Virus (life science)
| I | INTRODUCTION |
Virus (life
science), infectious agent found in virtually all life forms, including
humans, animals, plants, fungi, and bacteria. Viruses consist of genetic
material—either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)—surrounded
by a protective coating of protein, called a capsid, with or without an
outer lipid envelope. Viruses are between 20 and 100 times smaller than bacteria
and hence are too small to be seen by light microscopy. Viruses vary in size
from the largest poxviruses of about 450 nanometers (about 0.000014 in) in
length to the smallest polioviruses of about 30 nanometers (about 0.000001 in).
Viruses are not considered free-living, since they cannot reproduce outside of a
living cell; they have evolved to transmit their genetic information from one
cell to another for the purpose of replication.
Viruses often damage or kill the cells that
they infect, causing disease in infected organisms. A few viruses stimulate
cells to grow uncontrollably and produce cancers. Although many infectious
diseases, such as the common cold, are caused by viruses, there are no cures for
these illnesses. The difficulty in developing antiviral therapies stems from the
large number of variant viruses that can cause the same disease, as well as the
inability of drugs to disable a virus without disabling healthy cells. However,
the development of antiviral agents is a major focus of current research, and
the study of viruses has led to many discoveries important to human health.
| II | STRUCTURE AND CLASSIFICATION |
Individual viruses, or virus particles, also
called virions, contain genetic material, or genomes, in one of
several forms. Unlike cellular organisms, in which the genes always are made up
of DNA, viral genes may consist of either DNA or RNA. Like cell DNA, almost all
viral DNA is double-stranded, and it can have either a circular or a linear
arrangement. Almost all viral RNA is single-stranded; it is usually linear, and
it may be either segmented (with different genes on different RNA molecules) or
nonsegmented (with all genes on a single piece of RNA).
The viral protective shell, or capsid, can
be either helical (spiral-shaped) or icosahedral (having 20
triangular sides). Capsids are composed of repeating units of one or a few
different proteins. These units are called protomers or capsomers.
The proteins that make up the virus particle are called structural proteins.
Viruses also carry genes for making proteins that are never incorporated into
the virus particle and are found only in infected cells. These viral proteins
are called nonstructural proteins; they include factors required for the
replication of the viral genome and the production of the virus particle.
Capsids and the genetic material (DNA or
RNA) they contain are together referred to as nucleocapsids. Some virus
particles consist only of nucleocapsids, while others contain additional
structures.
Some icosahedral and helical animal viruses
are enclosed in a lipid envelope acquired when the virus buds through host-cell
membranes. Inserted into this envelope are glycoproteins that the viral
genome directs the cell to make; these molecules bind virus particles to
susceptible host cells.
The most elaborate viruses are the
bacteriophages, which use bacteria as their hosts. Some bacteriophages resemble
an insect with an icosahedral head attached to a tubular sheath. From the base
of the sheath extend several long tail fibers that help the virus attach to the
bacterium and inject its DNA to be replicated and to direct capsid production
and virus particle assembly inside the cell.
Viroids and prions are smaller
than viruses, but they are similarly associated with disease. Viroids are
plant pathogens that consist only of a circular, independently replicating RNA
molecule. The single-stranded RNA circle collapses on itself to form a rodlike
structure. The only known mammalian pathogen that resembles plant viroids is the
deltavirus (hepatitis D), which requires hepatitis B virus proteins to package
its RNA into virus particles. Co-infection with hepatitis B and D can
produce more severe disease than can infection with hepatitis B alone. Prions
are mutated forms of a normal protein found on the surface of certain animal
cells. The mutated protein, known as a prion, has been implicated in some
neurological diseases such as Creutzfeldt-Jakob disease and Bovine Spongiform
Encephalopathy. There is some evidence that prions resemble viruses in their
ability to cause infection. Prions, however, lack the nucleic acid found in
viruses.
Viruses are classified according to their
type of genetic material, their strategy of replication, and their structure.
The International Committee on Nomenclature of Viruses (ICNV), established in
1966, devised a scheme to group viruses into families, subfamilies, genera, and
species. The ICNV report published in 1995 assigned more than 4000 viruses into
71 virus families. Hundreds of other viruses remain unclassified because of the
lack of sufficient information.
| III | REPLICATION |
The first contact between a virus particle
and its host cell occurs when an outer viral structure docks with a specific
molecule on the cell surface. For example, a glycoprotein called gp120 on the
surface of the human immunodeficiency virus (HIV, the cause of acquired
immunodeficiency syndrome, or AIDS) virion specifically binds to the CD4
molecule found on certain human T lymphocytes (a type of white blood cell). Most
cells that do not have surface CD4 molecules generally cannot be infected by
HIV.
After binding to an appropriate cell, a
virus must cross the cell membrane. Some viruses accomplish this goal by fusing
their lipid envelope to the cell membrane, thus releasing the nucleocapsid into
the cytoplasm of the cell. Other viruses must first be endocytosed
(enveloped by a small section of the cell’s plasma membrane that pokes into the
cell and pinches off to form a bubblelike vesicle called an endosome) before
they can cross the cell membrane. Conditions in the endosome allow many viruses
to change the shape of one or more of their proteins. These changes permit the
virus either to fuse with the endosomal membrane or to lyse the endosome
(cause it to break apart), allowing the nucleocapsid to enter the cell
cytoplasm.
Once inside the cell, the virus replicates
itself through a series of events. Viral genes direct the production of proteins
by the host cellular machinery. The first viral proteins synthesized by some
viruses are the enzymes required to copy the viral genome. Using a combination
of viral and cellular components, the viral genome can be replicated thousands
of times. Late in the replication cycle for many viruses, proteins that make up
the capsid are synthesized. These proteins package the viral genetic material to
make newly formed nucleocapsids.
To complete the virus replication cycle,
viruses must exit the cell. Some viruses bud out of the cell’s plasma membrane
by a process resembling reverse endocytosis. Other viruses cause the cell to
lyse, thereby releasing newly formed virus particles ready to infect other
cells. Still other viruses pass directly from one cell into an adjacent cell
without being exposed to the extracellular environment. The virus replication
cycle can be as short as a couple of hours for certain small viruses or as long
as several days for some large viruses.
Some viruses kill cells by inflicting
severe damage resulting in cell lysis; other viruses cause the cell to kill
itself in response to virus infection. This programmed cell suicide is thought
to be a host defense mechanism to eliminate infected cells before the virus can
complete its replication cycle and spread to other cells. Alternatively, cells
may survive virus infection, and the virus can persist for the life of its host.
Virtually all people harbor harmless viruses.
Retroviruses, such as HIV, have RNA that is
transcribed into DNA by the viral enzyme reverse transcriptase upon entry
into the cell. (The ability of retroviruses to copy RNA into DNA earned them
their name because this process is the reverse of the usual transfer of genetic
information, from DNA to RNA.) The DNA form of the retrovirus genome is then
integrated into the cellular DNA and is referred to as the provirus. The
viral genome is replicated every time the host cell replicates its DNA and is
thus passed on to daughter cells.
Hepatitis B virus can also transcribe RNA
to DNA, but this virus packages the DNA version of its genome into virus
particles. Unlike retroviruses, hepatitis B virus does not integrate into the
host cell DNA.
| IV | DISEASE |
Most viral infections cause no symptoms and
do not result in disease. For example, only a small percentage of individuals
who become infected with Epstein-Barr virus or western equine encephalomyelitis
virus ever develop disease symptoms. In contrast, most people who are infected
with measles, rabies, or influenza viruses develop the disease. A wide variety
of viral and host factors determine the outcome of virus infections. A small
genetic variation can produce a virus with increased capacity to cause disease.
Such a virus is said to have increased virulence.
Viruses can enter the body by several
routes. Herpes simplex virus and poxviruses enter through the skin by direct
contact with virus-containing skin lesions on infected individuals. Ebola,
hepatitis B, and HIV can be contracted from infected blood products. Hypodermic
needles and animal and insect bites can transmit a variety of viruses through
the skin. Viruses that infect through the respiratory tract are usually
transmitted by airborne droplets of mucus or saliva from infected individuals
who cough or sneeze. Viruses that enter through the respiratory tract include
orthomyxovirus (influenza), rhinovirus and adenovirus (common cold), and
varicella-zoster virus (chicken pox). Viruses such as rotavirus, coronavirus,
poliovirus, hepatitis A, and some adenoviruses enter the host through the
gastrointestinal tract. Sexually transmitted viruses, such as herpes simplex,
HIV, and human papilloma viruses (HPV), gain entry through the genitourinary
route. Other viruses, including some adenoviruses, echoviruses, Coxsackie
viruses, and herpesviruses, can infect through the eye.
Virus infections can be either localized or
systemic. The path of virus spread through the body in systemic infections
differs among different viruses. Following replication at the initial site of
entry, many viruses are spread to their target organs by the bloodstream or the
nervous system.
The particular cell type can influence the
outcome of virus infection. For example, herpes simplex virus undergoes lytic
replication in skin cells around the lips but can establish a latent or dormant
state in neuron cell bodies (located in ganglia) for extended periods of time.
During latency, the viral genome is largely dormant in the cell nucleus until a
stimulus such as a sunburn causes the reactivation of latent herpesvirus,
leading to the lytic replication cycle. Once reactivated, the virus travels from
the ganglia back down the nerve to cause a cold sore on the lip near the
original site of infection. The herpesvirus genome does not integrate into the
host cell genome.
Virus-induced illnesses can be either acute,
in which the patient recovers promptly, or chronic, in which the virus remains
with the host or the damage caused by the virus is irreparable. For most acute
viruses, the time between infection and the onset of disease can vary from three
days to three weeks. In contrast, onset of AIDS following infection with HIV
takes an average of 7 to 11 years.
Several human viruses are likely to be
agents of cancer, which can take decades to develop. The precise role of these
viruses in human cancers is not well understood, and genetic and environmental
factors are likely to contribute to these diseases. But because a number of
viruses have been shown to cause tumors in animal models, it is probable that
many viruses have a key role in human cancers.
Some viruses—alphaviruses and flaviviruses,
for example—must be able to infect more than one species to complete their life
cycles. Eastern equine encephalomyelitis virus, an alphavirus, replicates in
mosquitoes and is transmitted to wild birds when the mosquitoes feed. Thus, wild
birds and perhaps mammals and reptiles serve as the virus reservoir, and
mosquitoes serve as vectors essential to the virus life cycle by ensuring
transmission of the virus from one host to another. Horses and people are
accidental hosts when they are bitten by an infected mosquito, and they do not
play an important role in virus transmission.
| V | DEFENSE |
Although viruses cannot be treated with
antibiotics, which are effective only against bacteria, the body’s immune system
has many natural defenses against virus infections. Infected cells produce
interferons and other cytokines (soluble components that are
largely responsible for regulating the immune response), which can signal
adjacent uninfected cells to mount their defenses, enabling uninfected cells to
impair virus replication. Some cytokines can cause a fever in response to viral
infection; elevated body temperature retards the growth of some types of
viruses. B lymphocytes produce specific antibodies that can bind and inactivate
viruses. Cytotoxic T cells recognize virus-infected cells and target them for
destruction. However, many viruses have evolved ways to circumvent some of these
host defense mechanisms.
The development of antiviral therapies has
been thwarted by the difficulty of generating drugs that can distinguish viral
processes from cellular processes. Therefore, most treatments for viral diseases
simply alleviate symptoms, such as fever, dehydration, and achiness.
Nevertheless, antiviral drugs for influenza virus, herpesviruses, and HIV are
available, and many others are in the experimental and developmental
stages.
Prevention has been a more effective method
of controlling virus infections. Viruses that are transmitted by insects or
rodent excretions can be controlled with pesticides. Successful vaccines are
currently available for poliovirus, influenza, rabies, adenovirus, rubella,
yellow fever, measles, mumps, and chicken pox. Vaccines are prepared from killed
(inactivated) virus, live (attenuated or weakened) virus, or isolated viral
proteins (subunits). Each of these types of vaccines elicits an immune response
while causing little or no disease, and there are advantages and disadvantages
to each. (For a more complete discussion of vaccines, see the Immunization
article.)
The principle of vaccination was discovered
by British physician Edward Jenner. In 1796 Jenner observed that milkmaids in
England who contracted the mild cowpox virus infection from their cows were
protected from smallpox, a frequently fatal disease. In 1798 Jenner formally
demonstrated that prior infection with cowpox virus protected those that he
inoculated with smallpox virus (an experiment that would not meet today’s
protocol standards because of its use of human subjects). In 1966 the World
Health Organization (WHO) initiated a program to eradicate smallpox from the
world. Because it was impossible to vaccinate the entire world population, the
eradication plan was to identify cases of smallpox and then vaccinate all of the
individuals in that vicinity. The last reported case of smallpox was in Somalia
in October 1977. An important factor in the success of eradicating smallpox was
that humans are the only host and there are no animal reservoirs for smallpox
virus. The strain of poxvirus used for immunization against smallpox was called
vaccinia. Introduction of the Salk (inactivated) and Sabin (live, attenuated)
vaccines for poliovirus, developed in the 1950s by the American physician and
epidemiologist Jonas Salk and the American virologist Albert Bruce Sabin,
respectively, was responsible for a significant worldwide decline in paralytic
poliomyelitis. However, polio has not been eradicated, partly because the virus
can mutate and escape the host immune response. Influenza viruses mutate so
rapidly that new vaccines are developed for distribution each year.
Viruses undergo very high rates of mutation
(genetic alteration) largely because they lack the repair systems that cells
have to safeguard against mutations. A high mutation rate enables the virus to
continually adapt to new intracellular environments and to escape from the host
immune response. Co-infection of the same cell with different related viruses
allows for genetic reassortment (exchange of genome segments) and intramolecular
recombination. Genetic alterations can alter virulence or allow viruses to gain
access to new cell types or new animal hosts. Many scientists believe that HIV
is derived from a closely related monkey virus, SIV (simian immunodeficiency
virus), that acquired the ability to infect humans. Many of today’s emerging
viruses may have similar histories.
| VI | DISCOVERY |
By the last half of the 19th century, the
microbial world was known to consist of protozoa, fungi, and bacteria, all
visible with a light microscope. In the 1840s, the German scientist Jacob Henle
suggested that there were infectious agents too small to be seen with a light
microscope, but for the lack of direct proof, his hypothesis was not accepted.
Although the French scientist Louis Pasteur was working to develop a vaccine for
rabies in the 1880s, he did not understand the concept of a virus.
During the last half of the 19th century,
several key discoveries were made that set the stage for the discovery of
viruses. Pasteur is usually credited for dispelling the notion of spontaneous
generation and proving that organisms reproduce new organisms. The German
scientist Robert Koch, a student of Jacob Henle, and the British surgeon Joseph
Lister developed techniques for growing cultures of single organisms that
allowed the assignment of specific bacteria to specific diseases.
The first experimental transmission of a
viral infection was accomplished in about 1880 by the German scientist Adolf
Mayer, when he demonstrated that extracts from infected tobacco leaves could
transfer tobacco mosaic disease to a new plant, causing spots on the leaves.
Because Mayer was unable to isolate a bacterium or fungus from the tobacco leaf
extracts, he considered the idea that tobacco mosaic disease might be caused by
a soluble agent, but he concluded incorrectly that a new type of bacteria was
likely to be the cause. The Russian scientist Dimitri Ivanofsky extended Mayer’s
observation and reported in 1892 that the tobacco mosaic agent was small enough
to pass through a porcelain filter known to block the passage of bacteria. He
too failed to isolate bacteria or fungi from the filtered material. But
Ivanofsky, like Mayer, was bound by the dogma of his times and concluded in 1903
that the filter might be defective or that the disease agent was a toxin rather
than a reproducing organism.
Unaware of Ivanofsky’s results, the Dutch
scientist Martinus Beijerinck, who collaborated with Mayer, repeated the filter
experiment but extended this finding by demonstrating that the filtered material
was not a toxin because it could grow and reproduce in the cells of the plant
tissues. In his 1898 publication, Beijerinck referred to this new disease agent
as a contagious living liquid—contagium vivum fluid—initiating a 20-year
controversy over whether viruses were liquids or particles.
The conclusion that viruses are particles
came from several important observations. In 1917 the French-Canadian scientist
Félix H. d’Hérelle discovered that viruses of bacteria, which he named
bacteriophage, could make holes in a culture of bacteria. Because each hole, or
plaque, developed from a single bacteriophage, this experiment provided the
first method for counting infectious viruses (the plaque assay). In 1935 the
American biochemist Wendell Meredith Stanley crystallized tobacco mosaic virus
to demonstrate that viruses had regular shapes, and in 1939 tobacco mosaic virus
was first visualized using the electron microscope.
In 1898 the German bacteriologists Friedrich
August Johannes Löffler and Paul F. Frosch (both trained by Robert Koch)
described foot-and-mouth disease virus as the first filterable agent of animals,
and in 1900, the American bacteriologist Walter Reed and colleagues recognized
yellow fever virus as the first human filterable agent. For several decades
viruses were referred to as filterable agents, and gradually the term
virus (Latin for “slimy liquid” or “poison”) was employed strictly for
this new class of infectious agents. Through the 1940s and 1950s many critical
discoveries were made about viruses through the study of bacteriophages because
of the ease with which the bacteria they infect could be grown in the
laboratory. Between 1948 and 1955, scientists at the National Institutes of
Health (NIH) and at Johns Hopkins Medical Institutions revolutionized the study
of animal viruses by developing cell culture systems that permitted the growth
and study of many animal viruses in laboratory dishes.
| VII | EVOLUTION |
Three theories have been put forth to
explain the origin of viruses. One theory suggests that viruses are derived from
more complex intracellular parasites that have eliminated all but the essential
features required for replication and transmission. A more widely accepted
theory is that viruses are derived from normal cellular components that gained
the ability to replicate autonomously. A third possibility is that viruses
originated from self-replicating RNA molecules. This hypothesis is supported by
the observation that RNA can code for proteins as well as carry out enzymatic
functions. Thus, viroids may resemble “prehistoric” viruses.
| VIII | IMPORTANCE OF VIRUSES |
Because viral processes so closely
resemble normal cellular processes, abundant information about cell biology and
genetics has come from studying viruses. Basic scientists and medical
researchers at university and hospital laboratories are working to understand
viral mechanisms of action and are searching for new and better ways to treat
viral illnesses. Many pharmaceutical and biotechnology companies are actively
pursuing effective antiviral therapies. Viruses can also serve as tools. Because
they are efficient factories for the production of viral proteins, viruses have
been harnessed to produce a wide variety of proteins for industrial and research
purposes. A new area of endeavor is the use of viruses for gene therapy. Because
viruses are programmed to carry genetic information into cells, they have been
used to replace defective cellular genes. Viruses are also being altered by
genetic engineering to kill selected cell populations, such as tumor cells. The
use of genetically engineered viruses for medical intervention is a relatively
new field, and none of these therapies is widely available. However, this is a
fast-growing area of research, and many clinical trials are now in progress. The
use of genetically engineered viruses extends beyond the medical field.
Recombinant insect viruses have agricultural applications and are currently
being tested in field trials for their effectiveness as pesticides.
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