Introduction to Modern Virology ebook

CONTENTS

Cover

Title Page

Copyright

Preface

About the Companion Website

Part I: The Nature of Viruses

Chapter 1: Towards a Definition of a Virus

1.1 Discovery of Viruses

1.2 Multiplication of Viruses

1.3 The Virus Multiplication Cycle

1.4 Viruses can be Defined in Chemical Terms

1.5 Multiplication of Bacterial and Animal Viruses is Fundamentally Similar

1.6 Viruses can be Manipulated Genetically

1.7 Properties of Viruses

1.8 Origin of Viruses

Key Points

Further Reading

Chapter 2: The Structure of Virus Particles

2.1 Virus Particles are Constructed from Subunits

2.2 The Structure of Filamentous Viruses and Nucleoproteins

2.3 The Structure is of Isometric Virus Particles

2.4 Enveloped (Membrane-Bound) Virus Particles

2.5 Virus Particles with Head-Tail Morphology

2.6 Frequency of Occurrence of Different Virus Particle Morphologies

2.7 Principles of Disassemply: Virus Particles are Metastable

Key Points

Further Reading

Chapter 3: Classification of Viruses

3.1 Classification on the Basis of Disease

3.2 Classification on the Basis of Host Organism

3.3 Classification on the Basis of Virus Particle Morphology

3.4 Classification on the Basis of Viral Nucleic Acids

3.5 Classification on the Basis of Taxonomy

3.6 Satellites, Viroids and Prions

Key Points

Further Reading

Chapter 4: The Evolution of Viruses

4.1 Mechanisms of Virus Evolution

4.2 The Potential for Rapid Evolution: Mutation and Quasispecies

4.3 Rapid Evolution: Recombination

4.4 Rapid Evolution: Reassortment

4.5 Evolution to Find a Host, and Subsequent Co-Evolution with the Host

Key Points

Questions

Further Reading

Chapter 5: Techniques for Studying Viruses

5.1 Culturing Wild Virus Isolates

5.2 Enumeration of Viruses

5.3 Measuring Infectious Virus Titres

5.4 Measuring Physical Virus Titres

5.5 Detecting Virus in a Sample

5.6 Understanding Virus Replication Cycles

5.7 Viral Genetics and Reverse Genetics

5.8 Systems-Level Virology

Key Points

Questions

Further Reading

Part II: Virus Growth in Cells

Chapter 6: The Process of Infection: I. Virus Attachment and Entry into Cells

6.1 Infection of Animal Cells: The Nature and Importance of Receptors

6.2 Infection of Animal Cells: Enveloped Viruses

6.3 Infection of Animal Cells: Non-Enveloped Viruses

6.4 Infection of Plant Cells

6.5 Infection of Bacteria

6.6 Infection of Cells: Post-Entry Events

6.7 Virus Entry: Cell Culture and the Whole Organism

Key Points

Questions

Further Reading

Chapter 7: The Process of Infection: IIA. The Replication of Viral DNA

7.1 The Universal Mechanism of DNA Synthesis

7.2 Replication of Circular Double-Stranded DNA Genomes

7.3 Replication of Linear Double-Stranded DNA Genomes that can Form Circles

7.4 Replication of Linear Double-Stranded DNA Genomes that do not Circularize

7.5 Replication of Single-Stranded Circular DNA Genomes

7.6 Replication of Single-Stranded Linear DNA Genomes

7.7 Dependency versus Autonomy Among DNA Viruses

Key Points

Questions

Further Reading

Chapter 8: The Process of Infection: IIB. Genome Replication in RNA Viruses

8.1 Nature and Diversity of RNA Virus Genomes

8.2 Regulatory Elements for RNA Virus Genome Synthesis

8.3 Synthesis of the RNA Genome of Baltimore Class 3 Viruses

8.4 Synthesis of the RNA Genome of Baltimore Class 4 Viruses

8.5 Synthesis of the RNA Genome of Baltimore Class 5 Viruses

8.6 Synthesis of the RNA Genome of Viroids and Hepatitis Delta Virus

Key Points

Questions

Further Reading

Chapter 9: The Process of Infection: IIC. The Replication of RNA Viruses with a DNA Intermediate and Vice Versa

9.1 The Retrovirus Replication Cycle

9.2 Discovery of Reverse Transcription

9.3 Retroviral Reverse Transcriptase

9.4 Mechanism of Retroviral Reverse Transcription

9.5 Integration of Retroviral DNA into Cell DNA

9.6 Production of Retrovirus Progeny Genomes

9.7 Spumaviruses: Retrovirus with Unusual Features

9.8 The Hepadnavirus Replication Cycle

9.9 Mechanism of Hepadnavirus Reverse Transcription

9.10 Comparing Reverse Transcribing Viruses

Key Points

Questions

Further Reading

Chapter 10: The Process of Infection: IIIA. Gene Expression in DNA Viruses and Reverse-Transcribing Viruses

10.1 The DNA Viruses and Retroviruses: Baltimore Classes 1, 2, 6 and 7

10.2 Polyomaviruses

10.3 Papillomaviruses

10.4 Adenoviruses

10.5 Herpesviruses

10.6 Poxviruses

10.7 Parvoviruses

10.8 Retroviruses

10.9 Hepadnaviruses

10.10 DNA Bacteriophages

Key Points

Questions

Further Reading

Chapter 11: The Process of Infection: IIIB. Gene Expression and its Regulation in RNA Viruses

11.1 The RNA Viruses: Baltimore Classes 3, 4 and 5

11.2 Reoviruses

11.3 Picornaviruses

11.4 Alphaviruses

11.5 Coronaviruses

11.6 Negative Sense RNA viruses with Segmented Genomes

11.7 Orthomyxoviruses

11.8 Arenaviruses

11.9 Negative Sense RNA Viruses with Non-Segmented, Single Stranded Genomes: Rhabdoviruses and Paramyxoviruses

Key Points

Questions

Further Reading

Chapter 12: The Process of Infection: IV. The Assembly of Viruses

12.1 Self-Assembly from Mature Virion Components

12.2 Assembly of Viruses with a Helical Structure

12.3 Assembly of Viruses with an Isometric Structure

12.4 Assembly of Complex Viruses

12.5 Sequence-Dependent and -Independent Packaging of Virus DNA in Virus Particles

12.6 The Assembly of Enveloped Viruses

12.7 Segmented Virus Genomes: The Acquisition of Multiple Nucleic Acid Molecules

12.8 Maturation of Virus Particles

Key Points

Questions

Further Reading

Part III: Virus Interactions with the Whole Organism

Chapter 13: Innate and Intrinsic Immunity

13.1 Innate Immune Responses in Vertebrates – Discovery of Interferon

13.2 Induction of Type 1 Interferon Responses

13.3 Virus Countermeasures to Innate Immunity

13.4 TRIM Proteins and Immunity

13.5 Intrinsic Resistance to Viruses in Vertebrates

13.6 Innate and Intrinsic Immunity and the Outcome of Infection

13.7 RNAi is an Important Antiviral Mechanism in Invertebrates and Plants

13.8 Detecting and Signalling Infection in Invertebrates and Plants

13.9 Virus Resistance Mechanisms in Bacteria and Archaea

Key Points

Questions

References

Chapter 14: The Adaptive Immune Response

14.1 General Features of the Adaptive Immune System

14.2 Cell-Mediated Immunity

14.3 Antibody-Mediated Humoral Immunity

14.4 Virus Evasion of Adaptive Immunity

14.5 Age and Adaptive Immunity

14.6 Interaction Between the Innate and Adaptive Immune Systems

Key Points

Questions

Further Reading

Chapter 15: Interactions between Animal Viruses and Cells

15.1 Acutely Cytopathogenic Infections

15.2 Persistent Infections

15.3 Latent Infections

15.4 Transforming Infections

15.5 Abortive Infections

15.6 Null Infections

15.7 How do Animal Viruses Kill Cells?

Key Points

Questions

Further Reading

Chapter 16: Animal Virus–Host Interactions

16.1 Cause and Effect: Koch's Postulates

16.2 A Classification of Virus–Host Interactions

16.3 Acute Infections

16.4 Subclinical Infections

16.5 Persistent and Chronic Infections

16.6 Latent Infections

16.7 Slowly Progressive Diseases

16.8 Virus-Induced Tumours

Key Points

Questions

Further Reading

Chapter 17: Mechanisms in Virus Latency

17.1 The Latent Interaction of Virus and Host

17.2 Gene Expression and the Lytic and Lysogenic Life of Bacteriophage λ

17.3 Herpes Simplex Virus Latency

17.4 Epstein-Barr Virus Latency

17.5 Latency in Other Herpesviruses

17.6 HIV-1 Latency

Key Points

Questions

Further Reading

Chapter 18: Transmission of Viruses

18.1 Virus Transmission Cycles

18.2 Barriers to Transmission

18.3 Routes of Horizontal Transmission in Animals

18.4 Vertical Transmission

18.5 Vector-Borne Viruses and Zoonotic Transmission

18.6 Epidemiology of Virus Infections

18.7 Sustaining Infection in Populations

Key Points

Questions

Further Reading

Part IV: Viruses and Human Disease

Chapter 19: Human Viral Disease: An Overview

19.1 A Survey of Human Viral Pathogens

19.2 Factors Affecting the Relative Incidence of Viral Disease

19.3 Factors Determining the Nature and Severity of Viral Disease

19.4 Common Signs and Symptoms of Viral Infection

19.5 Acute Viral Infection 1: Gastrointestinal Infections

19.6 Acute Viral Infection 2: Respiratory Infections

19.7 Acute Viral Infection 3: Systemic Spread

19.8 Acute Viral Disease: Conclusions

Key Points

Questions

Further Reading

Chapter 20: Influenza Virus Infection

20.1 The Origins of Human Influenza Viruses

20.2 Influenza Virus Replication

20.3 Influenza Virus Infection and Disease

20.4 Virus Determinants of Disease

20.5 Host Factors in Influenza Virus Disease

20.6 The Immune Response and Influenza Virus

20.7 Anti-Influenza Treatment

Key Points

Questions

Further Reading

Chapter 21: HIV and AIDS

21.1 Origins and Spread of the HIV Pandemic

21.2 Molecular Biology of HIV

21.3 HIV Transmission and Tropism

21.4 Course of HIV Infection: Pathogenesis and Disease

21.5 Immunological Abnormalities during HIV Infection

21.6 Prevention and Control of HIV Infection

Key Points

Questions

Further Reading

Chapter 22: Viral Hepatitis

22.1 The Signs and Symptoms of Hepatitis

22.2 Hepatitis A Virus Infections

22.3 Hepatitis E Virus Infections

22.4 Hepatitis B Virus Infections

22.5 Hepatitis D Virus Infections

22.6 Hepatitis C Virus Infections

Key Points

Questions

Further Reading

Chapter 23: Vector-Borne Infections

23.1 Arboviruses and Their Hosts

23.2 Yellow Fever Virus

23.3 Dengue Virus

23.4 Chikungunya Virus

23.5 West Nile Virus in the USA

Key Points

Questions

Further Reading

Chapter 24: Exotic and Emerging Viral Infections

24.1 Ebola and Marburg Viruses: Emerging Filoviruses

24.2 Hendra and Nipah Viruses: Emerging Paramyxoviruses

24.3 SARS and MERS: Emerging Coronaviruses

24.4 Predicting the Future: Clues from Analysis of the Genomes of Previously Unknown Viruses

Key Points

Questions

Further Reading

Chapter 25: Carcinogenesis and Tumour Viruses

25.1 Immortalization, Transformation and Tumourigenesis

25.2 Oncogenic Viruses

25.3 Polyomaviruses, Papillomaviruses and Adenoviruses: The Small DNA Tumour Viruses as Experimental Models

25.4 Papillomaviruses and Human Cancer

25.5 Polyomaviruses and Human Cancer

25.6 Herpesvirus Involvement in Human Cancers

25.7 Retroviruses as Experimental Model Tumour Viruses

25.8 Retroviruses and Naturally-Occurring Tumours

25.9 Hepatitis Viruses and Liver Cancer

25.10 Prospects for the Control of Virus-Associated Cancers

Key Points

Questions

Further Reading

Chapter 26: Vaccines and Immunotherapy: The Prevention of Virus Diseases

26.1 The Principles of Vaccination

26.2 Whole Virus Vaccines

26.3 Advantages, Disadvantages and Difficulties Associated with Whole Virus Vaccines

26.4 Subunit Vaccines

26.5 Advantages, Disadvantages and Difficulties Associated with Subunit Vaccines

26.6 Considerations for the Generation and Use of Vaccines

26.7 Adverse Reactions and Clinical Complications with Vaccines

26.8 Eradication of Virus Diseases by Vaccination

26.9 Immunotherapy for Virus Infections

26.10 Adverse Reactions and Clinical Complications with Immunotherapy

Key Points

Questions

Further Reading

Chapter 27: Antiviral Therapy

27.1 Scope and Limitations of Antiviral Therapy

27.2 Antiviral Therapy for Herpesvirus Infections

27.3 Antiviral Therapy for Influenza Virus Infections

27.4 Antiviral Therapy for HIV Infections

27.5 Antiviral Therapy for Hepatitis Virus Infections

27.6 Therapy for Other Virus Infections

Key Points

Questions

Further Reading

Chapter 28: Prion Diseases

28.1 The Spectrum of Prion Diseases

28.2 The Prion Hypothesis

28.3 The Aetiology of Prion Diseases

28.4 Prion Disease Pathogenesis

28.5 Bovine Spongiform Encephalopathy (BSE)

28.6 BSE and the Emergence of Variant CJD

28.7 Concerns About Variant CJD in the Future

28.8 Unresolved Issues

Key Points

Questions

Further Reading

Part V: Virology – the Wider Context

Chapter 29: The Economic Impact of Viruses

29.1 The Economics of Virus Infections of Humans

29.2 The Economics of Virus Infections of Animals

29.3 The Economics of Virus Infections of Plants

29.4 The Netherlands Tulip Market Crash

Key Points

Further Reading

Chapter 30: Recombinant Viruses: Making Viruses Work for Us

30.1 Recombinant Viruses as Vaccines

30.2 Recombinant Viruses for Gene Therapy

30.3 Retroviral Vectors for Gene Therapy

30.4 Adenovirus Vectors for Gene Therapy

30.5 Parvovirus Vectors for Gene Therapy

30.6 Oncolytic Viruses for Cancer Therapy

30.7 Recombinant Viruses in the Laboratory

Key Points

Questions

Further Reading

Chapter 31: Viruses: Shaping the Planet

31.1 Virus Infections can Give a Host an Evolutionary Advantage

31.2 Endogenous Retroviruses and Host Biology

31.3 Bacteriophage can be Pathogenicity Determinants for Their Hosts

31.4 Cyanophage Impacts on Carbon Fixation and Oceanic Ecosystems

31.5 Virology and Society: For Good or Ill

Key Points

Questions

Further Reading

Index

End User License Agreement

List of Tables

Table 2.1

Table 2.2

Table 2.3

Table 4.1

Table 6.1

Table 7.1

Table 12.1

Table 14.1

Table 15.1

Table 15.2

Table 15.3

Table 16.1

Table 16.2

Table 17.1

Table 19.1

Table 20.1

Table 20.2

Table 20.3

Table 21.1

Table 22.1

Table 23.1

Table 23.2

Table 24.1

Table 24.2

Table 25.1

Table 26.1

Table 26.2

Table 26.3

Table 28.1

List of Illustrations

Fig. 1.1

Fig. 1.2

Fig. 1.3

Fig. 1.4

Fig. 2.1

Fig. 2.2

Fig. 2.3

Fig. 2.4

Fig 2.5

Fig. 2.6

Fig. 2.7

Fig. 2.8

Fig. 2.9

Fig. 2.10

Fig. 2.11

Fig. 2.12

Fig. 2.13

Fig. 2.14

Fig. 2.15

Fig. 3.1

Fig. 3.2

Fig. 4.1

Fig. 4.2

Fig. 4.3

Fig. 4.4

Fig. 5.1

Fig. 5.2

Fig. 5.3

Fig. 5.4

Fig. 5.5

Fig. 5.6

Fig. 5.7

Fig. 5.8

Fig. 6.1

Fig. 6.2

Fig. 6.3

Fig. 6.4

Fig. 6.5

Fig. 6.6

Fig. 6.7

Fig. 6.8

Fig. 7.1

Fig. 7.2

Fig. 7.3

Fig. 7.4

Fig. 7.5

Fig. 7.6

Fig. 7.7

Fig. 7.8

Fig. 7.9

Fig. 8.1

Fig. 8.2

Fig. 8.3

Fig. 8.4

Fig. 9.1

Fig. 9.2

Fig. 9.3

Fig. 9.4

Fig. 9.5

Fig. 10.1

Fig. 10.2

Fig. 10.3

Fig. 10.4

Fig. 10.5

Fig. 10.6

Fig 10.7

Fig. 10.8

Fig. 10.9

Fig. 10.10

Fig. 11.1

Fig. 11.2

Fig. 11.3

Fig. 11.4

Fig. 11.5

Fig. 11.6

Fig. 11.7

Fig. 11.8

Fig. 11.9

Fig. 11.10

Fig. 11.11

Fig. 11.12

Fig. 11.13

Fig. 12.1

Fig. 12.2

Fig. 12.3

Fig. 12.4

Fig. 12.5

Fig. 12.6

Fig. 12.7

Fig. 12.8

Fig. 12.9

Fig. 13.1

Fig. 13.2

Fig. 13.3

Fig. 13.4

Fig. 14.1

Fig. 14.2

Fig. 14.3

Fig. 14.4

Fig. 14.5

Fig. 14.6

Fig. 15.1

Fig. 15.2

Fig. 15.3

Fig. 16.1

Fig. 16.2

Fig. 16.3

Fig. 16.4

Fig. 17.1

Fig. 17.2

Fig. 17.3

Fig. 17.4

Fig. 17.5

Fig. 17.6

Fig. 18.1

Fig. 18.2

Fig. 18.3

Fig. 18.4

Fig. 18.5

Fig. 19.1

Fig. 19.2

Fig. 19.3

Fig. 19.4

Fig. 19.5

Fig. 20.1

Fig. 20.2

Fig. 20.3

Fig. 20.4

Fig. A

Fig. B

Fig. C

Fig. 20.5

Fig. 20.6

Fig. 21.1

Fig. 21.2

Fig. 21.3

Fig. 21.4

Fig. 21.5

Fig. 21.6

Fig. 21.7

Fig. 22.1

Fig. 22.2

Fig. 22.3

Fig. 22.4

Fig. 22.5

Fig. 22.6

Fig. 23.1

Fig. 23.2

Fig. 23.3

Fig. 23.4

Fig. 23.5

Fig. 23.6

Fig. 23.7

Fig. 24.1

Fig. 24.2

Fig. 24.3

Fig. 25.1

Fig. 25.2

Fig. 25.3

Fig. 25.4

Fig. 25.5

Fig. 26.1

Fig. 26.2

Fig. 26.3

Fig. 26.4

Fig. 26.5

Fig. 26.6

Fig. 26.7

Fig. 27.1

Fig. 27.2

Fig. 27.3

Fig. 27.4

Fig. 27.5

Fig. 27.6

Fig. 27.7

Fig. 27.8

Fig. 28.1

Fig. 28.2

Fig. 28.3

Fig. 28.4

Fig. 28.5

Fig. 28.6

Fig. 28.7

Fig. 29.1

Fig. 29.2

Fig. 29.3

Fig. 29.4

Fig. 30.1

Fig. 30.2

Fig. 30.3

Fig. 30.4

Fig. 31.1

Fig. 31.2

Fig. 31.3

Guide

Cover

Table of Contents

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Part 1

Chapter 1

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Introduction to Modern Virology

Seventh Edition

This edition first published 2016 © 2016 by John Wiley & Sons, Ltd

First to sixth editions © 1974, 1980, 1987, 1994, 2001, 2007 by Blackwell Publishing Ltd

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Library of Congress Cataloging-in-Publication Data

Dimmock, N. J.

Introduction to modern virology / N. J. Dimmock, A. J. Easton, K. N. Leppard, School of Life Sciences, University of Warwick, Coventry. – Seventh edition.

pages cm

Includes index.

ISBN 978-1-119-97810-7 (pbk.)

1. Virology. 2. Virus diseases. I. Easton, A. J. (Andrew J.) II. Leppard, K. N. (Keith N.) III. Title.

QR360.D56 2016

579.2–dc23

2015031818

A catalogue record for this book is available from the British Library.

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Cover design by Jeremy Tilston

Preface

As before, our aim in this 7th edition of Introduction to Modern Virology is to provide a broad introduction to virology, which includes the nature of viruses, the interaction of viruses with their hosts, and the consequences of those interactions that lead to the diseases we see. In doing so, we have focused predominantly on viruses that infect humans, with some examples of viruses of other animals where they illustrate a specific point. However, in the sections covering general principles and processes of virology, we have also included bacterial and plant viruses. The revised text is aimed at undergraduate students at all levels and postgraduates who are learning virology as a new subject.

We have retained the four thematic sections that were introduced in the previous edition. These cover the fundamental nature of viruses, their growth in cells, their interactions with the host organism, and their role as agents of human disease. To complement these, we have added a fifth section that incorporates material relating to virology in a wider context. Each section contains a series of chapters that are typically focused on a topic rather than concentrating on a single virus. Inevitably, some of these topics relate to information in different parts of the book and we have included extensive cross-referencing to allow the reader to explore a broader picture than is possible within a single chapter.

The pace of discovery in the field of virology has continued unabated since the last edition. Our knowledge of the molecular detail of viruses, including their interaction with the host, has increased considerably and continues to grow. We have tried to explore the breadth of this new information while retaining a concise style. Inevitably, this has meant that we have had to choose specific examples while leaving out many others of interest, but we have tried to use examples which demonstrate broad principles as well as specific detail. There is suggested reading for those who want to follow up a subject in more depth.

The study of viruses is as topical and important as ever. The global impact of HIV and chronic hepatitis virus infections continues to be severe and, as we completed this edition, we are seeing hopeful indications of the ending of the most devastating Ebola virus outbreak ever recorded. Beyond these direct impacts on our health, viruses also continue to threaten us through effects on food supplies and our economies. Thus, a good basic understanding of viruses is important for generalists and specialists alike. Our aim in writing this book has been to try to make such understanding as accessible as possible, allowing students across the biosciences spectrum to improve their knowledge of these fascinating entities.

New to this Edition

This edition contains a number of important changes and innovations. A major change has been the expansion of the consideration of immunology which now covers two chapters, one on innate immunity and the other on adaptive immunity. This reflects the growing understanding of the importance of the immune system in determining the outcome of virus infection and the contribution of the immune system to viral diseases. These chapters also consider some of the ways that viruses evade the immune response. The consideration of vaccines and antivirals has been expanded and separated into two new chapters to reflect the importance of these approaches to prevention and treatment. Virus evolution is considered in more detail than previously, and we have added new chapters on viral hepatitis, influenza, vector-borne diseases, and exotic and emerging viral infections. Finally, in the last section we have introduced three new chapters on the broader aspects of the influence of viruses on our lives, focusing on the economic impact of virus infections, the ways we can use viruses in clinical and other spheres, and the impact that viruses have on the planet and almost every aspect of our lives.

The text is supplemented throughout by information boxes of two types. These are now distinguished by different colours. One type of box provides supporting information or additional detail about the subject matter of the chapter while the other provides the experimental evidence by which selected key points were established. The aim is to assist the reader in understanding the facts but to also allow them to appreciate the nature of the evidence that underpins them.

We very much hope that the 7th edition of Introduction to Modern Virology will enrich the virology experience of students and teachers alike.

Finally, we would like express our thanks the staff at Wiley for their generous support throughout the production of this book.

Nigel Dimmock, Andrew Easton and Keith Leppard

University of Warwick, October 2015

About the Companion Website

This book is accompanied by a companion website:

www.wiley.com/go/dimmock/virology

The website includes powerpoints of all figures from the book for downloading

Part IThe Nature of Viruses

1 | Towards a definition of a virus

2 | The structure of virus particles

3 | Classification of viruses

4 | The evolution of viruses

5 | Techniques for studying viruses

Chapter 1Towards a Definition of a Virus

Viruses occur universally, but they can only be detected indirectly. Viruses are obligate intracellular parasites that require a host within which they replicate. Although they are well known for causing disease, most viruses coexist peacefully with their hosts.

Chapter 1 Outline

1.1 Discovery of viruses

1.2 Multiplication of viruses

1.3 The virus multiplication cycle

1.4 Viruses can be defined in chemical terms

1.5 Multiplication of bacterial and animal viruses is fundamentally similar

1.6 Viruses can be manipulated genetically

1.7 Properties of viruses

1.8 Origin of viruses

Viruses are arguably the most ubiquitous and widespread group of organisms on the planet, with every animal, plant and protist species susceptible to infection. The efficiency of replication demonstrated by viruses is such that the infection of a single host can generate more new viruses than there are individuals in the host population. For example, a single human infected with influenza virus can shed sufficient virus particles to be theoretically capable of infecting the entire human population. While not every species has been examined for the presence of viruses, those that have been tested have all yielded up new virus isolates. Further, not only do viruses occur universally but each species has its own specific range of viruses that, by and large, infects only that species. In recent years, the application of new nucleic acid sequencing techniques has demonstrated that a vast array of previously unknown viruses remains to be studied.

Current estimates of the number of individual viruses on earth suggest that they considerably exceed the total number of stars in the known universe, i.e. more than 1023 (100 sextillion). This vast number raises questions as to what the viruses are doing there, and what selective advantage, if any, they afford to the species that host them. The answer to the first of these is the same as if the question was posed about any organism – it is simply occupying a particular environmental niche which, in the case of a virus, is another species. The answer to whether or not any benefit accrues for hosting a virus is usually not known, though the adverse effects of virus infections are all too well known. However, it is clear that, despite their adverse effects and the dramatic depictions of viruses in popular media and cinema, viruses have not made their hosts extinct.

1.1 Discovery of Viruses

Although much is known about viruses (Box 1.1), it is instructive and interesting to consider how this knowledge came about. It was only just over 100 years ago, at the end of the 19th century, that the germ theory of disease was formulated, and pathologists were then confident that a causative micro-organism would be found for each infectious disease. Further, they believed that these agents of disease could be seen with the aid of a microscope, could be cultivated on a nutrient medium, and could be retained by filters. There were, admittedly, a few organisms which were so fastidious that they could not be cultivated in the laboratory but the other two criteria were satisfied. However, in 1892, Dmitri Iwanowski was able to show that the causal agent of a mosaic disease of tobacco plants, manifesting as a discoloration of the leaf, passed through a bacteria-proof filter, and could not be seen or cultivated. Iwanowski was unimpressed by his discovery, but Beijerinck repeated the experiments in 1898, and became convinced that this represented a new form of infectious agent which he termed contagium vivum fluidum, what we now know as a virus. In the same year, Loeffler and Frosch came to the same conclusion regarding the cause of foot-and-mouth disease. Furthermore, because foot-and-mouth disease could be passed from animal to animal, with great dilution at each passage, the causative agent had to be reproducing and thus could not be a bacterial toxin. Viruses of other animals were soon discovered. Ellerman and Bang reported the cell-free transmission of chicken leukaemia in 1908, and in 1911 Rous discovered that solid tumours of chickens could be transmitted by cell-free filtrates. These were the first indications that some viruses can cause cancer (see Chapter 25).

Box 1.1 Properties Common to All Viruses

Viruses have a nucleic acid genome of either DNA or RNA.

Compared with a cell genome, viral genomes are small, but genomes of different viruses range in size by over 100-fold (ca 3000 nt to 1,200,000 bp)

Small genomes make small particles – again with a 100-fold size range.

Viral genomes are associated with protein that at its simplest forms the virus particle, but in some viruses this nucleoprotein is surrounded by further protein or a lipid bilayer.

The outermost proteins of the virus particle allow the virus to recognise the correct host cell and gain entry.

Viruses can only reproduce in living cells: they are obligate parasites.

Finally, bacterial viruses were discovered. In 1915, Twort published an account of a glassy transformation of micrococci. He had been trying to culture the smallpox agent on agar plates but the only growth obtained was that of some contaminating micrococci. Following prolonged incubation, some of the colonies took on a glassy appearance, and once this occurred no bacteria could be subcultured from the affected colonies. If some of the glassy material was added to normal colonies, they too took on a similar appearance, even if the glassy material was first passed through very fine filters to exclude all but the smallest material. Among the suggestions that Twort put forward to explain the phenomenon were either the existence of a bacterial virus or the secretion by the bacteria of an enzyme which could lyse the producing cells. This idea of self-destruction by secreted enzymes was to prove a controversial topic over the next decade. In 1917, d'Hérelle observed a similar phenomenon in dysentery bacilli. He observed clear spots on lawns of such cells, and resolved to find an explanation for them. Upon noting the lysis of broth cultures of pure dysentery bacilli by filtered emulsions of faeces, he immediately realized he was dealing with a bacterial virus. Since this virus was incapable of multiplying except at the expense of living bacteria, he called his virus a bacteriophage (literally a bacterium eater), or phage for short.

Thus the first definition of these new agents, the viruses, was presented entirely in negative terms: they could not be seen, could not be cultivated in the absence of cells and, most important of all, were not retained by bacteria-proof filters. However, these features define key characteristics of viruses: they are small parasites that require a host in which they replicate.

1.2 Multiplication of Viruses

Early studies focused on establishing the nature of viruses. d'Hérelle believed that the infecting phage particle multiplied within the bacterium and that its progeny were liberated upon lysis of the host cell, whereas others believed that phage-induced dissolution of bacterial cultures was merely the consequence of a stimulation of lytic enzymes endogenous to the bacteria. Yet another school of thought was that phages could pass freely in and out of bacterial cells and that lysis of bacteria was a secondary phenomenon not necessarily concerned with the growth of a phage. It was Delbruck who ended the controversy by pointing out that two phenomena were involved: lysis from within and lysis from without. The type of lysis observed was dependent on the ratio of infecting phages to bacteria (referred to as the multiplicity of infection). At a low multiplicity of infection (with the ratio of phages to bacteria no greater than 2:1), then the phages infect the cells, multiply and lyse the cells from within. When the multiplicity of infection is high, i.e. many hundreds of phages per bacterium, the cells are lysed directly, and rather than an increase in phage titre there is a decrease. Lysis is due to weakening of the cell wall when large numbers of phages are attached.

Convincing support for d'Hérelle's hypothesis was provided by the one-step growth experiment of Ellis and Delbruck (1939). A phage preparation such as bacteriophage λ (lambda) is mixed with a suspension of the bacterium Escherichia coli at a multiplicity of infection of 10 infectious phage particles per cell, ensuring that virtually all cells are infected. Then, after allowing 5 minutes for the phage to attach, the culture is centrifuged to pellet the cells and attached phage. Medium containing unattached phage is discarded. The cells are then resuspended in fresh medium. Samples of the culture are withdrawn at regular intervals, cells and medium are separated and assayed for infectious phage. The results obtained are shown in Fig. 1.1. After a latent period of 17 minutes during which no phage increase is detected in cell-free medium, there is a sudden rise in the detection of infectious phage in the medium. This ‘burst’ size represents the average of many different bursts from individual cells, and can be calculated from the total virus yield/number of cell infected. The entire growth cycle here takes around 30 minutes, although this will vary with different viruses and cells. The amount of cell-associated virus is determined by taking the cells pelleted from the medium, disrupting them and assaying for virus infectivity as before. The fact that virus appears inside the cells before it appears in the medium demonstrates the intracellular nature of phage replication. It can be seen also that the kinetics of appearance of intracellular phage particles are linear, not exponential. This is consistent with particles being produced by assembly from component parts rather than by binary fission.

Fig. 1.1 A one-step growth curve of bacteriophage λ following infection of susceptible bacteria (Escherichia coli). During the eclipse phase, the infectivity of the cell-associated, infecting virus is lost as it uncoats; during the maturation phase infectious virus is assembled inside cells (cell-associated virus), but not yet released; and the latent phase measures the period before infectious virus is released from cells into the medium. Total virus is the sum of cell-associated virus + released virus. Cell-associated virus decreases as cells are lysed. This classic experiment shows that phages develop intracellularly. A consideration of the methods used to determine the yield of viruses is given in Chapter 5.

1.3 The Virus Multiplication Cycle

We now know a great deal about the processes which occur during the multiplication of viruses within single cells. The precise details vary for individual viruses but have in common a series of events marking specific phases in the multiplication cycle. These phases are summarized in Fig. 1.2 and are considered in detail in Part II of this book. The first stage is that of attachment when the virus attaches to the potential host cell. The interaction is specific, with the virus attachment protein(s) binding to target receptor molecules on the surface of the cell. The initial contact between a virus and host cell is a dynamic, reversible one often involving weak electrostatic interactions. However, the contacts quickly become much stronger with more stable interactions which in some cases are essentially irreversible. The attachment phase determines the specificity of the virus for a particular type of cell or host species. Having attached to the surface of the cell, the virus must effect entry to be able to replicate in a process called penetration or entry. Once inside the cell, the genome of the virus must become available. This is achieved by the loss of many, or all, of the proteins that make up the particle in a process referred to as uncoating. For some viruses, the entry and uncoating phases are combined in a single process. Typically, these first three phases do not require the expenditure of energy in the form of ATP hydrolysis. Having made the virus genome available it is now used in the biosynthesis phase when genome replication, transcription of mRNA and translation of the mRNA into protein occur. The process of translation uses ribosomes provided by the host cell and it is this requirement for the translation machinery, as well as the need for molecules for biosynthesis, that makes viruses obligate intracellular parasites. The newly-synthesized genomes may then be used as templates for further rounds of replication and as templates for transcription of more virus mRNA in an amplification process which increases the yield of virus from the infected cells. When the new genomes are produced, they come together with the newly-synthesized virus proteins to form progeny virus particles in a process called assembly. Finally, the particles must leave the cell in a release phase after which they seek out new potential host cells to begin the process again. The particles produced within the cell may require further processing to become infectious and this maturation phase may occur before or after release.

Fig. 1.2 A diagrammatic representation of the six phases common to all virus multiplication cycles. See text for details.

Combining the consideration of the steps which make up a virus multiplication cycle with the information in the graph of the results of a single step growth curve, it can be seen that during the eclipse phase the virus is undergoing the processes of attachment, entry, uncoating and biosynthesis. At this time, the cells contain all of the elements necessary to produce viruses but the original infecting virus has been dismantled and no new infectious particles have yet been produced. It is only after the assembly step that we see virus particles inside the cell before they are released and appear in the medium.

1.4 Viruses can be Defined in Chemical Terms

The first virus was purified in 1933 by Schlessinger using differential centrifugation. Chemical analysis of the purified bacteriophage showed that it consisted of approximately equal proportions of protein and deoxyribonucleic acid (DNA). A few years later, in 1935, Stanley isolated tobacco mosaic virus in paracrystalline form, and this crystallization of a biological material thought to be alive raised many philosophical questions about the nature of life. In 1937, Bawden and Pirie extensively purified tobacco mosaic virus and showed it to be nucleoprotein containing ribonucleic acid (RNA). Thus virus particles may contain either DNA or RNA. However, at this time it was not known that nucleic acid constituted genetic material.

The Importance of Viral Nucleic Acid

In 1949, Markham and Smith found that preparations of turnip yellow mosaic virus comprised two types of identically sized spherical particles, only one of which contained nucleic acid. Significantly, only the particles containing nucleic acid were infectious. A few years later, in 1952, Hershey and Chase demonstrated the independent functions of viral protein and nucleic acid using the head-tail virus, bacteriophage T2 (Box 1.2).

Box 1.2 Evidence that DNA is the Genetic Material of Bacteriophage T2. The Hershey-Chase Experiment

Bacteriophage T2 was grown in E. coli in the presence of 35S (as sulphate) to label the protein moiety, or 32P (as phosphate) to mainly label the nucleic acid. Purified, labelled phages were allowed to attach to sensitive host cells and then given time for the infection to commence. The phages, still on the outside of the cell, were then subjected to the shearing forces of a Waring blender. Such treatment removes any phage components attached to the outside of the cell but does not affect cell viability. Moreover, the cells are still able to produce infectious progeny virus. When the cells were separated from the medium, it was observed that 75% of the 35S (i.e. phage protein) had been removed from the cells by blending but only 15% of the 32P (i.e. phage nucleic acid) had been removed. Thus, after infection, the bulk of the phage protein appeared to have no further function and this suggested (but does not prove – that had to await more rigorous experiments with purified nucleic acid genomes) that the nucleic acid is the carrier of viral heredity. The transfer of the phage nucleic acid from its protein coat to the bacterial cell upon infection also accounts for the existence of the eclipse period during the early stages of intracellular virus development, since the nucleic acid on its own cannot normally infect a cell (Fig. 1.3).

Fig. 1.3 The Hershey-Chase experiment proving that DNA (labelled with 32P) is the genetic material of bacteriophage T2.

In another classic experiment, Fraenkel-Conrat and Singer (1957) were able to confirm by a different means the hereditary role of viral RNA. Their experiment was based on the earlier discovery that particles of tobacco mosaic virus can be dissociated into their protein and RNA components, and then reassembled to give particles which are morphologically mature and fully infectious (see Chapter 12). When particles of two different strains (differing in the symptoms produced in the host plant) were each disassociated and the RNA of one reassociated with the protein of the other, and vice versa, the properties of the virus which was propagated when the resulting ‘hybrid’ particles were used to infect host plants were always those of the parent virus from which the RNA was derived (Fig. 1.4).

Fig. 1.4 The experiment of Fraenkel-Conrat and Singer which proved that RNA is the genetic material of tobacco mosaic virus.

The ultimate proof that viral nucleic acid is the genetic material came from numerous observations that, under special circumstances, purified viral nucleic acid is capable of initiating infection, albeit with a reduced efficiency. For example, in 1956 Gierer and Schramm, and Fraenkel-Conrat independently showed that the purified RNA of tobacco mosaic virus can be infectious, provided precautions are taken to protect it from inactivation by ribonuclease. An extreme example is the causative agent of potato spindle tuber disease which lacks any protein component and consists solely of RNA. Because such agents have no protein coat, they cannot be called viruses and are referred to as viroids.

Synthesis of Macromolecules in Infected Cells

Following introduction of the virus genetic material into the cell, the next phase of the replication cycle is the synthesis of new macromolecules that play a role in the replication process and/or find their way into the next generation of virus particles. The discovery in 1953, by Wyatt and Cohen, that the DNA of the T-even bacteriophages T2, T4 and T6 contains hydroxymethylcytosine (HMC) instead of cytosine made it possible for Hershey, Dixon and Chase to examine infected bacteria for the presence of phage-specific DNA at various stages of intracellular growth. DNA was extracted from T2-infected E. coli at different times after the onset of phage growth, and analyzed for its content of HMC. This provided an estimate of the number of phage equivalents of HMC-containing DNA present at any time, based on the total nucleic acid and relative HMC content of the intact T2 phage particle. The results showed that, with T2, synthesis of phage DNA commences about 6 minutes after infection and the amount present then rises sharply, so that by the time the first infectious particles begin to appear 6 minutes later there are 50–80 phage equivalents of HMC. Thereafter, the numbers of phage equivalents of DNA and of infectious particles increase linearly and at the same rate up until lysis, and continue to rise even if lysis is delayed beyond the normal burst time.

Hershey and his co-workers also studied the synthesis of phage protein, which can be distinguished from bacterial protein by its interaction with specific antibodies. During infection of E. coli by T2 phage, protein can be detected about 9 minutes after the onset of the latent period, i.e. after DNA synthesis begins and before infectious particles appear. A few minutes later there are approximately 30–40 phages inside the cell. Whereas the synthesis of viral protein starts about 9 minutes after the onset of the latent period, it was shown by means of pulse–chase experiments that the uptake of 35S into intracellular protein is constant from the start of infection. A small quantity (a pulse) of 35S (as sulphate) was added to the medium at different times after infection and was followed shortly after by a vast excess of unlabelled sulphate (chase) to stop any further incorporation of label. When the pulse was made from the 9th minute onward, the label could be chased into material identifiable by its reaction with antibody (i.e. serologically) as phage coat protein. However, if the pulse was made before 9 minutes of infection, although it could still be chased into protein and was non-bacterial, it did not react with antibodies to phage structural proteins. This early protein comprises mainly virus-specified enzymes that are concerned with phage replication but are not incorporated into phage particles. The concept of early and late, non-structural and structural viral proteins is discussed in Chapter 10.

These classical experiments are typical only of head-tail phages (see Section 2.5) infecting E. coli under optimum growth conditions. E. coli is normally found in the anaerobic environment of the intestinal tract, and it is doubtful that it grows with its optimal doubling time of 20 minutes under natural conditions. Other bacterial cells grow more slowly than E. coli and their viruses have longer multiplication cycles.

1.5 Multiplication of Bacterial and Animal Viruses is Fundamentally Similar

The growth curves and other experiments described above have been repeated with many animal viruses with essentially similar results. Both bacterial and animal viruses attach to their target cell through specific interactions with cell surface molecules. Like the T4 bacteriophage, the genomes of some animal viruses (e.g. HIV-1) enter the cell and leave their coat proteins on the outside. However, with most animal viruses, some viral protein, usually from inside the particle, enters the cell in association with the viral genome. In fact, it is now known that some phage protein enters the bacterial cells with the phage genome. Such proteins are essential for genome replication. Many other animal viruses behave slightly differently, and after attachment are engulfed by the cell membrane and taken into the cell inside a vesicle. However, strictly speaking this virus has not yet entered the cell cytoplasm, and is still outside the cell. The virus genome gains entry to the cytoplasm through the wall of the vesicle, when the particle is stimulated to uncoat. Again, the outer virion proteins stay in the vesicle – i.e. outside the cell. Animal viruses go through the same stages of eclipse, and virus assembly from constituent viral components with linear kinetics, as bacterial viruses. Release of progeny virions may happen by cell lysis (although this is not an enzymatic process as it is with some bacterial viruses), but frequently virus is released without major cell damage. The cell may die later, but death of the cell does not necessarily accompany the multiplication of all animal viruses. One major difference in the multiplication of bacterial and animal virus is that of time scale – animal virus growth cycles take in the region of 5–15 hours for completion.

1.6 Viruses can be Manipulated Genetically

One of the easiest ways to understand the steps involved in a particular reaction within an organism is to isolate mutants which are unable to carry out that reaction. Like all other organisms, viruses sport mutants in the course of their growth, and these mutations can affect all properties including the type of plaque formed, the range of hosts which the virus can infect, and the physico-chemical properties of the virus. One obvious caveat is that many mutations will be lethal to the virus and remain undetected. This problem was overcome in 1963 by Epstein and Edgar and their collaborators with the discovery of conditional lethal mutants. One class of these mutants, the temperature-sensitive mutants, was able to grow at a lower temperature than normal, the permissive temperature, but not at a higher, restrictive temperature at which normal virus could grow. Another class of conditional lethal mutants was the amber mutant. In these mutants a genetic lesion converts a codon within transcribed RNA into a triplet which terminates protein synthesis. They can only grow on a permissive host cell, which has an amber-suppressor transfer RNA (tRNA) that can insert an amino acid at the mutation site during translation.

The drawback to conditional lethal mutants is that mutation is random, but the advent of recombinant DNA technology has facilitated controlled mutagenesis, known as reverse genetics, at least for those viruses for which infectious particles can be reconstituted from cloned genomic DNA or cDNA (DNA that has been transcribed from RNA) inserted into a plasmid vector. This process is described in Section 5.7.

1.7 Properties of Viruses

With the assumption that the features of virus growth described above for particular viruses are true of all viruses, it is possible to compare and contrast the properties of viruses with those of their host cells. Whereas host cells contain both types of nucleic acid, DNA and RNA, each virus contains only one type. However, just like their host cells, viruses have their genetic information encoded in nucleic acid. Another difference is that the virus is reproduced solely from its genetic material, whereas the host cell is reproduced from the integrated sum of its components. Thus, the virus never arises directly from a pre-existing virus, whereas the cell always arises by division from a pre-existing cell. The experiments of Hershey and his collaborators showed quite clearly that the components of a virus are synthesized independently and then assembled into many virus particles. In contrast, the host cell increases its constituent parts, during which the individuality of the cell is continuously maintained, and then divides and forms two cells. Finally, viruses are incapable of synthesizing ribosomes, and depend on pre-existing host cell ribosomes for synthesis of viral proteins. These features clearly separate viruses from all other organisms, even Chlamydia species, which for many years were considered to be intermediate between bacteria and viruses.

1.8 Origin of Viruses

The question of the origin of viruses is a fascinating topic; as so often happens when hard evidence is scarce, discussion can be heated but often not illuminating. There are two popular theories: viruses are either degenerate cells or vagrant genes. Just as fleas are descended from flies by loss of wings, viruses may be derived from pro- or eukaryotic cells that have dispensed with many of their cellular functions (degeneracy). Alternatively, some nucleic acid might have been transferred accidentally into a cell of a different species (e.g. through a wound or by sexual contact) and, instead of being degraded as would normally be the case, might have survived and replicated (escape). Despite decades of discussion and argument there are no firm indications if either, or both, of these theories are correct. Rapid sequencing of viral and cellular genomes is now providing data for computer analysis that are giving an ever-better understanding of the relatedness of different viruses. However, while such analyses may identify, or more commonly infer, the progenitors of a virus, they cannot decide between degeneracy and escape. It is unlikely that all currently-known viruses have evolved from a single progenitor. Rather, viruses have probably arisen numerous times in the past by one or both of the mechanisms outlined above.

Key Points

Viruses are obligate intracellular parasites.

It is likely that every living organism on this planet is infected by a species-specific range of viruses.

Viruses multiply by assembling many progeny particles from a pool of virus-specified components, whereas cells multiply by binary fission.

Viruses have probably originated independently many times.

Further Reading

Flint, S. J., Enquist, L. W., Racaniello, V. R., Skalka, A. M. 2008.

Principles of Virology: Molecular Biology, Pathogenesis, and Control

, 3rd edn. ASM Press, Washington DC.

Hull, R. 2013.

Plant Virology

, 5th edn. Academic Press, San Diego.

Knipe, D. M., Howley, P. M. (2007).

Field's Virology

, 5th edn. Lippincott Williams & Wilkins, Philadelphia.

Maclachlan, N. J., Dubovi, E. J. 2010.

Fenner's Veterinary Virology

, 4th edn. Academic Press, San Diego.

Mahy, B. W. J., van Regenmortel, M. H. V. 2008.

Encyclopedia of Virology

, 3rd edn. Academic Press, San Diego.

Richman, D. D., Whitley, R. J., Hayden, F. G. 2009.

Clinical Virology

, 3rd edn. ASM Press, Washington DC.

Zuckerman, A. J., Banatvala, J., Griffiths, P. D., Schoub, B., Mortimer, P. 2009.

Principles and Practice of Clinical Virology

, 6th edn. John Wiley & Sons, Chichester.

Chapter 2The Structure of Virus Particles

All virus genomes are surrounded by proteins which:

protect nucleic acids from nuclease degradation and shearing