Virology is the study of
viruses and virus-like agents: their structure,
classification and evolution, their ways to infect and exploit
cells for virus reproduction, the
diseases they cause, the techniques to isolate and culture them,
and their use in research and therapy. Virology is often considered
a part of
microbiology or of
pathology.
Virus structure and classification
A major branch of virology is
virus
classification. Viruses can be classified according to the host
cell they infect: animal viruses,
plant
viruses,
fungal viruses, and
bacteriophages (viruses infecting
bacteria, which include the most complex viruses).
Another classification uses the geometrical shape of their
capsid (often a
helix or an
icosahedron) or the virus's structure
(e.g. presence or absence of a
lipid envelope). Viruses range in size from about
30 nm to about
450
nm, which means that most of them cannot be seen with
light microscopes. The shape and structure
of viruses can be studied with
electron microscopy, with
NMR spectroscopy, and most importantly with
X-ray crystallography.
The most useful and most widely used classification system
distinguishes viruses according to the type of
nucleic acid they use as genetic material and
the
viral replication method they
employ to coax host cells into producing more viruses:
In addition virologists also study
subviral particles,
infectious entities even smaller than viruses:
viroids (naked circular RNA molecules infecting
plants),
satellites (nucleic
acid molecules with or without a capsid that require a helper virus
for infection and reproduction), and
prions
(
proteins that can exist in a pathological
conformation that induces other prion molecules to assume that same
conformation).
The latest report by the
International
Committee on Taxonomy of Viruses (2005) lists 5450 viruses,
organized in over 2,000 species, 287 genera, 73 families and 3
orders.
The
taxa in virology are not necessarily
monophyletic. In fact, the evolutionary
relationships of the various virus groups remain unclear, and three
hypotheses regarding their origin exist:
- Viruses arose from non-living matter, separately from and in
parallel to other life forms, possibly in the form of
self-reproducing RNA ribozymes similar to viroids.
- Viruses arose from earlier, more competent cellular life forms
that became parasites to host cells and subsequently lost most of
their functionality; examples of such tiny parasitic prokaryotes
are Mycoplasma and Nanoarchaea.
- Viruses arose as parts of the genome of cells, most likely
transposons or plasmids, that acquired the ability to "break free"
from the host cell and infect other cells.
It is of course possible that different alternatives apply to
different virus groups.
Of particular interest here is
mimivirus,
a giant virus that infects
amoebae and
carries much of the molecular machinery traditionally associated
with bacteria. Is it a simplified version of a parasitic
prokaryote, or did it originate as a simpler virus that acquired
genes from its host?
The evolution of viruses, which often occurs in concert with the
evolution of their hosts, is studied in the field of
viral evolution.
While viruses reproduce and evolve, they don't engage in
metabolism and depend on a host cell for
reproduction. The often-debated question of whether they are alive
or not is a matter of definition that does not affect the
biological reality of viruses.
Viral diseases and host defenses
One main motivation for the study of viruses is the fact that they
cause many important infectious diseases, among them the
common cold,
influenza,
rabies,
measles, many
forms of
diarrhea,
hepatitis,
yellow
fever,
polio,
smallpox and
AIDS.
Herpes simplex causes cold sores and
genital herpes and is under investigation as a possible factor in
Alzheimer's.
Some viruses, known as
oncoviruses,
contribute to certain forms of
cancer. The
best studied example is the association between
Human papillomavirus and
cervical cancer: it is now acknowledged that
almost all cases of cervical cancer are caused by certain strains
of this sexually transmitted virus. Another example is infection
with
hepatitis B and
hepatitis C viruses, which are associated with
liver cancer.
Some subviral particles also cause disease: the
transmissible spongiform
encephalopathies, which include
Kuru,
Creutzfeldt-Jakob disease and
bovine spongiform
encephalopathy ("mad cow disease"), are caused by prions, and
hepatitis D is due to a satellite
virus.
The study of the manner in which viruses cause disease is
viral pathogenesis. The degree to which a
virus causes disease is its
virulence.
When the
immune system of a
vertebrate encounters a virus, it produces
specific
antibodies which bind to the virus
and mark it for destruction. The presence of these antibodies is
often used to determine whether a person has been exposed to a
given virus in the past, with tests such as
ELISA.
Vaccinations protect
against viral diseases, in part, by eliciting the production of
antibodies. Specifically constructed
monoclonal antibodies can also be used
to detect the presence of viruses, with a technique called
fluorescence microscopy.
A second defense of vertebrates against viruses,
cell-mediated immunity, involves
immune cells known as
T cells: the body's cells constantly display short
fragments of their proteins on the cell's surface, and if a T cell
recognizes a suspicious viral fragment there, the host cell is
destroyed and the virus-specific T-cells proliferate. This
mechanism is jump-started by certain vaccinations.
RNA interference, an important
cellular mechanism found in plants, animals and many other
eukaryotes, most likely evolved as a defense
against viruses. An elaborate machinery of interacting enzymes
detects double-stranded RNA molecules (which occur as part of the
life cycle of many viruses) and then proceeds to destroy all
single-stranded versions of those detected RNA molecules.
Every lethal viral disease presents a paradox: killing its host is
obviously of no benefit to the virus, so how and why did it evolve
to do so? Today it is believed that most viruses are relatively
benign in their natural hosts; the lethal viral diseases are
explained as resulting from an "accidental" jump of the virus from
a species in which it is benign to a new one that is not accustomed
to it (see
zoonosis). For example, serious
influenza viruses probably have pigs or birds as their natural
host, and
HIV is thought to derive from the
benign non-human primate virus
SIV.
While it has been possible to prevent (certain) viral diseases by
vaccination for a long time, the development of
antiviral drugs to
treat viral
diseases is a comparatively recent development. The first such drug
was
interferon, a substance that is
naturally produced by certain immune cells when an infection is
detected and stimulates other parts of the immune system.
Molecular biology research and viral therapy
Bacteriophages, the viruses which
infect
bacteria, can be relatively easily
grown as
viral plaques on
bacterial cultures. Bacteriophages
occasionally move genetic material from one bacterial cell to
another in a process known as
transduction, and this
horizontal gene transfer is one
reason why they served as a major research tool in the early
development of
molecular biology.
The
genetic code, the function of
ribozymes, the first
recombinant DNA and early
genetic libraries were all arrived at
using bacteriophages. Certain genetic elements derived from
viruses, such as highly effective
promoters, are commonly used in molecular biology
research today.
Growing animal viruses outside of the living host animal is more
difficult. Classically, fertilized chicken eggs have often been
used, but
cell cultures are
increasingly employed for this purpose today.
Since some viruses that infect
eukaryotes
need to transport their genetic material into the host cell's
nucleus, they are attractive tools for
introducing new genes into the host (known as
transformation or
transfection). Modified retroviruses are often
used for this purpose, as they integrate their genes into the
host's
chromosomes.
This approach of using viruses as gene vectors is being pursued in
the
gene therapy of genetic diseases.
An obvious problem to be overcome in viral gene therapy is the
rejection of the transforming virus by the immune system.
Phage therapy, the use of
bacteriophages to combat bacterial diseases, was a popular research
topic before the advent of
antibiotics
and has recently seen renewed interest.
Oncolytic viruses are viruses that
preferably infect
cancer cells. While early
efforts to employ these viruses in the therapy of cancer failed,
there have been reports in 2005 and 2006 of encouraging preliminary
results.
Other uses of viruses
A new application of genetically engineered viruses in
nanotechnology was recently described; see
Virus#Materials
science and nanotechnology. For a use in mapping
neurons see
Pseudorabies#Applications
in Neuroscience.
History of virology
A very early form of vaccination known as
variolation was developed several thousand years
ago in China. It involved the application of materials from
smallpox sufferers in order to immunize
others.
In
1717 Lady Mary Wortley
Montagu observed the practice in Istanbul
and
attempted to popularize it in Britain, but encountered considerable
resistance. In 1796
Edward
Jenner developed a much safer method, using
cowpox to successfully immunize a young boy against
smallpox, and this practice was widely adopted. Vaccinations
against other viral diseases followed, including the successful
rabies vaccination by
Louis Pasteur in 1886. The nature of viruses
however was not clear to these researchers.
In 1892
Dimitri Ivanovski showed
that a disease of
tobacco plants,
tobacco mosaic disease, could be
transmitted by extracts that were passed through filters fine
enough to exclude even the smallest known bacteria. In 1898
Martinus Beijerinck, also
working on tobacco plants, found that this "filterable agent" grew
in the host and was thus not a mere
toxin. The
question of whether the agent was a "living fluid" or a particle
was however still open.
In 1903 it was suggested for the first time that
transduction by viruses might cause
cancer. Such an
oncovirus in chickens was
described by
Francis Peyton Rous
in 1911; it was later called
Rous
sarcoma virus 1 and understood to be a
retrovirus. Several other cancer-causing
retroviruses have since been described.
The existence of viruses that infect bacteria (bacteriophages) was
first recognized by
Frederick Twort
in 1911, and, independently, by
Felix
d'Herelle in 1917. Since bacteria could be grown easily in
culture, this led to an explosion of virology research.
The cause of the devastating
Spanish flu
pandemic of 1918 was initially unclear. In late 1918, French
scientists showed that a "filter-passing virus" could transmit the
disease to people and animals, fulfilling
Koch's postulates.
While plant viruses and bacteriophages can be grown comparatively
easily, animal viruses normally require a living host animal, which
complicates their study immensely. In 1931 it was shown that
influenza virus could be grown in
fertilized chicken eggs, a method that is still used today to
produce vaccines. In 1937,
Max Theiler
managed to grow the
yellow fever virus
in chicken eggs and produced a vaccine from an attenuated virus
strain; this vaccine saved millions of lives and is still being
used today.
Max Delbrück, an important
investigator in the area of bacteriophages, described the basic
life cycle of a virus in 1937: rather than "growing", a virus
particle is assembled from its constituent pieces in one step;
eventually it leaves the host cell to infect other cells. The
Hershey-Chase experiment in
1952 showed that only
DNA and not protein enters
a bacterial cell upon infection with
bacteriophage T2.
Transduction of bacteria by
bacteriophages was first described in the same year.
In 1949
John F. Enders,
Thomas Weller and
Frederick Robbins reported that they had
been able to grow
poliovirus in cultured
human embryonal cells, the first significant example of an animal
virus grown outside of animals or chicken eggs. This work aided
Jonas Salk in deriving a polio vaccine
from killed polio viruses; this vaccine was shown to be effective
in 1955.
The first virus that could be
crystalized
and whose structure could therefore be elucidated in detail was
tobacco mosaic virus (TMV), the
virus that had been studied earlier by Ivanovski and Beijerink. In
1935,
Wendell Stanley
achieved its crystallization for
electron microscopy and showed that it
remains active even after crystallization. Clear
X-ray diffraction pictures of the
crystallized virus were obtained by Bernal and Fankuchen in 1941.
Based on such pictures,
Rosalind
Franklin proposed the full structure of the tobacco mosaic
virus in 1955. Also in 1955,
Heinz
Fraenkel-Conrat and
Robley
Williams showed that purified TMV
RNA and
its
capsid (coat) protein can assemble by
themselves to form functional viruses, suggesting that this simple
mechanism is likely the natural assembly mechanism within the host
cell, as Delbrück had proposed earlier.
In 1963, the
Hepatitis B virus was
discovered by
Baruch Blumberg who
went on to develop a vaccine against Hepatitis B.
In 1965,
Howard Temin described the
first
retrovirus: an RNA-virus that was
able to insert its genome in the form of DNA into the host's
genome.
Reverse transcriptase,
the key enzyme that retroviruses use to translate their RNA into
DNA, was first described in 1970, independently by Howard Temin and
David Baltimore. The first
retrovirus infecting
humans was identified by
Robert Gallo in 1974. Later it was
found that reverse transcriptase is not specific to retroviruses;
retrotransposons which code for
reverse transcriptase are abundant in the genomes of all
eukaryotes. About 10-40% of the human genome derives from such
retrotransposons.
In 1975 the functioning of oncoviruses was clarified considerably.
Until that time, it was thought that these viruses carried certain
genes called
oncogenes which, when inserted
into the host's genome, would cause cancer.
Michael Bishop and
Harold Varmus showed that the oncogene of
Rous sarcoma virus is in fact not
specific to the virus but is contained in the genome of healthy
animals of many species. The oncovirus can switch this pre-existing
benign proto-oncogene on, turning it into a true oncogene that
causes cancer.
1976 saw the first recorded outbreak of
Ebola hemorrhagic fever, a highly
lethal virally transmitted disease.
In 1977,
Frederick Sanger achieved
the first complete sequencing of the
genome
of any organism, the bacteriophage
Phi X
174. In the same year,
Richard
Roberts and
Phillip Sharp
independently showed that the genes of
adenovirus contain
introns
and therefore require
gene splicing.
It was later realized that almost all genes of eukaryotes have
introns as well.
A worldwide vaccination campaign led by the UN
World Health Organization resulted
in the eradication of
smallpox in
1979.
In 1982,
Stanley Prusiner
discovered
prions and showed that they cause
scrapie.
The first cases of
AIDS were reported in 1981,
and
HIV, the retrovirus causing it, was
identified in 1983 by
Robert Gallo and
Luc Montagnier. Tests detecting HIV
infection by detecting the presence of HIV antibody were developed.
Subsequent tremendous research efforts turned HIV into the best
studied virus.
Human Herpes Virus
8, the cause of
Kaposi's
sarcoma which is often seen in AIDS patients, was identified in
1994. Several
antiretroviral
drugs were developed in the late 1990s, decreasing AIDS
mortality dramatically in developed countries.
The
Hepatitis C virus was
identified using novel
molecular
cloning techniques in 1987, leading to screening tests that
dramatically reduced the incidence of post-
transfusion hepatitis.
The first attempts at
gene therapy
involving viral vectors began in the early 1980s, when retroviruses
were developed that could insert a foreign gene into the host's
genome. They contained the foreign gene but did not contain the
viral genome and therefore could not reproduce. Tests in mice were
followed by tests in
humans, beginning in
1989. The first human studies attempted to correct the genetic
disease
severe combined
immunodeficiency (SCID), but clinical success was limited. In
the period from 1990 to 1995, gene therapy was tried on several
other diseases and with different viral vectors, but it became
clear that the initially high expectations were overstated. In 1999
a further setback occurred when 18-year-old
Jesse Gelsinger died in a gene therapy
trial. He suffered a severe immune response after having received
an
adenovirus vector. Success in the gene
therapy of two cases of X-linked
SCID was reported in
2000.
In 2002 it was reported that
poliovirus
had been synthetically assembled in the laboratory, representing
the first synthetic organism. Assembling the 7741-base genome from
scratch, starting with the virus's published RNA sequence, took
about two years. In 2003 a faster method was shown to assemble the
5386-base genome of the bacteriophage
Phi X
174 in 2 weeks.
The giant
mimivirus, in some sense an
intermediate between tiny prokaryotes and ordinary viruses, was
described in 2003 and
sequenced in
2004.
The strain of
Influenza A
virus subtype H1N1 that killed up to 50 million people during
the
Spanish flu pandemic in 1918 was
reconstructed in 2005. Sequence information was pieced together
from preserved tissue samples of flu victims; viable virus was then
synthesized from this sequence. The
2009 flu pandemic involved another strain
of Influenza A H1N1, commonly known as "swine flu".
By 1985,
Harald zur Hausen had
shown that two strains of
Human
papillomavirus (HPV) cause most cases of
cervical cancer. Two vaccines protecting
against these strains were released in 2006.
In 2006 and 2007 it was reported that introducing a small number of
specific
transcription factor
genes into normal skin cells of mice or
humans
can turn these cells into
pluripotent
stem cells, known as
Induced Pluripotent Stem
Cells. The technique uses modified retroviruses to transform
the cells; this is a potential problem for human therapy since
these viruses integrate their genes at a random location in the
host's genome, which can interrupt other genes and potentially
causes cancer.
See also
References
- Viruses: The new cancer hunters, IsraCast, 1
March 2006
- The Medical and Scientific Conceptions of Influenza,
Human Virology at Stanford
- 2000 Albert Lasker Award for Clinical Medical
Research, The Lasker Foundation. Accessed 20 February 2008
- Zeger Debyser. A Short Course on Virology / Vectorology / Gene
Therapy, Current Gene Therapy, 2003, 3, 495-499
- Stem Cells—This Time without the Cancer,
Scientific American News, 30 November 2007
- Villarreal, L. P. (2005) Viruses and the Evolution
of Life. ASM Press, Washington DC ISBN
1-55581-309-7
- Samuel Baron (ed.) (1996) Medical Microbiology,
4th ed., Section 2: Virology (freely searchable online
book)
- Coffin, Hughes, Varmus. (1997) Retroviruses (freely searchable online
book)
External links and sources
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