मुख्य Introduction to Modern Virology

Introduction to Modern Virology

, ,

Praised forits clarity of presentation and accessibility, Introduction to Modern Virology has been a successful student text for over 30 years. It provides 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.  This new edition contains a number of important changes and innovations including:

  • The consideration of immunology now covers two chapters, one on innate immunity and the other on adaptive immunity, reflecting the explosion in knowledge of viral interactions with these systems. 
  • The coverage 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 infections in humans are considered in more detail with new chapters on viral hepatitis, influenza, vector-borne diseases, and exotic and emerging viral infections, complementing an updated chapter on HIV.  
  • The final section includes three new chapters on the broader aspects of the influence of viruses on our lives, focussing 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.

A good basic understanding of viruses is important for generalists and specialists alike. The aim of this book is to make such understanding as accessible as possible, allowing students across the biosciences spectrum to improve their knowledge of these fascinating entities.

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This new edition contains a number of important changes and
innovations, including:

• Expanded coverage of immunology, including innate immunity and adaptive immunity,
reflecting the explosion in knowledge of viral interactions with these systems.

• New chapters covering vaccines and antivirals, detailing the importance of these

Nigel Dimmock is an internationally acclaimed virologist who has spent the major part
of his career at the University of Warwick where he is an Emeritus Professor. His main
research interests are influenza virus and antiviral strategies.

Introduction to

A good understanding of viruses is important for students and researchers in all areas
of biology, biotechnology, medicine, public health and related topics. The aim of this
the biosciences spectrum to improve their knowledge of these fascinating entities.

Modern Virology

approaches to prevention and treatment.
• New chapters on viral hepatitis, influenza, vector-borne diseases, and exotic and
emerging viral infections, complementing a comprehensively revised chapter on HIV.
• A revised concluding section covering the influence of viruses on our lives, such as
the economic impact of virus infections, viruses in clinical and other spheres, and the
pervasive impact that viruses have on the planet and our day-to-day existence.

Dimmock, Easton and Leppard

Praised for its clarity of presentation and accessibility,
Introduction to Modern Virology has been a successful
student text for over 30 years. It provides 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 disease.



Seventh Edition

Introduction to



Andrew Easton is a Professor of Virology at the University of Warwick. His research
focuses on the molecular biology and pathogenesis of respiratory viruses, particu; larly
respiratory syncytial virus and influenza virus and the control of translation of virus

Seventh Edition

Keith Leppard is an Associate Professor (Reader) at the University of Warwick. His
research focuses on the molecular cell biology of adenovirus replication and interaction
with the host, particularly innate immunity, and on the development of the virus as a
gene delivery vehicle.


N.J. Dimmock, A.J. Easton and K.N. Leppard
Dimmock_Modern_7e_pbk.indd 1

02/12/2015 09:03

Introduction to
Modern Virology

Introduction to
Modern Virology
N. J. Dimmock
A. J. Easton
K. N. Leppard
School of Life Sciences
University of Warwick


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
Editorial ofﬁces: 9600 Garsington Road, Oxford, OX4 2DQ, UK
111 River Street, Hoboken, NJ 07030-5774, USA
For details of our global editorial ofﬁces, for customer services and for information about how to apply for permission to reuse
the copyright material in this book please see our website at www.wiley.com/wiley-blackwell.
The right of the author to be identiﬁed as the author of this work has been asserted in accordance with the UK Copyright,
Designs and Patents Act 1988.
Designs and Patents Act 1988, without the prior permission of the publisher.
and speciﬁcally disclaim any implied warranties of merchantability or ﬁtness for a particular purpose. It is sold on the
competent professional should be sought.
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
electronic books.
Cover design by Jeremy Tilston
Set in 10/12.5pt MeridienLTStd-Roman by Thomson Digital, Noida, India

1 2016

Contents in brief


About the companion website




Chapter 1
Chapter 2
Chapter 3
Chapter 4
Chapter 5

Towards a deﬁnition of a virus
The structure of virus particles
Classiﬁcation of viruses
The evolution of viruses
Techniques for studying viruses





Chapter 6
Chapter 7
Chapter 8
Chapter 9


Chapter 11
Chapter 12

The process of infection: I. Virus attachment and entry into cells
The process of infection: IIA. The replication of viral DNA
The process of infection: IIB. Genome replication in RNA viruses
The process of infection: IIC. The replication of RNA viruses with a DNA
intermediate and vice versa
The process of infection: IIIA. Gene expression in DNA viruses
and reverse-transcribing viruses
The process of infection: IIIB. Gene expression and its regulation in RNA viruses
The process of infection: IV. The assembly of viruses




Chapter 13
Chapter 14
Chapter 15
Chapter 16
Chapter 17
Chapter 18

Innate and intrinsic immunity
The adaptive immune response
Interactions between animal viruses and cells
Animal virus–host interactions
Mechanisms in virus latency
Transmission of viruses





Chapter 19
Chapter 20
Chapter 21

Human viral disease: an overview
Inﬂuenza virus infection


Chapter 10





Contents in brief

Chapter 22
Chapter 23
Chapter 24
Chapter 25
Chapter 26
Chapter 27
Chapter 28

Viral hepatitis
Vector-borne infections
Exotic and emerging viral infections
Carcinogenesis and tumour viruses
Vaccines and immunotherapy: the prevention of virus diseases
Antiviral therapy
Prion diseases





Chapter 29
Chapter 30
Chapter 31

The economic impact of viruses
Recombinant viruses: making viruses work for us
Viruses: shaping the planet






About the companion website




Chapter 1

Towards a deﬁnition of a virus
Discovery of viruses
Multiplication of viruses
The virus multiplication cycle
Viruses can be deﬁned in chemical terms
Multiplication of bacterial and animal viruses is fundamentally similar
Viruses can be manipulated genetically
Properties of viruses
Origin of viruses
Key points
Further reading


Chapter 2

The structure of virus particles
Virus particles are constructed from subunits
The structure of ﬁlamentous viruses and nucleoproteins
The structure is of isometric virus particles
Enveloped (membrane-bound) virus particles
Virus particles with head-tail morphology
Frequency of occurrence of different virus particle morphologies
Principles of disassemply: virus particles are metastable
Key points
Further reading


Chapter 3

Classiﬁcation of viruses
Classiﬁcation on the basis of disease
Classiﬁcation on the basis of host organism
Classiﬁcation on the basis of virus particle morphology
Classiﬁcation on the basis of viral nucleic acids
Classiﬁcation on the basis of taxonomy
Satellites, viroids and prions
Key points
Further reading






Chapter 4

The evolution of viruses
Mechanisms of virus evolution
The potential for rapid evolution: mutation and quasispecies
Rapid evolution: recombination
Rapid evolution: reassortment
Evolution to ﬁnd a host, and subsequent co-evolution with the host
Key points
Further reading


Chapter 5

Techniques for studying viruses
Culturing wild virus isolates
Enumeration of viruses
Measuring infectious virus titres
Measuring physical virus titres
Detecting virus in a sample
Understanding virus replication cycles
Viral genetics and reverse genetics
Systems-level virology
Key points
Further reading





Chapter 6

Infection of animal cells: the nature and importance of receptors
Infection of animal cells: enveloped viruses
Infection of animal cells: non-enveloped viruses
Infection of plant cells
Infection of bacteria
Infection of cells: post-entry events
Virus entry: cell culture and the whole organism
Key points
Further reading


Chapter 7

The process of infection: IIA. The replication of viral DNA
The universal mechanism of DNA synthesis
Replication of circular double-stranded DNA genomes
Replication of linear double-stranded DNA genomes that can form circles
Replication of linear double-stranded DNA genomes that do not circularize
Replication of single-stranded circular DNA genomes
Replication of single-stranded linear DNA genomes
Dependency versus autonomy among DNA viruses




Key points
Further reading


Chapter 8

The process of infection: IIB. Genome replication in RNA viruses
Nature and diversity of RNA virus genomes
Regulatory elements for RNA virus genome synthesis
Synthesis of the RNA genome of Baltimore class 3 viruses
Synthesis of the RNA genome of Baltimore class 4 viruses
Synthesis of the RNA genome of Baltimore class 5 viruses
Synthesis of the RNA genome of viroids and hepatitis delta virus
Key points
Further reading


Chapter 9

intermediate and vice versa
The retrovirus replication cycle
Discovery of reverse transcription
Retroviral reverse transcriptase
Mechanism of retroviral reverse transcription
Integration of retroviral DNA into cell DNA
Production of retrovirus progeny genomes
Spumaviruses: retrovirus with unusual features
The hepadnavirus replication cycle
Mechanism of hepadnavirus reverse transcription
9.10 Comparing reverse transcribing viruses
Key points
Further reading


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
Further reading


Chapter 10



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
Further reading


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
Further reading





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


Chapter 11

Chapter 12





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
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
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
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
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
Further reading





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
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
Further reading


Chapter 21

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
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
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
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
Further reading


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


Chapter 25





25.9 Hepatitis viruses and liver cancer
25.10 Prospects for the control of virus-associated cancers
Key points
Further reading


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
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
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
Further reading


Chapter 26







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
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
Further reading




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


Part I
The nature of viruses


Towards a deﬁnition of a virus 3
The structure of virus particles 13
Classiﬁcation of viruses 30
The evolution of viruses 39
Techniques for studying viruses 52

Chapter 1

Towards 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

Discovery of viruses
Multiplication of viruses
The virus multiplication cycle
Viruses can be deﬁned in chemical terms
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.

Introduction to Modern Virology, Seventh Edition. N. J. Dimmock, A. J. Easton and K. N. Leppard.
� 2016 John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd.



Part I The nature of viruses

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).
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

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.

Chapter 1 Towards a deﬁnition of a virus

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 bacteriaproof 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
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 cellassociated virus is determined by taking the
cells pelleted from the medium, disrupting


Part I The nature of viruses

1.3 The virus
multiplication cycle

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 (cellassociated 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.

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.

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

Chapter 1 Towards a deﬁnition of a virus


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

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.
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

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

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


Part I The nature of viruses

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).

In another classic experiment, FraenkelConrat 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

Box 1.2
Evidence that DNA is the genetic material of bacteriophage T2. The Hershey-Chase
Bacteriophage T2 was grown in E. coli in the
presence of 35 S (as sulphate) to label the
protein moiety, or 32 P (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 35 S (i.e. phage
protein) had been removed from the cells by
blending but only 15% of the 32 P (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 32 P) is the
genetic material of bacteriophage T2.

Chapter 1 Towards a deﬁnition of a virus


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).
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

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

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

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


Part I The nature of viruses

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 35 S into intracellular protein is
constant from the start of infection. A small
quantity (a pulse) of 35 S (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 virusspeciﬁed 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

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

Chapter 1 Towards a deﬁnition of a virus

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

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.


Part I The nature of viruses

1.8 Origin of viruses

Key points

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




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 virusspeciﬁed 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,
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 2

The structure of virus particles
All virus genomes are surrounded by proteins which:
protect nucleic acids from nuclease degradation and shearing
contain identiﬁcation elements that ensure a virus recognizes an appropriate target cell (but plant
viruses do not, and enter the cell directly by injection or injury)
a genome-release system that ensures that the virus genome is released from a particle only at
the appropriate time and location
• include enzymes that are essential for the infectivity of many, but not all, viruses
• are called structural proteins, as they are part of the virus particle.

Chapter 2 Outline
2.1 Virus particles are constructed from subunits
2.2 The structure of ﬁlamentous viruses and
2.3 The structure 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 disassembly: virus particles
are metastable
All viruses contain protein and nucleic acid with
at least 50%, and in some cases up to 90%, of
their mass being protein. At ﬁrst sight it would
appear that there are many ways in which
proteins could be arranged round the nucleic
acid. However, viruses use only a limited
number of designs. The limitation on the range
of structures is due to restrictions imposed by
the considerations of efﬁciency and stability.

2.1 Virus particles are
constructed from subunits
While proteins may have regular secondary
structure elements in the form of α helix and
β sheet structure, the tertiary structure of
the protein is not symmetrical. This is a
consequence of the fundamental asymmetry of
the amino acid chain making up the protein,
hydrogen bonding, disulphide bridges and the
incorporation of proline in the secondary
structure. Although it may be naïvely thought
that the nucleic acid could be covered by a
single, large protein molecule, this cannot be
the case since proteins are irregular in shape,
whereas most virus particles have a regular
morphology (Fig. 2.1). However, the
requirement for more than a single structural
protein forming the entirety of the virus particle
can also be deduced solely from considerations
of the coding potential of nucleic acid
molecules. A coding triplet has an Mr of




Part I The nature of viruses

Fig. 2.1 Electron micrographs of virus particles
showing their regular shape: rods and spheres.
(a) Tobacco mosaic virus, (b) poliovirus.

approximately 1000 but speciﬁes a single amino
acid with an average Mr of about 100. Thus a
nucleic acid can at best only specify one-tenth
of its mass of protein. Since viruses frequently
contain more than 50% protein by mass, it is
apparent that more than one protein must be
Obviously, less genetic material is required
if a single protein molecule is used as a

repeated subunit. However, it is not essential
that the protein coat be constructed from
identical subunits, provided the combined
molecular weight of the different subunits is
sufﬁciently small in relation to the nucleic acid
molecule which they protect. There is a further
advantage in constructing a virus from subunits,
since any misfolding of protein affects only a
small part of a structural unit. Thus, provided
that faulty subunits are not included in the virus
particle during assembly, an error-free structure
can be constructed with the minimum of
The necessary physical condition for the
stability of any structure is that it is in a state of
minimum free energy, so it can be assumed that
the maximum number of interactions is formed
between the subunits of a virus particle. Since
the subunits themselves are non-symmetrical,
the maximum number of interactions can be
formed only if they are arranged symmetrically,
and there are a limited number of ways this can
be done. Shortly after their seminal work on the
structure of DNA, Watson and Crick predicted
on theoretical grounds that the only two ways
in which asymmetric subunits could be
assembled to form virus particles would
generate structures with either cubic or helical
symmetry. (However, an important rider to the
energy status of virus particles is that at least
some are suspected of being metastable, and
that they can achieve a lower energy state
following interaction with the receptor and
other molecules during the uncoating process
when infecting a cell (see Section 2.7)).

2.2 The structure of
ﬁlamentous viruses and
One of the simplest ways of symmetrically
arranging nonsymmetrical components is to
place them round the circumference of a circle

Chapter 2 The structure of virus particles


factor governing this arrangement (see
Section 12.2). Many nucleoprotein structures
inside enveloped viruses (Fig. 2.14) are
constructed in the same way.

Fig. 2.2 Arrangement of identical asymmetrical
components around the circumference of a circle
to yield a symmetrical arrangement.

to form discs (Fig. 2.2). This gives a 2­
dimensional structure. If a large number of discs
are placed on top of one another, the result is a
‘stacked-disc’ structure. Thus a symmetrical
3-dimensional structure can be generated from
a non-symmetrical component such as protein
and still leave room for nucleic acid.
Examination of electron micrographs of viruses
reveals that some of them have a tubular
structure. One such virus is the tobamovirus,
tobacco mosaic virus (TMV) (Fig. 2.1).
However, closer examination reveals that the
TMV subunits are not arranged cylindrically, i.e.
in rings, but helically. The simplest explanation
for this comes from a consideration of stability.
In a stacked-disc structure the subunits at
different locations would not be identical in
terms of the way that they interact with their
neighbouring subunits. However, by arranging
the subunits helically, the maximum number of
bonds can be formed and each subunit will
interact with its neighbours in exactly the same
way as any other subunit, except, of course, for
those at either end. This is called equivalence of
bonding and it confers enhanced stability to the
structure. Similarly, a helical arrangement
offers greater stability than would be found
with a cylinder which has no linking along the
long axis. All ﬁlamentous viruses so far
examined are helical rather than cylindrical and
the insertion of the nucleic acid may be the

2.3 The structure is of
isometric virus particles
A second way of constructing a symmetrical
particle would be to arrange the smallest
number of subunits possible around the vertices
or faces of an object with cubic symmetry, e.g.
tetrahedron, cube, octahedron, dodecahedron
(constructed from 12 regular pentagons) or
icosahedron (constructed from 20 equilateral
triangles). Figure 2.3 shows possible
arrangements for objects with triangular and
square faces. Multiplying the minimum number
of subunits per face by the number of faces
gives the smallest number of subunits which
can be arranged around such an object. The
minimum number of subunits is determined by
the symmetry element of the face, i.e. a square
face will have four subunits, a triangular face
will have three subunits, etc. Thus, for a
tetrahedron the smallest number of subunits is
12, for a cube or octahedron it is 24 subunits,

Fig. 2.3 Symmetrical arrangement of identical
asymmetrical subunits by placing them on
the faces of objects with cubic symmetry.
(a) Asymmetrical subunits located at vertices of each
triangular facet. (b) Asymmetrical subunits placed at
vertices of each square facet. (c) Arrangement of
asymmetrical subunits placed at each corner of a
cube with faces as represented in (b).


Part I The nature of viruses

and for a dodecahedron or icosahedron it is
60 subunits. Although it may not be
immediately apparent, these represent the few
ways in which an asymmetrical object (such as
a protein molecule) can be placed
symmetrically on the surface of an object
resembling a sphere. (This can be checked by
using a ball and sticking on bits of paper of the
shape shown in Fig. 2.3.) Examination of
electron micrographs reveals that many viruses
appear spherical in outline, but actually have
icosahedral symmetry rather than octahedral,
tetrahedral or cuboidal symmetry. There are
two possible reasons for the selection of
icosahedral symmetry over the others. Firstly,
since it requires a greater number of subunits to
provide a sphere of the same volume, the size of
the repeating subunits can be smaller, thus
economizing on genetic information. Secondly,
there appear to be physical constraints which
prevent the tight packing of subunits required
by tetrahedral and octahedral symmetry.
An unusual virus structure based on an
icosahedron is seen with the geminiviruses. The
particles are formed by two isometric units
combined to form a geminate structure. An
example of a geminate maize streak virus
particle is shown in Fig. 29.3.

Symmetry of an icosahedron
An icosahedron is made up of 20 triangular
faces, ﬁve at the top, ﬁve at the bottom and
10 around the middle, with 12 vertices (Fig.
2.4c). Each triangle is itself symmetrical and so
it can be inserted in any orientation (Fig. 2.4a).
An icosahedron has three axes of symmetry:
ﬁvefold, threefold and twofold (Fig. 2.4b). The
simplest organization is that three capsid
protein molecules form the icosahedral face.
However, many viruses are icosahedral and yet
achieve a much greater size than can apparently
be accomplished with this simple arrangement
(see Box 2.1).

Fig. 2.4 (a) Properties of a regular icosahedron.
Each triangular face is equilateral and has the same
orientation whichever way it is inserted. Axes of
symmetry intersect in the middle of the
icosahedron. There are 12 vertices, which have
ﬁvefold symmetry, meaning that rotation of the
icosahedron by one-ﬁfth of a revolution achieves a
position such that it is indistinguishable from its
starting orientation; each of the 20 faces has a
threefold axis of symmetry and each of the 30 edges
has a twofold axis of symmetry (see (b)). The
icosahedron is built up of ﬁve triangles at the top,
ﬁve at the bottom and a strip of 10 around the
middle (c). (Copyright 1991, from Introduction to
Protein Structure by C. Branden & J. Tooze.
Reproduced by permission of Routledge Inc., part of
The Taylor & Francis Group.).

Chapter 2 The structure of virus particles

Box 2.1
The construction of more complex icosahedral virus particles
The combination of an icosahedral structure linked with evolutionary pressure to use small
repeating subunits to form virus particles imposes a restriction on the achievable size of the
virion. Since the size of the particle deﬁnes the maximum size of the nucleic acid that can be
packed within it, it appears that viruses should not be able to package large genomes. However,
many viruses have very long genomes and contain more than 60 subunits. This apparent
paradox is solved as follows: if 60n subunits are put on the surface of a sphere, one solution is to
arrange them in n sets of 60 units, but the
members of one set would not be equivalently
related to those in another set. If, in Fig. 2.5a,
all the subunits represented by open and closed
circles were identical, then those represented
by closed circles are related equivalently to
those represented by open circles, but open
circle units do not have the same spatial
arrangement of neighbours as closed circle
units and so cannot be equivalently related.
(The problem could be solved if the structure
was built out of n different subunits, but this
would require the virus to encode many more
structural proteins.) In order to construct a
spherical structure out of more than 60
asymmetrical subunits it is necessary to
subdivide the surface of the sphere into
triangular facets and organize them with
icosahedral symmetry. Each triangular facet
can be continuously subdivided into further
Fig 2.5 (a) Spatial arrangement of two
triangular units in a process called triangulation
sets of subunits. Note that any
(Fig. 2.5b). This is the same principle behind
the set represented by closed
the construction of geodesic domes which are
not have the same neighbours as a
extremely stable structures. The device of
member of the other set represented by open
triangulating the sphere represents the
circles. (b) Triangulation of an equilateral
optimum design for a closed shell built of
triangular face. The triangle on the left has
regularly bonded identical subunits. No other
been subdivided into 4 smaller equilateral
subdivision of a closed surface can give a
triangles. The triangle on the right has been
comparable degree of equivalence. This is a
subdivided into 3 smaller equilateral triangles
minimum-energy structure and is the probable
by distorting the plane of the original face.
reason for the preponderance of icosahedral
Each new triangle can be subdivided in turn
using either process.



Part I The nature of viruses

The triangulation of spheres – how
to make bigger virus particles
It is possible to enumerate all the ways in which
this subdivision of a spherical structure can be
carried out. This can be demonstrated with a
simple example. Starting with an icosahedron,
arranging the subunits around the vertices will
generate 12 groups of ﬁve subunits (Fig. 2.6a).
Subdividing each triangular face into four
smaller and identical equilateral triangular
facets and incorporation of subunits at the
vertices of those smaller triangles gives a
structure containing a total of 240 subunits
(Fig. 2.6b). At the vertices of each of the original
icosahedron faces there will be rings of ﬁve
subunits, called pentamers (solid circles).
However, at all the other (new) vertices
generated by the triangular facets will be rings
of six subunits, called hexamers (open circles).
Since some of the subunits are arranged as

pentamers and others as hexamers, it should be
apparent that they cannot be equivalently
related; hence they are called quasi-equivalent,
but this still represents the minimum-energy
shape. Thus with the subunit being kept a
constant size, greater subdivision allows the
formation of larger virus particles.

T = 1: the smallest virus particle –
satellite tobacco necrosis virus
In its simplest form, one subunit used in the
construction of a virus particle subunit will
consist of one protein. However, no
independently replicating virus is known to
consist of only 60 protein subunits, but satellite
viruses do (Table 2.1). These encode one coat
protein but depend upon coinfection with a
helper virus to provide missing replicative
functions. The single-stranded RNA genome of

Box 2.2
Calculating the number of subunits in a virus particle
The way in which each triangular face of the icosahedron can be subdivided into smaller,
identical equilateral triangles is governed by the law of solid geometry. This can be calculated
from the expression:
T  Pf 2 ;
where T, the triangulation number, is the number of smaller, identical equilateral triangles,
P is given by the expression h2 + hk + k2. In this expression, h and k are any pair of integers
without common factors, i.e. h and k cannot be divided by any whole number to give the
same values.
f  1; 2; 3; 4; etc:
For viruses examined so far, the values of P are 1 (h = 1, k = 0), 3 (h = 1, k = 1) and 7 (h = 1,
k = 2). Representative values of T are shown in Table 2.1. Once the number of triangular
subdivisions is known, the total number of subunits can easily be determined since it is equal
to 60T.

Chapter 2 The structure of virus particles

Fig. 2.6 Arrangement of 60n identical subunits on
the surface of an icosahedron. (a) n = 1 and the
60 subunits are distributed such that there is one
subunit at the vertices of each of the 20 triangular
faces. Note that each subunit has the same
arrangement of neighbours and so all the subunits
are equivalently related. (b) n = 4. Each triangular
face is divided into 4 smaller, but identical,
equilateral triangular facets and a subunit is again
located at each vertex. In total, there are 240
subunits. Note that each subunit, whether
represented by an open or closed circle, has the
identical arrangement of neighbours: see the face
in which triangles 1–4 have been drawn. However,
since some subunits are arranged in pentamers and
others in hexamers, the members of each set are
‘quasi-equivalently’ related.

satellite tobacco necrosis virus is about 1000 nt.
Presumably the volume of a 60-subunit
structure is too small to accommodate the larger
genome that is needed by an independent virus.


The virion is only 18 nm in diameter, compared
the 30 nm of small independent viruses.
Detailed determination of the structure of a
virus depends primarily on being able to grow
crystals of puriﬁed virus, although only slightly
lower resolution information can be obtained
from cryoelectron microscopic examination of
virus frozen in vitreous ice. The conditions
required for crystallization of virus particles or
proteins are not fully understood, and many
will not form crystals at all. Large stable crystals
are required that are then bombarded with
X-rays. These are diffracted by atoms within the
virion, and the image captured. Knowledge of
the amino acid sequence of the proteins which
comprise the particle makes it possible to
determine the 3-dimensional crystal structure.
X-ray analysis gives resolution to around
0.3 nm and the latest developments in
cryoelectron microscopy allow resolution to
around 0.4 nm. Both processes require highpowered computers that are used to make the
necessary calculations and for image
The morphological units of virus particles
seen by electron microscopy are called
capsomers and the number of these need not be the
same as the number of protein subunits. The
numbers of morphological units seen will
depend on the size and physical packing of the

Table 2.1
Values of capsid parameters in a number of icosahedral viruses. The value of T was obtained from
examination of electron micrographs, thus enabling the values of P and f to be calculated.


T (= Pf 2)

No of subunits (60T)






Tobacco necrosis satellite virus
Tomato bushy stunt virus, picornaviruses∗
Sindbis virus

In fact, picornaviruses have a pseudo T = 3 structure (see below).
see text.




Part I The nature of viruses

subunits and on the resolution of electron
micrographs. A repeating subunit may consist
of a complex of several proteins, such as the four
structural proteins of poliovirus (see below and
Section 12.3), or a fraction of a protein, such as
the adenovirus hexon protein, half of which is
considered to be a single repeating subunit.

T = 3: the molecular basis for quasiequivalent packing of chemically
identical polypeptides – tomato
bushy stunt virus
Some plant virus particles achieve the T = 3,
180-subunit structure (Fig. 2.7) while encoding

Fig. 2.7 Schematic diagram of a T = 3, 180­
subunit virus. Each triangle is composed of three
subunits, A, B and C, which are asymmetric by
virtue of their relationship to other subunits
(pentamers or hexamers). (Copyright 1991, from
Introduction to Protein Structure by C. Branden & J.
Tooze. Reproduced by permission of Routledge
Inc., part of The Taylor & Francis Group.).

only a single virion polypeptide. They
compensate for the physical asymmetry of
quasi-equivalence by each polypeptide
adopting one of three subtly different
conformations. The virion polypeptide of
tomato bushy stunt virus has three domains P, S
and R (Fig. 2.8a): this is folded so that P and S
are external and hinged to each other, while R
is inside the virion and has a disordered
structure. An arm (a) connects S to R, h
connects S and P (Fig. 2.8b).
Each triangular face is made of three
identical polypeptides, but these are in different
conformations to accommodate the quasiequivalent packing. For example, the C subunit
has the S and P domains orientated differently
from the A and B subunits (Fig. 2.8c), while the
arm (a) is ordered in C and disordered in A and
B (not shown). The S domains form the viral
shell with tight interactions, while the P

Fig. 2.8 (a) The linear arrangement of domains
present in the single virion polypeptide of tomato
bushy stunt virus. (b) Conformation of the
polypeptide. The S domain forms the shell of the
virion, while P points outwards and R is internal.
(c) This shows a triangular face, composed of
subunits A, B and C, and the interaction of the P
domains to form dimeric projections (see text).
(Copyright 1991, from Introduction to Protein
structure by C. Branden & J. Tooze. Reproduced by
permission of Routledge Inc., part of The Taylor &
Francis Group.).

Chapter 2 The structure of virus particles

domains (total = 180) interact across the
twofold axes of symmetry to form 90 dimeric
protrusions. This virion is 33 nm in diameter
and can accommodate a single-stranded RNA
genome about fourfold larger than that of the
satellite viruses. Thus a larger particle can be
achieved without any more genetic cost.

T = 3: with icosahedra constructed
of four different polypeptides –
Picornaviruses are made of 60 copies of each of
four polypeptides: VP1, VP2, VP3 and VP4. VP4
is entirely internal. The repeating subunit of
picornaviruses is the complex of VP1, VP2 and
VP3. This should generate a T = 1 particle.
However, despite the signiﬁcant differences in
amino acid sequence, the proteins adopt very
similar conformations and, in geometric terms,
appear as separate repeating subunits. For this
reason, the assembled picornavirus particles
appear to have a T = 3 structure; more
accurately, this is a pseudo T = 3 (compare
Figs 2.10 and 2.7).
The pentamers contain 15 polypeptides,
with ﬁve molecules of VP1 forming a central
vertex. These pentamers are the buildingblocks in the cell from which the virion is
assembled. Use of three polypeptides gives a
chemically more diverse structure and may
be an adaptation to cope with the immune
system of animal hosts.

The cell receptor attachment site
of picornavirus particles
Many virus proteins, including the VP1, VP2
and VP3 of picornaviruses, have the same type
of structure – an antiparallel β barrel also
known as a ‘jelly-roll’ (Fig. 2.9).
Crystallographic, biochemical and


immunological data have together identiﬁed a
depression within the β barrel of VP1 which is
the attachment site of picornaviruses. There
are 60 attachment sites per virion. The
arrangement of the β strands of VP1 is such
that an annulus is formed around each ﬁvefold
axis of symmetry (Fig. 2.10). In the rhino
(common cold) viruses, this is particularly
deep and is called a ‘canyon’. The canyon lies
within the structure of the β barrel. Amino
acids within the canyon are invariant, as
expected from their requirement if they have
to interact with the cell receptor, while amino
acids on the rim of the canyon are variable.
Only the latter interact with antibody. It is
thought that the ﬂoor of the canyon has
evolved so that it physically cannot interact
with antibody. This avoids immunological
pressure to accumulate mutations in order to
escape from reaction with antibody, since
these would at the same time render the
attachment site non-functional, and hence be
lethal to the virus.

An unknown structure: virus
particles with 180 + 1 subunits
and no jelly-roll β barrel – RNA
The leviviruses are 24 nm icosahedral RNA
bacteriophages, and include MS2, R17 and Qβ.
They encode two coat proteins. There are 180
subunits of one of these arranged with T = 3,
but only a single copy of the second ‘A’ protein
in each particle. This is the attachment protein.
It is not known how the single subunit is
incorporated into the particle. The main coat
protein does not form a jelly-roll β barrel like
those described above, but instead has ﬁve
antiparallel β strands arranged like the vertical
elements of battlements. Two subunits interact
to form a sheet consisting of 10 antiparallel
β strands.


Part I The nature of viruses

T = 25: more complex animal virus
particles – adenoviruses
Careful examination of electron micrographs of
adenoviruses shows that they have a T = 25
structure, with 240 hexons and 12 pentons, and
a ﬁbre projecting from each vertex (Fig. 2.11a,
b). The ﬁbres, the pentons and the hexons are
all constructed from different proteins. This
presents the problem of arranging not one, but
three different proteins in a regular fashion,
while adhering to the design principles outlined
above. This can be achieved by arranging the
pentons and the ﬁbres at the vertices of the
icosahedron and the hexons on the faces (Fig.
2.11c). However, the formula 60T gives the
number of subunits as 1500 (Table 2.1). How is
this difference resolved? The 240 hexons are
composed of three identical polypeptides and
each functions as two repeating subunits. Thus
there are 1440 hexon subunits. The 12 pentons
are formed from ﬁve identical polypeptides and
each functions as a subunit, making 60 of these.
Thus 1440 hexon subunits + 60 penton
subunits make up the 1500 predicted subunits.
Actually, the hexons are not all spatially
equivalent, as those surrounding the vertex
pentons contact ﬁve other hexons, while the
others contact six hexons.

Fig. 2.9 The jelly-roll or antiparallel ß barrel: a
common structure of plant and animal virion
proteins. The formation of an antiparallel ß barrel
from a linear polypeptide can be visualized to
occur in three stages. First, a hairpin structure
forms where ß strands are hydrogen-bonded to
each other: 1 with 8, 2 with 7, 3 with 6, and 4 with
5, creating antiparallel ß strand pairs separated by
loop regions of variable length (a). Second, these
pairs become arranged side by side, so that further

hydrogen bonds can be formed by newly adjacent
strands, e.g. 7 with 4 (b) Third, the strand pairs
wrap around an imaginary barrel forming a
3-dimensional structure. The eight ß strands are
arranged in two sheets, each composed of four
strands: strands 1, 8, 3 and 6 form one sheet and
strands 2, 7, 4 and 5 form the second sheet (c). The
dimensions of the barrel are such that each protein
forms a wedge, and these wedges are subunits that
are assembled into virus particles (d). ((a–c)
(Copyright 1991, from Introduction to Protein
Structure by C. Branden & J. Tooze; reproduced by
permission of Routledge Inc., part of The Taylor &
Francis Group. (d) From Hogle et al., 1985 Science
229, 1358.)

Chapter 2 The structure of virus particles


Fig. 2.10 A picornavirus particle (a) and the attachment site formed by VP1 shown as an annulus around
the ﬁvefold axis of symmetry, (from Smith et al., 1993, Journal of Virology, 67, 1148.) (b) A vertical section
through a VP1 pentamer where the cross-section of the annulus is referred to as the ’canyon’. (From Luo
et al., 1987, Science 235, 182).

Triple-shelled particles: capsids
within capsids – rotaviruses
A different and very complex structural
arrangement is found in another class of
isometric viruses, the rotaviruses, the particles
of which contain three distinct layers of capsids

surrounding a core structure. Rotavirus
encodes 12 polypeptides. Of these, six are
located in the virion: three forming the inner
shell, one forming the middle shell and two
forming the outer shell (Table 2.2). The outer
and middle shells have icosahedral symmetry
with the outer shell having a T = 13 symmetry

Fig. 2.11 The structure of adenoviruses. (a) A negatively stained electron micrograph of an adenovirus.
(b) Model of an adenovirus to show arrangements of the capsomers. (c) Schematic diagram to show the
arrangements of the subunits on one face of the icosahedron. Note the subdivision of the face into 25
smaller equilateral triangles. (Photographs courtesy of Nicholas Wrigley.)


Part I The nature of viruses

Table 2.2
Rotavirus proteins and their location in the virion, and some of their properties. The non-structural
proteins are also shown.
Location in virion Protein Encoding Number of
or non-structural
segment per virion















(13 × 60 subunits) and the intermediate having
T = 2 symmetry (2 × 60 subunits). The inner
shell consists of 120 molecules of the VP2
protein which forms a stable structure to
support the middle shell comprised of the
VP6 protein. The core contains the genome
comprising 11 segments of dsRNA and single
molecules of the VP1 and VP3 proteins,
which form the virion RNA polymerase,
located at each of the 12 vertices of the
icosahedron (Fig. 2.12). The polymerase
forms an integral component of the structure
at the vertices and is required for the
production of virus mRNA (see Section 11.2).
The precise 3-dimensional arrangement of
all of the molecules in the rotavirus particle
has been determined. The 11 doublestranded RNAs are thought to be tightly
coiled like the DNA inside phage heads.
Each molecule is thought to be associated
with a polymerase complex and tethered
near a vertex.

Virus RNA dependent RNA polymerase
Structural protein of inner capsid
Guanylyltransferase of virus RNA dependent
RNA polymerase
Structural protein of middle capsid
Outer capsid spike (dimer) converted by
cleavage into VP5∗ and VP8∗
Outer capsid structural glycoprotein
Binds several host proteins during infection
Binds 3’ end of virus mRNA for translation
ssRNA binding protein
Virus enterotoxin
ss RNA binding protein
Interacts with NSP5

Fig. 2.12 The triple shelled structure of rotavirus
showing the location of polypeptides in the virion.

2.4 Enveloped (membrane­
bound) virus particles
Although they appear complex, enveloped
viruses have a conventional isometric or helical

Chapter 2 The structure of virus particles

structure that is surrounded by a membrane – a
4 nm-thick lipid bilayer containing proteins.
The internal structure is usually referred to as a
nucleocapsid to differentiate it from the capsid
of viruses that lack an envelope. Examples of
enveloped viruses include many of the larger
animal viruses, but only a few plant and
bacterial viruses. Traditionally, the enveloped
viruses were distinguished from non-enveloped
viruses by treatment with detergents or organic
solvents, which disrupts the membrane and
destroys infectivity. Thus they were sometimes
referred to as ‘ether-sensitive viruses’. The
envelope, which is derived from host cell
membranes, is obtained by the virus budding
from cell membranes, and most contain no cell
proteins (see Section 12.6). How cell proteins
are excluded and why some viruses do not
exclude cell proteins from their virions is not

An isometric core surrounded
by an isometric envelope:
Sindbis virus particles
Sindbis virus (a togavirus) has an icosahedral
nucleocapsid that comprises a single protein,
surrounded by an envelope from which viral
spike proteins protrude. The core has T = 3
and 180 subunits, exactly like tomato bushy
stunt virus described above. Surprisingly, the
envelope also has icosahedral symmetry, but
to everyone’s surprise this is T = 4 and has
240 subunits. This apparent paradox was
resolved when it was found that the two
structures are complementary, so that the
internal ends of the spike proteins ﬁt exactly
into depressions between the subunits of the
nucleocapsid (Fig. 2.13). So far, this and its
near relations are the only enveloped viruses
that are known to have a geometrically
symmetrical envelope.


Fig. 2.13 Sindbis virus: an enveloped
icosahedron. The core is T = 3, but the envelope is
T = 4. See text for the explanation. (Courtesy of
S. D. Fuller.)

A helical core surrounded by an
approximately spherical envelope:
the inﬂuenza virus particle
One of the best studied groups of enveloped
viruses is the inﬂuenza viruses. The helical core
is composed of the matrix (M1) protein
surrounding ribonucleoprotein, itself composed
of ﬂexible rods of RNA and NP protein. This is
constructed as described in Section 2.2, and
arranged in a twisted hairpin structure. The
genome is segmented RNA and there are eight
separate core structures. Each is associated with
a transcriptase complex. The core is contained
within a lipid envelope that is only roughly
spherical, and hence often described as
pleomorphic (Fig. 2.14).
In electron micrographs (Fig. 2.14), a large
number of protein spikes projecting about
13.5 nm from the viral envelope can be
observed. These spikes, which have an overall
length of 17.5 nm, are transmembrane
glycoproteins like many of those in cell
membranes. The spike layer consists solely of


Part I The nature of viruses

Fig. 2.14 Inﬂuenza A virus (an orthomyxovirus) and vesicular stomatitis virus (a rhabdovirus): viruses
with enveloped helical structures. Although their morphology is different, these viruses are constructed in
the same way. (a) Negatively stained electron micrograph of inﬂuenza A virus showing the internal
helical ribonucleoprotein (RNP) core and the surface spikes. (b) Aggregates of puriﬁed neuraminidase.
(c) Aggregates of puriﬁed haemagglutinin. Note the triangular shape of the spikes when viewed end-on.
(d) Schematic representation of the structure of inﬂuenza virus. (e) Negatively stained electron
micrograph of vesicular stomatitis virus. (f) Schematic representation of the structure of vesicular
stomatitis virus. (Electron micrographs courtesy of Nicholas Wrigley and Chris Smale.)

virus-speciﬁed glycoproteins, and comprises
about 800 haemagglutinin (HA) and 200
neuraminidase (NA) proteins. HA proteins are
trimers and NA proteins are tetramers. NA
spikes are arranged non-randomly in clusters

on the virion surface. The HA protein functions
in attachment and fusion-entry, and the NA
protein releases infecting virus from receptors
that do not lead to entry and infection. The NA
also releases progeny virions which reattach to

Chapter 2 The structure of virus particles


the host cell in which they were formed.
Receptor analogues (e.g. oseltamivir) are
antivirals that prevent virus release (see
Section 27.3). The two types of spike are
morphologically distinct. A few molecules of an
ion channel protein called M2 are also found in
the membrane. This allows the passage of
protons into the core and is necessary for
secondary uncoating.

A helical core surrounded by a
non-spherical envelope: rhabdovirus
This group of viruses has a helical core
consisting of just nucleoprotein, and an
envelope like the inﬂuenza viruses. What is
distinctive about these viruses is that they not
isometric, but either bullet-shaped or
bacilliform (rounded at both ends). These are
unique morphologies. There are both plant and
animal rhabdoviruses, and the latter are all
bullet-shaped. The envelope contains a dense
layer of spikes comprising just one protein, the
viral attachment protein, G. The matrix protein
underlies the membrane. Apart from their
strikingly different overall shape, rhabdoviruses
and inﬂuenza viruses have fundamentally a
very similar structure (Fig. 2.14d, f). The length
of the bullet appears to be controlled by the size
of the RNA genome as defective-interfering
rhabdoviruses, which have a massively deleted
genome, form small bullet-shaped particles.
Nothing is known of the structural geometry
involved the formation of rhabdovirus particles.

2.5 Virus particles with
head-tail morphology
The head-tail architectural principle is unique
to bacterial viruses (Fig. 2.15), although many
bacterial viruses have other morphologies

Fig. 2.15 Electron micrograph of bacteriophage
T2 with six long tail ﬁbres. Tail pins are not evident
but a short ﬁbre (indicated by the arrow) can be
seen. The bar is 100 nm. (Courtesy of L. Simon.)

(Table 2.3). There is a large variation on the
head-tail structural theme and bacteriophages
can be subdivided into those with short tails,
long non-contractile tails, and complex
contractile tails. A number of other structures,
such as base plates, collars, etc., may be present.
Despite their complex structure, the design
principles involved in head-tail phages are
identical to those outlined earlier for the viruses
of simpler architecture. Heads usually possess
icosahedral symmetry, whereas tails usually
have helical symmetry. All other structures,
base plates, collars, etc., also possess a deﬁned
symmetry. The evolution of these elaborate
structures may be connected with the way in
which these bacterial viruses infect susceptible
cells (see Section 6.5). In brief, the phage
attaches to a bacterium via its tail, enzymatically
lyses a hole in the cell wall and inserts its DNA,
which is tightly packed into the phage head,
into the cell using the tail as a conduit.
Some of the larger viruses ﬁt none of these
structures, and the rules governing their
formation have not yet been elucidated. For
example, the poxviruses of animals have a
complex enveloped structure enclosing two
lateral bodies and a biconcave core that includes


Part I The nature of viruses

Table 2.3
Distribution of the various types of virus particle structure among families of animal, plant and
bacterial viruses.
Type of particle

Animal viruses

Plant viruses

Bacterial viruses

Non-enveloped helical
Enveloped icosahedral



Uncommon: cortico-, levivi-,
micro-, and tectiviruses
Rare: ino- and rudiviruses
Rare: cystoviruses

Enveloped helical

Not known
Uncommon: arteri-,
Not known
asfar-, borna-, ﬂavi-,
and togaviruses
Uncommon: bunya­
and rhabdoviruses
Not known
Not known

all the enzymes required for viral mRNA
synthesis, and the giant mimivirus, that infects
protozoa, has a 400 nm non-enveloped,
spherical particle that is surrounded by an
icosahedral capsid and ﬁbrils.

2.6 Frequency of
occurrence of different
virus particle morphologies
The different virus morphologies discussed
above do not occur with equal frequency
among animal, plant and bacterial viruses
(Table 2.3). There are relatively few purely
icosahedral viruses in bacteria; non-enveloped
helical viruses are common and occur almost
exclusively in plants; enveloped icosahedral
viruses and enveloped helical viruses are
common in animals and rare in plants and
bacteria. Finally, head-tail virus morphology, in
which an isometric head and a helical tail are
joined together, is found only in bacteria.
Unfortunately, there is no real explanation as to
why there should be these restrictions. There
also exist some very large, very complex viruses

Rare: lipothrixviruses

(e.g. poxviruses of animals and mimivirus of
amoebae) whose morphogenesis is beyond our
current comprehension.

2.7 Principles of
disassemply: virus particles
are metastable
It is important to remember that all virus
particles not only have to be constructed to
protect the genome, but they also have to
disassemble to permit the genome to enter a
new target cell. This is supremely important to
the virus particle as it has only one chance to do
this successfully and hence have the chance to
propagate its genome. One theory to explain
this paradox is that the particle is metastable,
i.e. it is stable but it can be triggered by
interaction with the receptor, and other events
to descend to a lower energy level and, in doing
so, releases its genome. Not surprisingly, there
are a number of fail-safe devices that tell the
virus when it is safe to let go the genome. One
of the simplest systems is used by enveloped
animal viruses like HIV-1. This virus undergoes

Chapter 2 The structure of virus particles

a succession of interactions between cell
receptors and virus envelope protein binding
sites, each interaction providing a molecular
password that is needed to gain entry to the
next level. If everything is in order, the
metastable envelope protein then undergoes
profound rearrangements that allow a hidden
hydrophobic segment to insert into the cell
membrane. This initiates fusion of the lipid
bilayer of the virus with that of the cell plasma
membrane, and the virus genome automatically
enters the cell cytoplasm. However, if the
sequence of passwords proves incorrect, the
virus detaches from the cell and the process can
be repeated until the correct cell is found.
Mechanisms of entry are discussed in Chapter 6.

Key points






Virus particles consist mainly of nucleic acid
and protein, arranged to form regular
geometric structures.
Some viruses have particles that are
surrounded by a membrane.
Virus proteins protect the viral genome,
identify the appropriate target cell, and get
the genome into the target cell.
Some viruses contain proteins with
enzymatic functions that are needed for
genome replication, and these enter the cell
with the genome.
Elongated virus particles have their protein
subunits arranged in a helix, and are said to
have helical symmetry.
Isometric virus particles are usually
icosahedrons – structures with 20 faces, with
protein subunits arranged to retain the
elements of icosahedral symmetry.
Membrane-bound viruses have an internal
nucleoprotein structure with helical
symmetry or with isometric symmetry.


Further reading
Branden, C., Tooze, J. 1999. Introduction to Protein
Structure, 2nd edn. Garland Publishing, New
Butler, P. J. G. 1984. The current picture of the
structure and assembly of tobacco mosaic virus.
Journal of General Virology 65, 253–279.
Caspar, D. L. D., Klug, A. 1962. Physical principles
in the construction of regular viruses. Cold
Spring Harbor Symposium of Quantitative Biology
27, 1–24.
Eiserling, F. A. 1979. Bacteriophage structure. In
Comprehensive Virology (H. Fraenkel-Conrat, R. R.
Wagner, Eds), Vol. 13, pp. 543–580. Plenum Press,
New York.
Crowther, R. A. 2008. The Leeuwenhoek Lecture
2006. Microscopy goes cold: frozen viruses reveal
their structural secrets. Philosophical Transactions of
the Royal Society of London B: Biological Sciences 363,
Johnson, J. E. 2003. Virus particle dynamics.
Advances in Protein Chemistry 64, 197–218.
Rixon, F. J., Chiu, W. 2003. Studying large viruses.
Advances in Protein Chemistry 64, 379–408.
Smith, T. J., Baker, T. 1999. Picornaviruses: epitopes,
canyons, and pockets. Advances in Virus Research 53,
Stuart, D. 1993. Virus structures. Current Opinion in
Structural Biology 3, 167–174.
Tyler, K. L., Oldstone, M. B. A. 1998. Reoviruses I.
Structure, proteins and genetics. Current Topics in
Microbiology and Immunology 233, 1–213.
Wiley, D. C., Skehel, J. J. 1987. The structure and
function of the hemagglutinin membrane
glycoprotein of inﬂuenza virus. Annual Review of
Biochemistry 56, 365–394.
Zhou, Z. H., Chiu, W. 2003. Determination of
icosahedral virus structures by electron
cryomicroscopy at sub-nanometer resolution.
Advances in Protein Chemistry 64, 93–124.
For images of virus particles see the Virus Particle
Explorer (VIPER) website: http://viperdb.scripps

Chapter 3

Classiﬁcation of viruses
Viruses are found throughout the world and infect all known organisms. Viruses may cause a range of
different diseases and display a diversity of host range, morphology and genetic makeup. Bringing order to
this huge diversity requires the designation of classiﬁcation groups to permit study of representative viruses
that can inform us about their less well-studied relatives.

Chapter 3 Outline
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
3.4 Classiﬁcation on the basis of viral nucleic
3.5 Classiﬁcation on the basis of taxonomy
3.6 Satellites, viroids and prions

Viruses represent one of the most successful
types of parasite in the world and have been
isolated from representatives of every known
group of organisms from the smallest singlecelled bacterium to the largest mammal. Whilst
in most cases the virus is speciﬁc for the host
species in which it has been identiﬁed, some
viruses are able to infect species from different
phyla and even different kingdoms. The
number of known viruses now exceeds 3000
with new viruses being discovered all the time.
This very large number contains a diverse array
of viruses which at ﬁrst sight is very
bewildering. To make the study of viruses easier
and to bring order to this apparent diversity,
over the years a number of different systems

have been proposed to generate classiﬁcation
schemes which will allow us to study
representative viruses rather than each
individually. All of the proposed classiﬁcation
schemes have different strengths and
weaknesses but there is now general consensus.
The International Committee on Taxonomy of
Viruses (ICTV) has responsibility for assignment
of new viruses to speciﬁc phylogenetic

3.1 Classiﬁcation on the
basis of disease
The ﬁrst, and most common, experience of
viruses is as agents of disease and it is possible to
group viruses according to the nature of the
disease with which they are associated. Thus,
one can discuss hepatitis viruses or viruses
causing the common cold. This is attractively
simple. However, this method of grouping
viruses, though reﬂecting an important