Table Of ContentFenner and White’s Medical Virology
Fenner and White’s Medical
Virology
Fifth Edition
Christopher J. Burrell
School of Molecular and Biomedical Science,
University of Adelaide, Adelaide, South Australia, Australia
Colin R. Howard
College of Medicine and Dentistry, University of Birmingham, United Kingdom
Frederick A. Murphy
University of Texas Medical Branch, Galveston, Texas, USA
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Dedication
This book is dedicated to our friends Frank J. Fenner (1914– an independent scientific and medical discipline and a
2010) and David O. White (1931–2004), the founders of the significant contributor to human, animal, and environmental
series of books now spanning five editions of MEDICAL well-being. We hope our students will come to understand
VIROLOGY and five editions of VETERINARY VIROLOGY. the “big picture” of medical virology as well as Frank and
They set a standard of scholarship that is impossible to David achieved throughout their outstanding careers.
match and a joie de vivre that made the writing and editing We would also like to dedicate this book to our wives
almost fun. and families, our teachers and mentors, together with our
They taught us that the subject of virology must be seen students, all of whom have shaped our thinking and provided
within the context of society as a whole as well as within the us inspiration over the years in so many different ways.
context of science. They envisioned virology as extending
broadly, from its roots in the science of microbiology and Christopher J. Burrell
the practice of infectious disease, through its key roles in Colin R. Howard
the development of molecular and cell biology, to become Frederick A. Murphy
Foreword
To say that this new version of the classic Medical Virology institutional structures that they established, or the insights
text by Frank Fenner (1914–2010) and David White (1931– they developed. My current office is in the Department
2004) is timely is, to say the least, an understatement. It’s of Microbiology and Immunology at the University of
been 21 years since the fourth edition, with authors Chris Melbourne, which was headed for many years by David
Burrell, Colin Howard, and Fred Murphy building on that White. Perhaps, as Isaac Newton (1642–1726) said “we stand
much respected foundation to produce a greatly refreshed on the shoulders of giants” though, when I’ve met the “giants”
fifth edition. The basic philosophy and structure that made of science, they’ve pretty much turned out to be hard working,
this such a useful volume for many generations of advanced smart, and dedicated people who quietly and systematically
medical students, clinicians, and pathologists remain but, as built a body of knowledge and a tradition of scholarship. That
all who have been even peripherally involved in molecular very much describes the discipline of virology.
science over the past two decades will realize, there was an Thus, while reflecting on the up-to-date understanding
enormous amount of new information that had to be read, of the authors, and of other researchers who have provided
sifted, and selected for relevance to the information needs key insights concerning each particular pathogen, Fenner
of this target audience. and White’s Medical Virology reflects a cumulated wisdom
Basic virology has, of course, been well served by the that goes back to the early days of 20th century virology.
many revisions of Bernie Fields’ (1938–1995) exhaustive Back then, the thinking and technical range of mammalian
text and, following the example set by Field’s Virology, the virologists was very much focused on pathogenesis and
fifth edition will appear as Fenner and White’s Medical disease process. Now, after decades of illuminating the
Virology. It is a fitting tribute. Taken together, the original molecular characteristics of viruses and infected cells, it
authors, and those responsible for this latest version, have is gratifying to see these precise investigative tools being
variously been active and publishing on one or the other applied to the understanding of what actually happens in
aspect of virus-induced disease and/or pathology since an infected individual. This is a great time for any medical
1948: and the virology lineage goes back even further! researcher who is fascinated by the linked issues of disease
Frank Fenner was the student of MacFarlane Burnet process, pathology, and treatment.
(1899–1985) who, applying technical and conceptual This fifth edition provides an accessible and informative
approaches learned from his early studies with bacteriophage, account of medical virology, based on both contemporary
pioneered quantitative mammalian virology, and genetics. science and what went before. It constitutes an excellent
David White began his career as a virologist in the university resource for both the physician and the research investigator.
microbiology department headed by Frank Fenner. Both Fred New discoveries are constantly being made and, while
Murphy and I worked for a time and Chris Burrell completed much remains unclear, the rate of advance in understanding
his PhD in that same department, where Rolf Zinkernagel and is extraordinary. Hopefully, we will not need to wait another
I did the experiments in viral immunity that led to a Nobel 20 years for the next edition of this seminal text.
Prize. Reflecting on lineages and the solid foundations that
enable the work of subsequent generations, I realize that I’ve Peter C. Doherty
met all the people named above in one or other professional University of Melbourne
or personal context and have benefitted from either the December 10, 2015
xvii
Preface
Enormous strides have taken place since the fourth edition of responsible. Much of the approach adopted has been shaped
this book in regard to our understanding of virus properties by the authors’ experience in teaching virology to science
and how viral diseases can be controlled, treated, and and medical students and graduates—which has itself been
prevented. Considerable advances have been made across shaped by earlier editions of this book.
the whole spectrum of virology, particularly in relation to This edition is designed to meet the needs of advanced
virus structure and replication, “point-of-care” diagnostics medical students, clinicians and pathologists, university
and the wide use of antiviral therapies. This progress has teachers, researchers, and public health workers who are
done much to contribute to a substantial improvement in seeking a single accessible source of key information about
public health across the globe. the range of major human viruses and the options for treatment
At the same time, we have seen the emergence of new and control. We have included historical perspectives, so that
viral agents, and older agents in new guises, sometimes readers gain some insight into the paths and the personalities
creating a need for radically new concepts to guide our involved in our reaching this current state of knowledge;
understanding and clinical and public health actions. we have also highlighted gaps in knowledge, and unmet
Notable examples include HIV/AIDS; SARS and its recently challenges in the management and control of virus diseases.
appearing relative MERS; Hendra and Nipah viral diseases; However, in a book of this size it is not feasible to include all
the more recent epidemic manifestations of Ebola; the details, and thus readers seeking a more complete discussion
appearance in humans of novel influenza A viruses; and the of the diagnosis and management of a particular condition
ever-increasing range of manifestations of “older” viruses should refer to the appropriate source. Similarly, although
in immunosuppressed individuals. Paradoxically, other not intended as a comprehensive summary of current
aspects of virology, for example, the clinical descriptions research into a particular viral agent, we hope to prime the
of common infections and the principles of management, reader’s enthusiasm to explore further aspects in the scientific
remain as valid as when they were first made. Our challenge literature. We are acutely aware of the need to foster the next
is to transmit hard-learned experiences, within the context of generation of virologists, and if reading this book plays a
new advances, to an ever-widening audience of newcomers small part in this process, then we will be gratified.
entering the medical, scientific, and related professions. We wish to acknowledge a number of friends and
In keeping with the advice of many colleagues, we have colleagues who kindly agreed to review certain chapters:
renamed this edition Fenner and White’s Medical Virology. Peter Balfe (replication), Michael Beard (innate immunity,
We have retained the layout of chapters as first set out in flaviviruses), Shaun McColl (adaptive immunity), Geoff
1970 by Frank Fenner and David White, as we believe Higgins (laboratory diagnosis), Yu-Mei Wen (oncogenic
this structure still provides an excellent framework for the viruses, adenoviruses, paramyxoviruses, coronaviruses),
discipline. Tony Cunningham (herpesviruses), Wendy Howard
Part I deals with the principles of animal virology, and (influenza), Stephen Locarnini (hepadnaviruses), David
includes chapters on basic virology and viral replication, Shaw (retroviruses), Sharon Lewin (retroviruses), Barbara
host immunity, pathogenesis of infection, viral oncogenesis, Coulson (reoviruses), Lorena Brown (orthomyxoviruses),
viral diagnostics, vaccinology, chemotherapy, epidemiology, Peter McMinn (picornaviruses), Bill Rawlinson (caliciviruses,
surveillance, and emergence. astroviruses), and Mike Catton (viral syndromes). We also
Part II systematically examines in turn each of the virus thank our graphic artist Richard Tibbitts for his work on the
families containing human pathogens. Chapters in Part II diagrams, and Steven Polyak for the chemical structures of
are for the most part set out in a standardized format to antiviral drugs in the chapter “Antiviral Chemotherapy.”
allow the reader more rapid access to the information being
Christopher J. Burrell
sought. Of course, virus infections in clinical practice
Colin R. Howard
present as syndromes and do not identify themselves by
their virus family, so a key final chapter associates common Frederick A. Murphy
viral syndromes with the etiological agents usually
xix
Chapter 1
History and Impact of Virology
the development of medical thought overall, particularly
Infectious disease is one of the few genuine adventures left in
in applying scientific rigor in understanding pathological
the world. The dragons are all dead and the lance grows rusty
processes. Advances in understanding infectious agents
in the chimney corner.... About the only sporting proposition
have led to improvements in human health and well-being
that remains unimpaired by the relentless domestication of
a once free-living human species is the war against those that arguably have exceeded the contribution of any other
ferocious little fellow creatures, which lurk in the dark corners branch of science. Indeed, no less than 35 workers in this
and stalk us in the bodies of rats, mice, and all kinds of and closely related fields have been awarded the Nobel
domestic animals; which fly and crawl with the insects, and Prize in Physiology or Medicine in recognition of their
waylay us in our food and drink and even in our love. achievements.
Infectious disease discoveries have had a profound
So wrote the great microbiologist Hans Zinsser in his book effect on life expectancy and well-being across the world.
Rats, Lice and History, written in 1935, as he reflected on For example, epidemics of smallpox, yellow fever, and
his life in infectious disease research. Zinsser’s thoughts poliom yelitis, commonplace until well into the 20th
have stimulated generations of students and professionals century, have been virtually eliminated by the application of
ever since. Infectious diseases of today present challenges various prevention and control strategies. However, hitherto
that are different but just as demanding as those facing unrecognized diseases have emerged over the past half-
Zinsser over 80 years ago. century at the rate of at least one per year. Many of the viruses
This book presents the subject of medical virology from dealt with in this edition were unknown when the first edition
the perspective of its traditional base as a life science and was published over 45 years ago. The epidemiology of other
its application to clinical practice and public health. It is the viruses has radically changed as humans continue to alter
perspective established by Frank Fenner and David White, the environment in so many ways. Meeting the challenges
who in 1970 conceived the rationale for this book, and posed by emerging diseases requires the medical virologist
maintained it through the previous four editions. It is the to acquire ever more increasing expertise and access to ever
perspective that many others have used to teach and learn more complex technologies. Today diseases such as HIV/
medical virology. AIDS, hepatitis C, influenza, and diarrheal diseases represent
The foundations of the science of medical virology significant threats to public health. Tomorrow it will be
are intertwined with the other life sciences, particularly other diseases, the nature and means of control for which are
microbiology and infectious diseases. Medical virology has largely unpredictable. One positive note is that all emerging
a relatively brief history, spanning just over a century, but it viral diseases of recent years have been found to be caused
is crowded with intriguing discoveries, stories of immense by members of previously recognized families of viruses.
personal courage and numerous practical applications, Thus a thorough knowledge of representative members
many of which have had an overwhelmingly positive of each family is likely to facilitate and inform the rapid
benefit on humankind. Its origins involved the replacement development of knowledge about any new pathogen.
of centuries-old beliefs and theories with discoveries borne
out of rigorous scientific investigation. Targeted prevention
WHY STUDY VIROLOGY?
and control strategies could only be developed and
implemented once the concept of the specificity of disease As many bacterial infections have succumbed to treatment
causation had been accepted, namely that infectious diseases with antibiotics, viral infections now pose proportionally
are caused not by some common miasma (a mysteriously a much greater threat to global public health than was
poisonous substance), but rather by specific agents. In a wider the case, say, a half-century ago. Viral diseases exact a
sense, the microbial sciences have played a pivotal role in particularly heavy toll among young children and infants in
Fenner and White’s Medical Virology. DOI:http://dx.doi.org/10.1016/B978-0-12-375156-0.00001-1
© 22001172 Elsevier Inc. All rights reserved. 3
4 PART | I Principles of Virology
the economically less developed nations where healthcare This was despite the thesis of Girolamo Fracastoro
resources are limited. Ironically, there is a resurgence of who suggested as early as 1546 that epidemic diseases
interest in viruses that target bacteria (bacteriophages) as were disseminated by minute particles carried over long
an alternative strategy for the control of some increasingly distances. Anton van Leeuwenhoek first saw bacteria
drug-resistant bacterial infections (e.g., cholera). through his microscope in 1676 and Lazarro Spallanzani
Although this book focuses on viral infections of medical first grew bacteria in culture in 1775. Remarkably, Edward
significance, the reader needs to be aware that viruses are Jenner developed vaccination against smallpox in 1796
a major threat to livestock and plant species, and thereby against a backdrop of prevailing opinion that such diseases
of great importance in human nutrition and food supply. were caused by environmental factors rather than specific
Human adaptation to diseases of livestock and crops has microscopic agents.
played a major role in the development of all civilizations. The establishment of microbiology as a scientific
Virology is much broader than linking a particular discipline owes much to the work of Louis Pasteur, who in
disease to a specific pathogen: there are literally hundreds of 1857 discovered the specificity of microbial fermentation,
new viruses being discovered that do not apparently relate who then went on in 1865 to elaborate the nature of diseases
to any known pathological condition of either animals or of silkworms. But it was his work on rabies that signaled
humans. Many of these may in the future be linked to human the start of the virus discovery era. In 1885, Pasteur looked
illnesses and thus the reader needs to be aware of the wider on as his first rabies vaccine was given to a boy, Joseph
scope of the virological landscape, if not in detail at least Meister, bitten severely by a rabid dog, thus opening up the
to the point of “expecting the unexpected.” Conversely, the strategy of vaccine development through a process of virus
tantalizing goal remains to clarify what role, if any, viruses attenuation (Fig. 1.1).
may play in well-known diseases of uncertain etiology, for The early pioneering work of the 19th century linking
example, multiple sclerosis. disease to specific bacteria was greatly assisted by the
The vast majority of new viral threats emerging earlier development of the unglazed porcelain ultrafilter by
annually either originate from an animal host (zoonosis) or Charles Chamberland who worked in Pasteur’s laboratory.
are the result of host range extension (that is, “host species These filters originally were used to sterilize water and
jumping”), or other changes in the epidemiology, ecology, other fluids by preventing the passage of bacteria. Dimitri
and/or pathogenicity of the etiological agent. Since the last Ivanovsky (1892) and Martinus Beijerinck (1898) showed
edition of this book, virus emergence has become a major that the agent causing mosaic disease in tobacco plants
focus of virological research. (now known to be tobacco mosaic virus [TMV]) passed
The discovery of a new human pathogen often stimulates through ultrafilters retaining bacteria. Beijerinck realized
the discovery of related, but hitherto unidentified agents he was dealing with something other than a microbe but
that may, or may not, present threats to human health at erroneously thought that the entity that passed through the
some point in the future. A prime example is the emergence ultrafilter was an infectious liquid and not a particle—he
of SARS virus, a coronavirus, and the subsequent explosion called it a “contagium vivum fluidum.” Friedrich Loeffler
in our knowledge of coronaviruses of animals. This helped and Paul Frosch were the first to correctly conclude that an
in the later rapid recognition of another human respiratory ultrafilterable infectious agent was indeed a submicroscopic
coronavirus—MERS coronavirus (Middle East Respiratory particle. Studying the cause of foot-and-mouth disease
Syndrome coronavirus). of cattle, Loeffler and Frosch found that the causative
agent passed through a Chamberland ultrafilter but not the
finer Kitasato ultrafilter. Thus these first virologists saw
A BRIEF HISTORY OF VIROLOGY
ultrafiltration in a new way—they focused attention on what
The history of virology can be divided into a number of eras: passed through the ultrafilter rather than what was retained,
these span (1) the discovery of viruses as entities distinct and thereby established an experimental methodology widely
from other disease-causing pathogens, (2) the association adopted in the early 20th century. In quick succession, further
of many major human diseases with causative viruses, diseases were shown to be caused by ultrafilterable agents:
(3) the development of methods for virus isolation and in 1900 the first human virus, yellow fever virus, and its
characterization, (4) the defining of the chemical properties mosquito transmission cycle was discovered by Walter Reed,
of viruses, and (5) the design and application of vaccines James Carroll and the US Army Yellow Fever Commission
and therapeutics. A summary of the major milestones in the in Havana, Cuba, a discovery that was guided by the earlier
development of virology is given in Table 1.1. work of the Cuban physician Carlos Findlay (Fig. 1.2).
Virology has its foundations in the initial discoveries The concept of ultrafilterable infectious agents became
of bacteria and related diseases. Up to the 19th century the more widely acceptable when Karl Landsteiner and Erwin
prevailing view was that diseases of humans and animals were Popper showed conclusively in 1909 that poliomyelitis was
the result of miasmas and other environmental influences. caused by an ultrafilterable agent. Importantly, as early as
History and Impact of Virology Chapter | 1 5
TABLE 1.1 Some Milestones in the History of Virology
Date Discoverer(s) Discovery(ies)
1796 E. Jenner Application of cowpox virus for vaccination against smallpox
1885 L. Pasteur Development of rabies vaccine
1892 D. Ivanovsky, M. Beijerinck Ultrafiltration of tobacco mosaic virus
1898 F. Loeffler, P. Frosch Ultrafiltration of foot-and-mouth disease virus—clear proof of
virus etiology of disease—discovery of the first virus
1898 G. Sanarelli Discovery of myxoma virus
1900 W. Reed, J. Carroll, A. Agramonte, Discovery of yellow fever virus and its transmission by
J. Lazear, C. Finlay mosquitoes
1903 M. Remlinger, Riffat-Bay, A. di Vestea Discovery of rabies virus
1907 P. Ashburn, C. Craig Discovery of dengue viruses
1909 K. Landsteiner, E. Popper Discovery of polioviruses
1911 P. Rousa Discovery of the first tumor virus: Rous sarcoma virus
1911 J. Goldberger, J. Anderson Discovery of measles virus
1915 F. Twort, F. d’Herelle Discovery of bacterial viruses (bacteriophages)
1918 Beginning of global pandemic of influenza
1919 A. Löwenstein Discovery of herpes simplex virus
1930 K. Meyer, C. Haring, B. Howitt Discovery of Western equine encephalitis virus
1931 M. Theilera Attenuation of yellow fever virus—vaccine development
1933 C. Andrews, P. Laidlaw, W. Smith Isolation of human influenza viruses in ferrets
1933 R. Muckenfuss, C. Armstrong, H. McCordock, Discovery of St. Louis encephalitis virus
L. Webster, G. Fite
1934 C. Johnson, E. Goodpasture Discovery of mumps virus
1934 M. Hayashi, S. Kasahara, R. Kawamura, T. Taniguchi Discovery of Japanese encephalitis virus
1935 W. Stanleya Purification/crystallization of tobacco mosaic virus
1936 C. Armstrong, T. Rivers, E. Traub Discovery of lymphocytic choriomeningitis virus
1937 L. Zilber, M. Chumakov, Discovery of tick-borne encephalitis virus (Russian spring
N. Seitlenok, E. Levkovich summer encephalitis virus)
1938 B. von Borries, H. Ruska, E. Ruska First electron micrograph of viruses (ectromelia, vaccinia
viruses)
1939 E. Ellis, M. Delbrück Development of one-step growth curve—bacteriophage
1940 K. Smithburn, T. Hughes, A. Burke, J. Paul Discovery of West Nile virus
1941 G. Hirst Discovery of agglutination of red blood cells by influenza
virus
1945 M. Chumakov, G. Courtois, colleagues Discovery of Crimean-Congo hemorrhagic fever virus
1948 G. Dalldorf, G. Sickles Discovery of Coxsackieviruses
1949 J. Endersa, T. Wellera, F. Robbinsa Development of cell culture methodology for polio, measles,
and other vaccines
1950 L. Florio, M. Miller, E. Mugrage Discovery of Colorado tick fever virus
1952 R. Dulbecco, M. Vogt Development of plaque assay for animal viruses—
polioviruses, Western equine encephalitis virus
1953 W. Rowe Discovery of human adenoviruses
(Continued)
