of RNA Genomes

Import of DNA Genomes

Import of Retroviral Genomes

Perspectives

References

Study Questions

6 Synthesis of RNA from RNA Templates

Introduction

The Nature of the RNA Template

Secondary Structures in Viral RNA

Naked or Nucleocapsid RNA

The RNA Synthesis Machinery

Identification of RNA-Dependent RNA Polymerases

Three-Dimensional Structures of RNA-Dependent RNA Polymerases

Mechanisms of RNA Synthesis

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

Ambisense RNA

Double-Stranded RNA

Unique Mechanisms of mRNA and Genome Synthesis of Hepatitis Delta Satellite Virus

Do Ribosomes and RNA Polymerases Collide?

Origins of Diversity in RNA Virus Genomes

Misincorporation of Nucleotides

Segment Reassortment and RNA Recombination

RNA Editing

Perspectives

References

Study Questions

7 Synthesis of RNA from DNA Templates

Introduction

Properties of Cellular RNA Polymerases That Transcribe Viral DNA

Some Viral Genomes Must Be Converted to Templates Suitable for Transcription

Transcription by RNA Polymerase II

Regulation of RNA Polymerase II Transcription

Common Properties of Proteins That Regulate Transcription

Transcription of Viral DNA Templates by the Cellular Machinery Alone

Viral Proteins That Govern Transcription of DNA Templates

Patterns of Regulation

The Human Immunodeficiency Virus Type 1 Tat Protein Autoregulates Transcription

The Transcriptional Cascades of DNA Viruses

Entry into One of Two Alternative Transcriptional Programs

Transcription of Viral Genes by RNA Polymerase III

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

Study Questions

8 Processing

Introduction

Covalent Modification during Viral Pre-mRNA Processing

Capping the 5' Ends of Viral mRNA

Synthesis of 3' Poly(A) Segments of Viral mRNA

Internal Methylation of Adenosine Residues

Splicing of Viral Pre-mRNA

Regulated Processing of Viral Pre-mRNA

Editing of Viral mRNAs

Export of RNAs from the Nucleus

The Cellular Export Machinery Export of Viral mRNA

Posttranscriptional Regulation of Viral or Cellular Gene Expression by Viral Proteins

Temporal Control of Viral Gene Expression

Viral Proteins Can Inhibit Cellular mRNA Production

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

Noncoding RNAs

Small Interfering RNAs and Micro-RNAs

Long Noncoding RNAs

Circular RNAs

Perspectives

References

Study Questions

9 Replication of DNA Genomes

Introduction

DNA Synthesis by the Cellular Replication Machinery

Eukaryotic Replicons

Cellular Replication Proteins

Mechanisms of Viral DNA Synthesis

Lessons from Simian Virus 40

Replication of Other Viral DNA Genomes

Properties of Viral Replication Origins

Recognition of Viral Replication Origins

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

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

Limited Replication of Viral DNA Genomes

Integrated Parvoviral DNA Can Be Replicated as Part of the Cellular Genome

Different Viral Origins Regulate Replication of Epstein-Barr Virus

Limited and Amplifying Replication from a Single Origin: the Papillomaviruses

Origins of Genetic Diversity in DNA Viruses

Fidelity of Replication by Viral DNA Polymerases

Modulation of the DNA Damage Response

Recombination of Viral Genomes

Perspectives

References

Study Questions

10 Reverse Transcription and Integration

Retroviral Reverse Transcription

Discovery

Impact

The Process of Reverse Transcription

General Properties and Structure of Retroviral Reverse Transcriptases

Other Examples of Reverse Transcription

Retroviral DNA Integration

The Pathway of Integration: Integrase-Catalyzed Steps

Integrase Structure and Mechanism

Hepadnaviral Reverse Transcription

A DNA Virus with Reverse Transcriptase

The Process of Hepadnaviral Reverse Transcription

Perspectives

References

Study Questions

11 Protein Synthesis

Introduction

Mechanisms of Eukaryotic Protein Synthesis

General Structure of Eukaryotic mRNA

The Translation Machinery

Initiation

Elongation and Termination

The Diversity of Viral Translation Strategies

Polyprotein Synthesis

Leaky Scanning

Reinitiation

StopGo Translation

Suppression of Termination

Ribosomal Frameshifting

Bicistronic mRNAs

Regulation of Translation during Viral Infection

Inhibition of Translation Initiation after Viral Infection

Regulation of eIF4F

Regulation of Poly(A)-Binding Protein Activity

Regulation of eIF3

Interfering with RNA

Stress-Associated RNA Granules

Perspectives

References

Study Questions

12 Intracellular Trafficking

Introduction

Assembly within the Nucleus

Import of Viral Proteins for Assembly

Assembly at the Plasma Membrane

Transport of Viral Membrane Proteins to the Plasma Membrane

Sorting of Viral Proteins in Polarized Cells

Disruption of the Secretory Pathway in Virus-Infected Cells

Signal Sequence-Independent Transport of Viral Proteins to the Plasma Membrane

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

Study Questions

13 Assembly, Release, and Maturation

Introduction

Methods of Studying Virus Assembly and Egress

Structural Studies of Virus Particles

Visualization of...