Overview of Viruses and Virus Infection
tive of viruses as a whole so that some overall understand-
INTRODUCTION
ing of this fascinating group of agents can emerge. Thus, we
The Science of Virology
consider many nonhuman viruses that are important for our
understanding of the evolution and biology of viruses.
The science of virology is relatively young. We can rec-
ognize specific viruses as the causative agents of epidem-
ics that occurred hundreds or thousands of years ago from
Viruses Cause Disease but Are Also
written descriptions of disease or from study of mummies
Useful as Tools
with characteristic abnormalities. Furthermore, immuniza-
Viruses are of intense interest because many cause serious
tion against smallpox has been practiced for more than a mil-
illness in humans or domestic animals, and others damage
lennium. However, it was only approximately 100 years ago
crop plants. During the last century, progress in the control
that viruses were shown to be filterable and therefore distinct
of infectious diseases through improved sanitation, safer
from bacteria that cause infectious disease. It was only about
water supplies, the development of antibiotics and vaccines,
60 years ago that the composition of viruses was described,
and better medical care have dramatically reduced the threat
and even more recently before they could be visualized as
to human health from these agents, especially in developed
particles in the electron microscope. Within the last 20 years,
countries. This is illustrated in Fig. 1.1, in which the death
however, the revolution of modern biotechnology has led to
rate from infectious disease in the United States during the
an explosive increase in our knowledge of viruses and their
last century is shown. At the beginning of the twentieth cen-
interactions with their hosts. Virology, the study of viruses,
tury, 0.8% of the population died each year from infectious
includes many aspects: the molecular biology of virus repli-
diseases. Today the rate is less than one-tenth as great. The
cation; the structure of viruses; the interactions of viruses and
use of vaccines has led to effective control of the most dan-
hosts and the diseases they cause in those hosts; the evolution
gerous of the viruses. Smallpox virus has been eradicated
and history of viruses and viral diseases; virus epidemiology,
worldwide by means of an ambitious and concerted effort,
the ecological niche occupied by viruses and how they spread
sponsored by the World Health Organization, to vaccinate all
from victim to victim; and the prevention of viral disease by
people at risk for the disease. Poliovirus and measles virus
vaccination, drugs, or other methods. The field is vast and
have been eliminated from the Americas by intensive vac-
any treatment of viruses must perforce be selective.
cination programs. There is hope that these two viruses will
Viruses are known to infect most organisms, including
also be eradicated worldwide in the near future. Vaccines
bacteria, blue-green algae, fungi, plants, insects, and verte-
exist for the control of many other viral diseases includ-
brates, but we attempt here to provide an overview of virol-
ing, among others, mumps, rabies, rubella, yellow fever,
ogy that emphasizes their potential as human disease agents.
Japanese encephalitis, rotaviral gastroenteritis, and, very
Because of the scope of virology, and because human viruses
recently, papillomaviral disease that is the primary cause of
that cause disease, especially epidemic disease, are not uni-
cervical cancer.
formly distributed across virus families, the treatment is not
The dramatic decline in the death rate from infectious dis-
intended to be comprehensive. Nevertheless, we feel that it is
ease has led to a certain amount of complacency. There is a
important that the human viruses be presented in the perspec-
40 States
1000
Have
Influenza Pandemic
Health
Departments
800
600
Last Human to Human
Transmission of Plague
First Continuous
400
First Use of
Municipal Use
Penicillin
of Chlorine in
Salk Vaccine
Water in the
Start of the AIDS
Introduced
United States
200
Epidemic
0
1900
1920
1940
1960
1980
2000
Year
FIGURE 1.1 Death rate from infectious diseases in the United States, 19001996. The death rate dropped over the
twentieth century from around 800 deaths per 100,000 population per year to about 50. Significant milestones in public
health are shown. After dropping steadily for 80 years, interrupted only by the influenza pandemic of 19181919, the
death rate began to rise in 1980 with the advent of the AIDS (acquired immunodeficiency syndrome) epidemic. From
Morbidity and Mortality Weekly Report (MMWR) (1999), Vol. 48, #29, p. 621.
small but vocal movement in the United States and Europe
current time. Human immunodeficiency virus (HIV), illus-
to eliminate immunization against viruses, for example.
trated in the figure, is a case in point.
However, viral diseases continue to plague humans, as do
The persistence of viruses is in part due to their ability
infectious diseases caused by bacteria, protozoa, fungi, and
to change rapidly and adapt to new situations. HIV is the
multicellular parasites. Deaths worldwide due to infectious
most striking example of the appearance of a virus that has
disease are shown in Fig. 1.2, divided into six categories. In
recently entered the human population and caused a plague of
2002 more than 3 million deaths occurred as a result of acute
worldwide importance. The arrival of this virus in the United
respiratory disease, much of which is caused by viruses.
States caused a noticeable rise in the total number of deaths
More than 2 million deaths were attributed to diarrheal dis-
from infectious disease, as seen in Fig. 1.1. Other, previously
eases, about half of which are due to viruses. AIDS killed 3
undescribed viruses also continue to emerge as serious patho-
million people worldwide in 2002, and measles is still a sig-
gens. Sin Nombre virus, a previously unknown virus associ-
nificant killer in developing countries. Recognition is grow-
ated with rodents, caused a 1994 outbreak in the United States
ing that infectious diseases, of which viruses form a major
of hantavirus pulmonary syndrome with a 50% case fatality
component, have not been conquered by the introduction of
rate, and it is now recognized as being widespread in North
vaccines and drugs. Viral diseases and disease caused by
America. Junin virus, the cause of Argentine hemorrhagic
other pathogens continue to resist elimination. Furthermore,
fever, as well as related viruses have become a more serious
the overuse of antibiotics has resulted in an upsurge in anti-
problem in South America with the spread of farming. Ebola
biotic-resistant bacteria, which has exacerbated the problems
virus, responsible for several small African epidemics with
caused by them.
a case fatality rate of 70%, was first described in the 1970s.
The incidence of disease in various parts of the world
Nipah virus, a previously unknown virus of bats, appeared
caused by a number of widespread viruses is illustrated in
in 1998 and caused 258 cases of encephalitis, with a 40%
Fig. 1.3. In the Americas and, for most viruses, Europe as
fatality rate, in Malaysia and Singapore. The SARS virus,
well, widespread use of vaccines has almost eliminated dis-
also a previously unknown virus of bats, caused an epidemic
ease caused by viruses for which vaccines exist. In devel-
that killed more than 700 humans worldwide in 20022003.
oping countries, measles, poliovirus, yellow fever virus,
The H5N1 strain of influenza, known as "bird flu," has killed
and rabies virus, as well as others not shown in the figure,
more than 150 humans in the last few years and there is fear
still cause serious problems although good vaccines exist.
that it might eventually cause a worldwide pandemic with
However, developed countries as well as developing coun-
hundreds of millions of deaths. It is obvious that the poten-
tries suffer from viruses for which no vaccines exist to the
tial for rapid spread of all viruses is increasing as faster and
Acute Respiratory
Disease
Diarrheal Disease
AIDS
Tuberculosis
2002
Malaria
1998
1995
Measles
0
1
2
3
4
5
Millions of Deaths per Year
FIGURE 1.2 Six leading infectious diseases as causes of death. Data are the totals for all ages worldwide in 1995,
1998, and 2002. The data came from the World Health Organization Web site: http://www.who.int/infectious-disease-
report/pages/graph 5.html, and the World Health Report 2003 at: (http://www.who.int/whr/2003/en/).
more extensive travel becomes ever more routine. The pos-
the United States, 1% of the population died during the epi-
sibility exists that any of these viruses could become more
demic and perhaps half of all deaths were due to influenza
widespread, as has HIV since its appearance in Africa per-
(Fig. 1.1). Continuing study of virus replication and virus
haps half a century ago, and as has West Nile virus, which
interactions with their hosts, surveillance of viruses in the
spread to the Americas in 1999. A discussion of emerging
field, and efforts to develop new vaccines as well as other
and reemerging viral diseases is found in Chapter 8.
methods of control are still important.
Newly emerging viruses are not the only ones to plague
The other side of the coin is that viruses have been use-
humans, however. Many viruses that have been known
ful to us as tools for the study of molecular and cellular
for a long time continue to cause widespread problems.
biology. Further, the development of viruses as vectors
Respiratory syncytial virus, as an example, is a major cause
for the expression of foreign genes has given them a new
of pneumonia in infants. Despite much effort, it has not yet
and expanded role in science and medicine, including their
been possible to develop an effective vaccine. Even when
potential use in gene therapy (Chapter 11). As testimony to
vaccines exist, problems may continue. For example, influ-
the importance of viruses in the study of biology, numerous
enza virus changes rapidly and the vaccine for it must be
Nobel Prizes have been awarded in recognition of important
reformulated yearly. Because the major reservoir for influ-
advances in biological science that resulted from studies
enza is birds, it is not possible to eradicate the virus. Thus,
that involved viruses (Table 1.1). To cite a few examples,
to control influenza would require that the entire population
Max Delbrück received the prize for pioneering studies in
be immunized yearly. This is a formidable problem and the
what is now called molecular biology, using bacteriophage
virus continues to cause annual epidemics with a signifi-
T4. Cellular oncogenes were first discovered from their
cant death rate (Chapter 4). Although primarily a killer of
presence in retroviruses that could transform cells in cul-
the elderly, the potential of influenza to kill the young and
ture, a discovery that resulted in a prize for Francis Peyton
healthy was shown by the worldwide epidemic of influenza
Rous for his discovery of transforming retroviruses, and
in 1918 in which 20100 million people died worldwide. In
for Michael Bishop and Harold Varmus, for showing that a
Americas
Europe
Measles HCV
Measles HCV
HIV
Canada
SE Asia
SARS
Mideast
Oceania
N. A.
Rabies Avian HCV HIV SARS
Measles
HIV WNV
Polio
Flu
Carib.
Measles Polio HCV
HIV
HIV
Africa
Measles HIV
HCV
S. A.
Cases
Vaccine
No Vaccine
Preventable
YFV HIV
107
106
Ebola HCV HIV
Measles
YF
Polio
Rabies
105
104
104
103
103
102
102
FIGURE 1.3 Incidence of selected infectious diseases worldwide and the effect of vaccination. The number of cases
is shown on a log scale such that each division represents 10-fold more cases than the division below it. The diseases for
which vaccines exist are shown in red. Adapted from Lattanzi et al. (2006), Figure 1. SARS, severe acute respiratory
syndrome; HIV, human immunodeficiency virus; WNV, West Nile virus; YFV, yellow fever virus; HCV, hepatitis C virus.
transforming retroviral gene had a cellular counterpart. As
of the RNA world that existed before the invention of DNA.
a third example, the development of the modern methods
All would accept the idea that viruses have been present for
of gene cloning have relied heavily on the use of restriction
hundreds of millions of years and have helped to shape the
enzymes and recombinant DNA technology, first devel-
evolution of their hosts. Viruses are capable of very rapid
oped by Daniel Nathans and Paul Berg working with SV40
change, both from drift due to nucleotide substitutions that
may occur at a rate 106-fold greater than that of the plants and
virus, and on the use of reverse transcriptase, discovered
by David Baltimore and Howard Temin in retroviruses. As
animals that they infect, and from recombination that leads
another example, the study of the interactions of viruses
to the development of entirely new families of viruses. This
with the immune system has told us much about how this
makes it difficult to trace the evolution of viruses back more
essential means of defense against disease functions, and
than a few millennia or perhaps a few million years. The
this resulted in a prize for Rolf Zinkernagel and Peter
development of increasingly refined methods of sequence
Doherty. The study of viruses and their use as tools has told
analysis, and the determination of more structures of virally
us as much about human biology as it has told us about the
encoded proteins, which change far more slowly than do the
viruses themselves.
amino acid sequences that form the structure, have helped
In addition to the interest in viruses that arises from their
identify relationships among viruses that were not at first
medical and scientific importance, viruses form a fascinat-
obvious. The coevolution of viruses and their hosts remains
ing evolutionary system. There is debate as to how ancient
a study that is intrinsically interesting and has much to tell
are viruses. Some argue that RNA viruses contain remnants
us about human biology.
TABLE 1.1 Nobel Prizes Involving Virologya
Year
Names
Nobel citation; virus group or family
1946 [Chemistry]
Wendell Stanley
Isolation, purification and crystallization of tobacco mosaic virus; Tobamovirus
1951
Max Theiler
Development of yellow fever vaccine; Flaviviridae
1954
John F. Enders, Thomas Weller,
Growth and cultivation of poliovirus; Picornaviridae
Frederick C. Robbins
1958
Joshua Lederberg
Transforming bacteriophages
1965
Francois Jacob, André Lwoff, Jacques Monod
Operons; bacteriophages
1966
Francis Peyton Rous
Discovery of tumor-producing viruses; Retroviridae
1969
Max Delbrück, Alfred D. Hershey,
Mechanism of virus infection in living cells; bacteriophages
Salvador E. Luria
1975
David Baltimore, Howard M. Temin,
Discoveries concerning the interaction between tumor viruses and the genetic
Renato Dulbecco
material of the cell; Retroviridae
1976
D. Carleton Gajdusek, Baruch S. Blumberg
New mechanisms for the origin and dissemination of infectious diseases; B with
Hepadnaviridae, G with prions
1978b
Daniel Nathans
Application of restriction endonucleases to the study of the genetics of SV40;
Polyomaviridae
1980 [Chemistry]
Paul Berg
Studies of the biochemistry of nucleic acids, with particular regard to
recombinant DNA (SV40); Polyomaviridae
1982 [Chemistry]
Aaron Klug
Development of crystallographic electron microscopy and structural
elucidation of biologically important nucleic acidprotein complexes;
Tobamovirus and Tymovirus
1988b
George Hitchings, Gertrude Elion
Important principles of drug treatment using nucleotide analogues (acyclovir)
1989
J. Michael Bishop, Harold E. Varmus
Discovery of the cellular origin of retroviral oncogenes; Retroviridae
1993
Phillip A. Sharp, Richard J. Roberts
Discoveries of split (spliced) genes; Adenoviridae
1996
Rolf Zinkernagel, Peter Doherty
Presentation of viral epitopes by MHC
1997
Stanley Prusiner
Prions
2006
Andrew Fire, Craig Mello
Discovery of RNAi
a
All prizes listed are in Physiology or Medicine except those three marked [Chemistry].
b
In these two instances, the prize was shared with unlisted recipients whose work did not involve viruses.
The Nature of Viruses
the cell, sometimes still in association with protein ("uncoat-
Viruses are subcellular, infectious agents that are obligate
ing"). The genome then redirects the cell to the replication
intracellular parasites. They infect and take over a host cell
of itself and to the production of progeny virions. The cel-
in order to replicate. The mature, extracellular virus particle
lular machinery that is in place for the production of energy
is called a virion. The virion contains a genome that may be
(synthesis of ATP) and for macromolecular synthesis, such
DNA or RNA wrapped in a protein coat called a capsid or
as translation of mRNA to produce proteins, is essential.
nucleocapsid. Some viruses have a lipid envelope surround-
It is useful to think of the proteins encoded in viral
ing the nucleocapsid (they are "enveloped"). In such viruses,
genomes as belonging to three major classes. First, most
glycoproteins encoded by the virus are embedded in the lipid
viruses encode enzymes required for replication of the
envelope. The function of the capsid or envelope is to protect
genome and the production of mRNA from it. RNA viruses
the viral genome while it is extracellular and to promote the
must encode an RNA polymerase or replicase, since cells do
entry of the genome into a new, susceptible cell. The struc-
not normally replicate RNA. Most DNA viruses have access
ture of viruses is covered in detail in Chapter 2.
to the cellular DNA replication machinery in the nucleus,
The nucleic acid genome of a virus contains the infor-
but even so, many encode new DNA polymerases for the
mation needed by the virus to replicate and produce new
replication of their genomes. Even if they use cellular DNA
virions after its introduction into a susceptible cell. Virions
polymerases, many DNA viruses encode at least an initiation
bind to receptors on the surface of the cell, and by processes
protein for genome replication. An overview of the replica-
described later the genome is released into the cytoplasm of
tion strategies used by different viruses is presented later,
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