Although
viruses were originally discovered and characterized on the basis of
the diseases they cause, most viruses that infect bacteria, plants, and
animals (including humans) do not cause disease. In fact,
bacteriophages may be helpful in that they rapidly transfer genetic
information from one bacterium to another, and viruses of plants and
animals may convey genetic information among similar species, helping
their hosts survive in hostile environments. In the future this could
also be true for humans. Recombinant DNA biotechnology shows great
promise for the repair of genetic defects. Afflicted persons are
injected with cells transformed by viruses that carry a functional copy
of the defective human gene. The virus integrates the normal gene into
the DNA of the human cell.
Of those viruses that cause disease,
some cause short-term (acute) diseases and others recurring or
long-term (chronic) diseases. Some viruses cause acute disease from
which there is fairly rapid recovery but may persist in the tissues,
remaining dormant for long periods of time, and then become active
again, bringing about serious disease decades later. Slowly progressive
viruses have long incubation periods before the onset of disease. As
mentioned above, the DNA of certain viruses becomes integrated into the
genome of the host cell, often resulting in malignant transformation of
cells, which become cancers.
The nature of the disease caused by
a virus is generally a genetic property of the virus as well as of the
host cells. Many viruses, however, can remain dormant in the tissues of
the host (latency). Viruses that cause acute disease are generally, but
not always, those that rapidly harm or destroy cells (cytopathic effects) and have the capacity to shut off protein or nucleic acid synthesis within the host cell.
Human poliovirus and related picornaviruses
that infect other animal species are examples of acute infectious
agents that shut down protein synthesis in the host cell soon after
infection; these picornaviruses also inhibit cellular RNA and DNA
synthesis. Another virus that rapidly kills the infected cell is the
negative-strand vesicular
stomatitis virus (VSV) of the family Rhabdoviridae; viral RNA newly
synthesized by infectious VSV rapidly shuts off cellular RNA synthesis
and, to a somewhat lesser extent, cellular protein synthesis. In both
poliovirus and VSV, the infected cell dies within hours of the
inhibition of cellular RNA and protein synthesis. Influenza A viruses
of the family Orthomyxoviridae, which cause a highly contagious
respiratory disease in humans, inhibit cellular macromolecular
synthesis by several unique mechanisms, including blocking the
maturation of cellular mRNAs and cleaving off the ends of cellular
mRNAs in the nucleus of infected cells. Other viruses that inhibit
cellular macromolecule synthesis and produce acute infections include
the poxviruses, reoviruses, togaviruses, adenoviruses, and herpesviruses; the latter two persist in host tissues for long periods of time and cause chronic infection as well.
Many,
if not most, diseases resulting from viral infection of vertebrates are
caused not by a direct effect of the virus but rather by a secondary
immune response. Essentially all viral proteins are recognized by
vertebrate animals as immunologically foreign, and the immune systems
of these animals mount two kinds of immune response, humoral and cellular. In humoral immunity, B lymphocytes, usually triggered by helper T lymphocytes, make antibodies
(proteins that recognize and bind foreign molecules) to the viral
protein. The antibody synthesized as a result of the immune response
against a specific viral antigen
usually benefits the infected host because that antibody can neutralize
the infectivity of the specific virus in the blood and tissues of the
infected host. Viruses inside the cell are not accessible to the
antibody, because it cannot cross the cell membrane barrier.
In cellular immunity, a killer T cell
recognizes and kills a virus-infected cell because of the viral antigen
on its surface, thus aborting the infection because a virus will not
grow within a dead cell. If the virus-infected cells are not essential
for host functions, the killer T cell can prevent the spread of the
infecting virus to other cells and distant tissues. Not infrequently,
the virus-specific T lymphocyte kills vital cells such as nerve cells (neurons), muscle cells, and liver cells, all of which carry out important functions. In addition, the death of cells results in an inflammatory response,
which also can damage vital tissues. Therefore, the cellular immune
response to a viral infection can cause disease. In general, diseases
caused by chronic viral infections, but also occasionally by subacute
(between acute and chronic) viral infections, are caused by cellular
immune responses that damage the virus-infected tissue.
Infectious patterns
Acute
viral infections are of two types—local and systemic—both usually
resulting from a direct effect of the invading virus on host tissue
cells. Acute local infections generally occur at the site of viral
infection. For example, acute respiratory infections include (1) the common cold, in which the rhinovirus infects only the nasal mucosa, (2) influenza,
in which the virus is found in both nasal and bronchial mucosa, where
severe damage can result in death, (3) flulike illnesses caused by
adenoviruses localized in lymphoid tissue of the throat (although infection also can occur in the intestine and the eye or be spread to the heart), and (4) severe respiratory infections of infants and children, caused by parainfluenza viruses or respiratory syncytial viruses, which may be life-threatening. Examples of acute infections localized to the intestine include those that result in enteritis (bowel inflammation), which may be accompanied by diarrhea; these are often caused by rotaviruses and coronaviruses.
Many
viruses transmitted by the respiratory route (from sneezes and coughs,
for example) and limited to humans begin their cycle of infection in
the upper respiratory tract (nose and throat) and then enter the
bloodstream, where they are spread to distant tissues. Examples of such
diseases are measles, mumps, and chickenpox,
in which the growth of the specific virus in the mucosal cells of the
throat during the first few days of infection usually results in mild
fever and achiness; this stage is called the prodromal period of the illness. During the next few days, the virus enters the draining lymph nodes
and then the bloodstream, where it is spread throughout the tissues of
the body, resulting in fever and rash (in the case of measles and
chickenpox) and inflammation of the parotid glands and, less frequently, the testes, ovaries, and joints (in the case of mumps). Varicella (chickenpox) virus rarely causes pneumonia, but all these viruses can cause meningitis and, rarely, encephalitis. A similar pattern of infection formerly occurred with smallpox, a disease that was more frequently fatal but now ostensibly has been eradicated.
A large number of viruses of the digestive tract (enteroviruses)—among them poliovirus, Coxsackie viruses, and echoviruses
(enteric cytopathic human orphan virus)—also cause a two-phase illness.
Enteroviruses grow initially in the intestinal tract and are
transmitted by mouth through water, food, and other materials
contaminated with feces. The viruses are resistant to the acid normally
found in the stomach
and thus reach the intestinal tract, where they multiply in living
mucosal cells. This initial period of viral invasion and growth in the
intestine causes either an initial mild febrile illness or is
asymptomatic. Over the next few days these enteroviruses are spread
from the intestinal mucosa to the draining lymph nodes, from which they
invade the bloodstream, resulting in a condition known as viremia. From
the bloodstream the viruses are widely spread to all tissues, but in
most cases no symptomatic disease occurs. Poliovirus in less than 1
percent of cases affects the spinal cord or brain, resulting in paralysis
or death. Different types of Coxsackie viruses and echoviruses can
cause acute, usually nonfatal, illnesses such as meningitis, carditis, pleurisy, or rashes.
Many viral diseases are transmitted by bites of insects or other arthropods,
and these infections usually begin in the skin or lymph nodes and
rapidly invade the bloodstream. The nature of the disease caused by
these arthropod-borne viruses (arboviruses) is determined by the affinity (tropism)
of each virus for specific organs. Many that have an affinity for brain
tissue cause encephalitis or meningitis, but others primarily infect
the muscles, liver, heart, or kidneys. Virtually all these diseases are epidemic
in character, and the viruses that cause them are the primary pathogens
of birds and mammals. The insect, usually a certain species of
mosquito, takes a blood meal from the infected host bird or mammal and
shortly thereafter bites a human, thus transmitting the virus. These
arboviruses do not ordinarily multiply in the insect but simply reside
on its proboscis. Examples of human epidemic diseases resulting from
transmission of these often fatal arboviruses are encephalitis caused
by viruses of the family Togaviridae and Flaviviridae,
yellow fever and dengue caused by viruses of the family Flaviviridae,
and hemorrhagic fevers caused by viruses of the families Bunyaviridae and Arenaviridae. Of considerable interest and concern is the identification of new strains of viruses, particularly a hantavirus
of the Bunyaviridae family that was responsible for an epidemic in the
early 1990s in the southwestern United States that resulted in
considerable numbers of fatal human infections.
Latency
Inapparent
infections (those that do not cause specific signs and symptoms) often
result after exposure to picornaviruses, influenza viruses,
rhinoviruses, herpesviruses, and adenoviruses but less frequently to
measles and chickenpox viruses. In cases of inapparent infection,
long-lasting immunity develops, but only to the strain of virus that
has the same antigenic composition as the original infecting virus.
Certain
of these viruses persist in the tissues of the host after the initial
infection despite the presence of circulating antibodies to it in the
blood and tissues. Such viruses probably reside inside cells, where
they are protected from antibodies that cannot penetrate the cell
membrane. Among persistent viruses are adenoviruses, measles virus,
and, in particular, many kinds of herpesviruses. The genetic
information of herpesviruses and adenoviruses can be integrated into
the genome of the host cell, but it is believed that these viruses
frequently, and the measles virus invariably, reside in cells in the
form of extrachromosomal
genes (genes not integrated in chromosomes). These dormant viruses can
be activated by many factors, such as trauma, another infection,
emotional stress, menstruation, excessive exposure to sunlight, and
various illnesses.
The phenomenon of latency and reactivation is
particularly common among viruses of the family Herpesviridae, which
cause chronic or recurrent diseases: (1) herpes simplex virus
type 1, which causes recurrent cold sores, (2) herpes simplex virus
type 2 in genital tissue, which causes repeated herpetic infections of
the vagina or penis, (3) cytomegalovirus, which usually produces an inapparent infection activated by simultaneously occurring disease to cause severe liver, lung, or nervous-system
disease, and (4) varicella virus, which is the causative agent of
chickenpox but which can be activated decades later to produce herpes zoster (shingles). A rare, but invariably fatal, disease of the nervous system is subacute sclerosing panencephalitis
(SSPE), which is a progressive, degenerative condition caused by
measles virus (a paramyxovirus) lying dormant in brain cells for many
years and then reactivated, usually in adolescence. There is no simple
explanation for why latent viruses, such as those in the family Herpesviridae, that are present in the tissues of most adult humans can be activated to cause disease in some people but not in others.
Chronic and slowly progressive diseases
Although
some viruses multiply slowly, this is not always the explanation for
the chronicity or the slow progression of the diseases caused by these
viruses. Hepatitis,
for example, is a subacute or chronic disease, with a long latent
period, that is caused by at least five viruses with different
properties. Hepatitis A is caused by a picornavirus usually transmitted by the fecal-oral route in a manner similar to that of poliovirus. Hepatitis B is caused by a small DNA virus that contains its own DNA polymerase and is transmitted by transfusion of blood
and other blood products, by the sharing of nonsterile hypodermic
needles among drug users, by sexual intercourse, or from mother to
neonate. Hepatitis B virus is classified with similar viruses of birds in the family Hepadnaviridae. Most cases of hepatitis
spread by the transfusion of blood or blood products or by needles
shared by drug users are caused by a third, completely distinct
virus—originally called non-A, non-B hepatitis but now known to be a
member of the virus family Flaviviridae—designated hepatitis C virus. A
fourth unique agent that causes hepatitis is designated hepatitis delta virus,
which has not yet been classified taxonomically but is a small,
enveloped virus containing a circular RNA genome; hepatitis B virus
serves as a helper for replication of hepatitis delta virus, the
virions of which contain hepatitis B surface antigen (HBsAg).
The fifth causative agent of viral hepatitis, largely occurring in Asia
and Africa, is a small RNA virus tentatively classified as a member of
the family Caliciviridae and designated hepatitis E virus.
Many other agents that appear to cause chronic and slowly progressive diseases, particularly those affecting the nervous system, have been identified. A fatal neurological disorder of sheep, called scrapie, has an incubation period of years and may be caused by a heat-resistant protein called a prion,
which is self-replicating. Similar, rather obscure agents have been
identified for two uncommon fatal disorders of the nervous system
called Creutzfeldt-Jakob disease and kuru.
The disease now known as AIDS
was first recognized in homosexuals and hemophiliacs about 1981 and
continues to be disseminated throughout the world to become one of the
most devastating epidemics of all time. AIDS is caused by HIV,
a member of a genetically more complex group of the family Retroviridae
called lentiviruses. Closely related viruses of monkeys and cats cause
similar diseases. HIV is transmitted by blood and other body fluids and
infects primarily helper T lymphocytes and other cells with CD4 surface
receptors (cell surface proteins that react with antigens), to which
the virus binds. After the virus has been dormant for years,
destruction of T lymphocytes results in drastic depression of the
immune system. Death almost invariably results from “opportunistic”
infections such as pneumonia—caused by ordinarily nonpathogenic
organisms such as Pneumocystis carinii—or tuberculosis or by cancers such as Kaposi sarcoma and lymphomas.
The
spread of many viral diseases can be prevented by hygienic factors such
as efficient sanitation facilities, effective waste disposal, clean
water, and personal cleanliness. Active immunization by vaccines
(antigen-containing preparations that elicit the synthesis of
antibodies and thus immunity) has been useful in preventing common
epidemics caused by acutely infectious viruses.
The best example of such a preventable disease is smallpox, caused by a disease-producing virus that at one time was found worldwide. In 1796 the English physician Edward Jenner discovered that the milder cowpox virus
could serve as a live vaccine (an antigenic preparation consisting of
viruses whose disease-producing capacity has been weakened) for
preventing smallpox; Jenner published his findings in 1798. The program
of vaccination that resulted from Jenner's discovery is one of the
greatest success stories in the annals of medicine; in 1980 the World Health Organization declared that the disease had been eliminated.
A different prospect is presented by rabies,
an invariably fatal viral disease mentioned in ancient Greek
literature. Transmitted by the bite of dogs and other domestic and wild
animals, the rabies virus is more difficult to eradicate because it is
present in wild animals throughout the world, except in certain island
countries such as Great Britain and Australia. Influenza virus is also
distributed worldwide, but, of the three major immunologic types, only
one (type A) is responsible for large epidemics. The worldwide epidemic
(pandemic) of influenza at the end of World War I is estimated to have
caused 20 million deaths, mostly of adolescents and young adults.
Because of virus mutations that produce minor antigenic changes every
year and major antigenic shifts about every 10 years, influenza
viruses have the capacity to resist inactivation by antibodies acquired
by previous infection or vaccination. Development of effective vaccines
to combat influenza is a difficult task, although existing vaccines are
partially effective and are recommended for people at high risk—i.e.,
the elderly and those with chronic disease of the respiratory or
circulatory systems.
Vaccines are most successful when directed
against those viruses that do not mutate and that infect only humans.
In addition to smallpox, a successful vaccine program has been carried
out against polio.
Polioviruses exist in only three antigenic types, each of which has not
changed significantly for decades. The vaccines available are the
“killed” (Salk) vaccine, composed of inactivated virus of the three types, and the “live” (Sabin)
vaccine, composed of genetically attenuated viruses of the three types.
These vaccines, which were introduced in the 1950s, have lowered the
incidence in developed countries of paralysis resulting from polio. The
disease still occurs in developing countries and recurs in some
developed countries where vaccination programs have not been enforced.
Rare cases of polio occur from the Sabin vaccine strain of type-3
poliovirus, which is genetically unstable and occasionally reverts to
the virulent form.
Vaccination can prevent diseases caused by strictly human viruses that exist in only one antigenic and stable type. Measles
has been prevented in developed countries with routine vaccination.
Measles, however, may still be the major cause of death in children in
developing countries. Vaccination for mumps and chickenpox
promises to be successful because the causative viruses of these
diseases show little tendency to vary antigenically and are confined to
humans. On the other hand, development of vaccines for the common cold caused by rhinoviruses,
similar to polioviruses, will be a formidable, if not impossible, task
because there are at least 100 antigenic types of the rhinovirus. Also
daunting is the task of developing a vaccine against HIV.
The major antigenic component of this virus is a
surface-membrane-inserted glycoprotein (gp120), which has a startling
rate of mutation. The extreme antigenic diversity that results from the
mutability of the gene that codes for this protein would prevent HIV
from being identified and attacked by circulating antibodies or killer
T lymphocytes.
Unlike
bacteria, viruses mimic the metabolic functions of their host cells.
Antibiotics are not effective against viruses. It is difficult to
identify chemical compounds that inhibit the multiplication of viruses
but do not slow the functions of, or are not toxic to, the host cell.
Despite this difficulty, an effective antiviral drug has been developed
against influenza virus. This drug targets a viral enzyme called the
neuraminidase and is orders of magnitude less active against nonviral
neuraminidases. These neuraminidase inhibitors are most effective when
administered prophylactically or within the first 30 hours of symptom
onset and can be used to limit the spread of influenza virus and to
complement the administration of vaccines. Other chemicals that exert a
selectively greater effect on viral replication than they do on cell
replication include ribavirin, acyclovir, and zidovudine (azidothymidine
[AZT]). These drugs have been partially effective in improving, if not
curing, viral diseases without causing major toxic side effects. AZT
has been used with some success in prolonging the lives of patients
with AIDS.
Certain natural products of cells, called interferons,
may have potential antiviral and anticancer properties. Interferons are
proteins normally synthesized by the cells of vertebrates, including
humans, either intrinsically and without stimulation or in response to
certain viral infections, chemicals, or immune reactions. In general,
the multiplication of viruses is inhibited by interferons, some to a
much greater extent than others. Interferons are generally
species-specific; i.e., they are effective in inhibiting viral
infection only in cells of the same species that naturally synthesize
the interferon.
There are three classes of interferons: α-interferons, produced by blood leukocytes; β-interferons, produced by tissue cells and fibroblasts; and γ-interferons (also called immune interferons or interleukins),
produced by immune reactions in blood lymphocytes. Interferons are now
known to be a subset of a large group of natural cellular substances
called cytokines,
which signal cells to perform specific functions. Until recently,
interferons were difficult to produce commercially because cells and
tissues synthesize only small amounts of them. Through recombinant DNA
technology, however, large amounts of interferon can be produced.
There has been some success in using interferons to treat viral diseases, such as colds caused by rhinoviruses, infections caused by herpesviruses, and benign tumours and warts caused by papillomaviruses.
Local administration at the sites of viral infection affords the best
results, although injections of large amounts of interferons can be
harmful, probably because they tend to inhibit protein synthesis in the
host cell.
