C1 History of Virology
C1 History of Virology
C1 History 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
(Continued)
6 PART | I Principles of Virology
(Continued)
History and Impact of Virology Chapter | 1 7
FIGURE 1.2 In 1900, Walter Reed and his colleagues discovered yellow fever virus, the first human virus, and its transmission cycle. This is a famous
allegorical painting, entitled Conquerors of Yellow Fever by Dean Cornwell. It depicts Walter Reed (in white uniform) and Carlos Finlay (with white
hair) looking on as Jesse Lazear, who died of yellow fever a month later, applies an infected mosquito to the arm of James Carroll. The painting includes
Aristides Agramonte (behind Lazear), Leonard Wood (in brown helmet), Jefferson Kean (in white helmet), and several of the volunteers who subsequently
were infected in the same way. Carroll became infected as a result of this experiment—he survived, and went on to have a distinguished career as a
microbiologist, but suffered from chronic illness leading to an early death, said to be a consequence of his yellow fever infection. Purchased copy, used
with permission.
in remote parts of the world (Fig. 1.5). As is described in immune system recognizes virus-infected cells; and Georges
Chapter 11: Vaccines and Vaccination, vaccine research has Kohler and Cesar Milstein, who in 1975 developed the first
often exploited novel concepts, for example, the use of plasma monoclonal antibodies.
from chronically infected humans as a source of hepatitis B
virus (HBV) envelope protein to stimulate immunity against
THE VIROSPHERE
hepatitis B virus (1976), and the use of genetically modified
naked DNA preparations to induce the expression of antigens We live in what many now describe as the virosphere, since
in the tissues of vaccine recipients. almost all living multicellular and unicellular organisms
In 1957, Alick Isaacs and Jean Lindemann discovered are susceptible to virus infection. Take as an example the
interferons, molecules that represent the initial mammalian oceans: every liter of seawater is populated with up to 10
response to infection. Great hope was placed on the use billion viruses. It is estimated that there are around 5 × 1030
of interferons in the treatment of a wide spectrum of bacteria on planet Earth, and that viruses are numerically
human virus infections: although of proven use in certain at least more common; this means there are more viruses
conditions, however, the use of interferons has not lived up in the world than all life forms. The vast majority are
to the earlier wide promise suggested by laboratory studies. most likely viruses of bacteria (bacteriophages) serving
The sciences of immunology and cell and molecular to aid the recycling of organic matter, but some have a
biology have been intertwined with that of virology: more sophisticated role in the environment, for example,
landmark discoveries were made by Peter Doherty and determining insect behavior as an essential part of an
Rolf Zinkernagel, who in 1974 discovered how the cellular arthropod life cycle. This staggeringly large repertoire of
10 PART | I Principles of Virology
FIGURE 1.3 Thin-section electron microscopy of selected viruses. The remarkable diversity of the viruses is clearly revealed by thin-section electron
microscopy of infected cells—and this technique provides important information about morphogenesis and cytopathology. (A) Family Poxviridae, genus
Orthopoxvirus, variola virus. (B) Family Herpesviridae, genus Simplexvirus, human herpesvirus 1. (C) Family Adenoviridae, genus Mastadenovirus,
human adenovirus 5. (D) Family Togaviridae, genus Alphavirus, Eastern equine encephalitis virus. (E) Family Bunyaviridae, genus Hantavirus, Sin
Nombre virus. These images represent various magnifications; the details of the morphogenesis of the various viruses are given in the chapters of Part II
of this book.
FIGURE 1.4 Negative contrast electron microscopy of selected viruses. The remarkable diversity of the viruses is revealed by all kinds of electron
microscopy methods, but none better than by negative staining. (A) Family Poxviridae, genus Orthopoxvirus, vaccinia virus. (B) Family Papovaviridae,
genus Papillomavirus, human papillomavirus. (C) Family Filoviridae, Ebola virus. (D) Family Reoviridae, genus Rotavirus, human rotavirus. (E)
Family Herpesviridae, genus Simplexvirus, human herpesvirus 1 (capsid only, envelope not shown). (F) Family Rhabdoviridae, genus Lyssavirus, rabies
virus. (G) Family Caliciviridae, genus Norovirus, human norovirus. (H) Family Bunyaviridae, genus Phlebovirus, Rift Valley fever virus. (I) Family
Orthomyxoviridae, genus Influenzavirus A, influenza virus A/Hong Kong/1/68 (H3N2). These images represent various magnifications; the size of the
various viruses is given in Chapter 2: Classification of Viruses and Phylogenetic Relationships and in the chapters of Part II of this book.
repository of genetic information, and also contain various Viruses, on the other hand, are neither cellular nor
species of RNA and most, if not all, of the machinery microorganisms. The key differences between viruses and
for producing energy and macromolecules. These microorganisms are listed in Table 1.2. Viruses do not
microorganisms grow by synthesizing macromolecular possess functional organelles (e.g., mitochondria, Golgi,
constituents (nucleic acids, proteins, carbohydrates, and chloroplasts, and endoplasmic reticulum), and thus are
lipids), and most multiply by binary fission. totally dependent on the host for the machinery of energy
12 PART | I Principles of Virology
FIGURE 1.5 The World Health Organization Global Polio Eradication Initiative aims for global eradication of poliomyelitis by about 2018. The Initiative is
led by the World Health Organization, UNICEF, and the Rotary and Gates Foundations; it has reduced the number of cases from the many thousands per year to
less than 100 (359 cases in 2014; 74 cases in 2015). Polio will be the third disease globally eradicated, after smallpox and rinderpest. The most important step in
polio eradication is interruption of endemic transmission by universal infant vaccination using oral vaccine (OPV; often by organizing “national immunization
days”), supplementary IPV vaccination campaigns where needed, intensive surveillance of cases of flaccid paralysis, and in some places detection of virus in
sewage. Figures (clockwise from top left). An Egyptian stele (slab) thought to depict a polio victim—18th Dynasty (1403–1365 BC); patients with permanent
respiratory muscle paralysis after recovery from poliomyelitis would spend the rest of their lives requiring assisted respiration (immersed in an “iron lung”);
patients with permanent lower limb weakness following poliomyelitis; those remaining countries reporting cases of poliomyelitis in 2014; oral administration
of polio vaccine; in 1921, 39-year-old Franklin D. Roosevelt was diagnosed with poliomyelitis and was left with permanent paralysis from the waist down,
but was rarely photographed in a wheelchair. He was elected US president in 1932.
production and synthesis of macromolecules. Viruses contain and natural selection of those variants that survive the best.
only one type of functional nucleic acid, either DNA or Some viruses have continued to evolve in long association
RNA, never both, and differ from microorganisms in having with each associated hosts (e.g., herpesviruses, some
a life cycle divisible into two clearly defined phases. Outside retroviruses); others have evolved by “host species jumping”
of the host cell, the viruses are metabolically inert and can (e.g.,
influenza viruses), and yet others by developing
be considered as complexes of large macromolecules; zoonotic transmission schemes (e.g., rabies virus).
during this extracellular phase of the viral life cycle, virus Several important practical consequences follow from
transmission is dependent upon movements of air and fluid, understanding that viruses are different from microorganisms
and in some cases the life cycle of insect vectors. Once and all life forms: for example, some viruses can
inside the host cell, however, viruses behave with many of persist for the lifetime of the host cell by the integration of
the properties of living organisms; viruses are metabolically the DNA genome (or a DNA copy of the RNA genome) into
active in that the viral genome exploits the machinery of the the genome of the host cell, or by the carriage of viral DNA
host to produce progeny genome copies, viral messenger genomes by the host cell in episomal form. Since viruses
RNA, and viral proteins (often along with carbohydrates use the replicative machinery of the host, virus infections
and lipids), all of which are then assembled to form new present major challenges to antiviral drug development.
virions (virion, the complete virus particle). This assembly Drugs that interfere with viral replication nearly always
from pools of precursor molecules is in contrast to the interfere with essential host cell functions. This is in
multiplication of cellular organisms by binary fission. In contrast to bacteria, which have unique metabolic pathways
contrast to any microorganism, many viruses can reproduce different from those of the host, enabling these to be
even if only the viral DNA or RNA genome is introduced exploited as targets for antibiotics.
into the host cell. These qualities have been used to argue The simplest viruses consist of a DNA or RNA genome
the question, “Are viruses alive?” One answer is to envision contained within a protein coat, but there are classes of even
viruses “at the edge of life,” in some ways fulfilling the simpler infectious agents: (1) satellites, which are defective
criteria we use to define life, but mostly not. viruses, dependent upon a helper virus to supply essential
Given the unique characteristics of viruses, where might functions such as nucleic acid replication functions or
viruses have originated? There are three principal theories structural elements such as capsid proteins; (2) viroids,
that have been argued for many years. First, viruses may which as noted above consist of a naked RNA molecule that
have originated as escaped eukaryotic genes, that is nucleic is infectious; and (3) prions, the agents of the spongiform
acid sequences, that evolved to encode protective protein encephalopathies, consisting of an infectious protein
coats to allow survival outside of the environment of the cell without any associated nucleic acid.
(transposons and retrotransposons have been suggested as the
progenitors of retroviruses). Second, viruses may be degenerate
SCOPE OF THIS BOOK
forms of intracellular parasites, having lost most cellular
functions (bacteria have been suggested as the progenitors of From its beginning medical virology has been intertwined
mitochondria, chloroplasts, and poxviruses); and third, viruses with many related sciences. Even though this book deals
may have originated independently along with other primitive with medical virology per se—the viruses infecting humans
molecules and developed with self-replicating capabilities. and the diseases so caused—understanding the full scope
In the absence of fossil remains, insight as to virus of the subject requires a continuing appreciation and
evolution relies almost entirely on sequence analyses of integration of related sciences, from cell biology to medical
virus genomes. For example, the genome of a plant viroid epidemiology and extending to human social behavior. The
(a subviral agent comprised of infectious naked RNA), perspective represented by this book, of medical virology as
potato spindle tuber viroid, seems to be a self-replicating an infectious disease science, is meant to provide a starting
RNA copy of a part of the host potato DNA. Many of the point, an anchor, for those who must relate the subject to
genes of poxviruses are similar to those of eukaryote hosts. clinical practice, public health practice, scholarly research,
In any case, it seems certain from sequence analyses of and other endeavors.
viral genomes that all presently recognized viruses did not Part I of this book thus deals with the properties of
evolve from a single progenitor; rather, different kinds of viruses, how viruses replicate, and how viruses cause
viruses likely arose independently from different origins, disease. These chapters are then followed by an overview
and then continued to diversify and adapt survival and of the principles of diagnosis, epidemiology, and how virus
transmission qualities to better fit particular niches by the infections can be controlled. This first section is concluded
usual Darwinian process of mutation and natural selection. by a discussion on emergence and attempts to predict the
It should be stressed that the genetic blueprint of next major public health challenges. These form a guide for
all viruses is under continuing evolutionary pressure, delving into the specific diseases of interest to the reader as
sometimes showing dramatic examples of genetic change described in Part II.
14 PART | I Principles of Virology
FURTHER READING Knipe, D.M., Howley, P.M., et al., 2013. Field’s Virology, sixth ed. Lippincott
Williams and Wilkins, Philadelphia, ISBN 978-145-110563-6.
Crawford, D.H., 2011. A Very Short Introduction to Viruses. Oxford MacLachlan, N.J., Dubovi, E.J., 2011. Fenner’s Veterinary Virology, fourth
University Press, Oxford. ed. Academic Press, London, ISBN 978-0-12-375158-4.
Flint, S.J., Racaniello, V.R., Rall, G.F., Skalka, A.M., Enquist, L., Waterson, A.P., Wilkinson, L., 1978. An Introduction to the History of Virology.
2015. Principles of Virology, two volumes, fourth ed. ASM Press, Cambridge University Press, Cambridge, ISBN 978-0-521-21917-5.
Washington, DC, ISBN-10: 1555819516. Zimmer, C., 2011. A Planet of Viruses. University of Chicago Press,
Kaslow, R.A., Stanberry, L.R., LeDuc, J.W., 2014. Viral Infections of Chicago, ISBN 978-0-226-98335-6.
Humans, Epidemiology and Control, fifth ed. Springer, New York, Zinsser, H., 1935, reprinted 2007. Rats, Lice and History. Transaction
ISBN 978-1-4899-7447-1. Publishers, New Brunswick, USA, ISBN 978-1-4128-0672-5.