Bacteriology at UW-Madison
The Microbial World
Lectures in Microbiology by Kenneth Todar PhD University of Wisconsin-Madison Department of Bacteriology
Herpes and Related Viruses
© 2009 Kenneth Todar PhD
replication cycle of Herpes Simplex virus. 1. Specific proteins in the
viral envelope attach to host cell receptors on the cell membrane. 2.
Penetration is achieved when the viral envelope fuses with the cell
membrane releasing the nucleocapsid directly into the cytoplasm. 3. The
virion is uncoated and the viral DNA is transported into the nucleus.
4. In the nucleus, the viral DNA is transcribed into early mRNAs which
are transported to the cytoplasm for the translation of early proteins.
These early proteins are brought back into the nucleus and participate
in the replication of the virus DNA into many copies. The viral DNA is
then transcribed into the late mRNAs which exit to the cytoplasm for
translation into the late (nucleocapsid and envelope) proteins. 5. The
capsid proteins encapsidate the newly replicated genomes. The envelope
proteins are imbedded in the nuclear membrane. 6. The nucleocapsids are
enveloped by budding through the nuclear membrane, and the mature
viruses are released from the cell through cytoplasmic channels. To
an animation of the life cycle of Herpes go to the Homepage
of Dr. Edward K. Wagner at U Cal Irvine
Herpes viruses are a leading cause of human viral disease, second only
to influenza and cold viruses. They cause overt disease such as cold
sores and chickenpox, or they may remain latent for many years to
be reactivated in later life, as in shingles.
The name herpes is derived
from the Greek word herpein
which means to creep. This reflects the spreading or creeping nature of
the skin lesions caused by many herpes viruses.
There are 25 types of herpes viruses. Six types cause
medical problems in humans.
Viruses that are Pathogens of Humans
1. Herpes simplex
HSV-1 - causes fever blisters (cold
sores), gingivostomatitis, herpes keratitis, eczema herpeticum, HSV
HSV-2 - causes genital lesions, neonatal
infections, HSV meningitis, HSV proctitis
2. Varicella-Zoster virus (VZV) - chickenpox, congenital varicella
3. Epstein-Barr Virus (EBV) - infectious mononucleosis, Burkitt's
lymphoma, nasopharyngeal cancer
4. Cytomegalovirus (CMV) - usually asymptomatic infections
herpes virus 6 (HHV-6) - exanthum subitum or roseola infantum
6. Human herpes virus 8 (HHV-8) or Kaposi's
sarcoma-associate herpes virus (KSHV) - found in the saliva of many
AIDS patients and associated with
Herpes viruses are fairly large, icosahedral, enveloped dsDNA viruses.
Their pattern of infection and replication is illustrated and explained
in the introductory material on viruses that occurs earlier in this
Herpes viruses are shown in this TEM negative stain.
Viruses Pathogenic for Humans
Herpes simplex 1 and 2
Herpes simplex 1 and 2 (HSV-1 and HSV-2) can
infect both humans and other animals, but only humans show symptoms of
disease. The hallmark of herpes
infection is the ability to infect epithelial mucosal cells or
lymphocytes. The virus then travels up peripheral nerves to a nucleated
neurone where it may stay for years and be followed by reactivation.
Pathogenesis of HSV-1 and HSV-2
The site of the initial infection is usually the oral or genital
mucosa, depending on the way in which the
person acquires the virus. It is often noted that HSV-1 infects above
the waist and HSV-2 infects below the waist,
but either virus can infect at either locale, and this reflects the
transmission rather than any
property of the virus. Both types of HSV can also persistently infect
macrophages and lymphocytes.
Once mucosal epithelial cells are infected, the virus replicates around
the lesion and enters into the innervating neurone. The virus
travels along the neurone (by a process called retrograde axoplasmic
the ganglion. In the case of herpes infections of the oral mucosa, the
virus goes to the trigeminal ganglia, whereas in genital infections the
virus invades the sacral ganglia.
When the virus infects neurones it enters into latency. If breakage of
latency occurs in these cells, the virus travels back down the
nerve axon and recurrence of infection (and therefore symptoms)
occurs at the same site as the initial infection. Vesicles containing
infectious virus are formed on the muscosa and the virus spreads. As
long as the virus is kept moist it can remain
infectious. The vesicle heals and there is usually no scar as a result.
There are several agents that seem to trigger recurrence, most of which
are stress-related. It also appears that exposure to strong sunlight
and perhaps fever can lead to recurrence. Recurrent infections
are usually less pronounced than the primary infection and resolve more
HSV-1 and 2 infections are
life-long and although latency is soon set up, the infected patient can
infect others as a result of recurrence. The virus is found in the
lesions on the skin but can also be present in a variety of body fluids
including saliva and vaginal secretions. Despite the apparent "above
the waist/below the waist" rule, both types of HSV can infect oral
or genital mucosa depending on the regions of contact.
HSV-1 can set up a primary infection in the lips, move
to the trigeminal ganglion where it can remain latent. The virus can
subsequently reactivate, move to the original site of infection and
result in cold sores.
HSV-1 is usually spread mouth to mouth (kissing or the use of utensils
contaminated with saliva) or by transfer of infectious virus to the
hands after which the virus may enter the body via any wound or through
A large proportion of the population has evidence of HSV-1 infection as
judged by presence of antibodies. As a result of poor hygiene in
countries, HSV-1 antibodies are found in more than 90% of children.
HSV-2 is normally spread
sexually and is found in the anus, rectum and upper alimentary tract as
well as the genital area. In addition, an infant can be infected at
birth by a genitally-infected mother. The infant can also be infected in utero if
the mother's infection spreads. Because of the infant's underdeveloped
immune system, the resulting infection can be very severe and sometimes
lead to death.
Anyone who comes in contact
with fluid containing infectious virus is at risk. There is a disease
that affects health care workers called herpetic whitlow that results
in lesions on the fingers (it can be caused by either type of HSV).
HSV-2 infections are more prevalent later in life as the number of
sexual contacts increases. Thus, the lowest rates of infection are
found in children and the highest rates in prostitutes among whom as
many as 80% are infected with HSV-2.
caused by HSV-1 and HSV-2
sores can be the result of an HSV-1 or an HSV-2 infection. The
initial lesion looks the same - a clear vesicle containing infectious
virus with a red (erythomatous) lesion at its base. From this
vesicle, encrusted lesions and ulcers may
sore on the lower lip caused by HSV-1 on the second day after onset.
In primary herpetic gingivostomatitis,
the typical clear lesions develop first followed by ulcers that have a
white appearance. The infection, often initially on the lips, spreads
all parts of the mouth and pharynx. Reactivation from the trigeminal
ganglia can result in cold sores.
Herpes pharyngitis is often
associated with other viral infections of the upper respiratory tract.
The disease is more severe in immunosuppressed people such as AIDS
keratitis is an infection of the eye and is primarily
caused by HSV-1. It can be recurrent and may lead to blindness. It is a
leading cause of corneal blindness in the United States.
Herpes whitlow is disease of persons who
come in manual contact with herpes-infected body secretions. It can be
caused by either type of HSV and enters the body via small wounds on
hands or wrists. It can also be caused by autoinoculation of HSV-2 from
genitals to the hands.
Eczema herpeticum is found in
children with active eczema. The virus spreads over the skin at the
site of eczema lesions. It can spread to other organs such as the liver
Genital Herpes is usually the
result of HSV-2 infection with about 10% of cases being caused HSV-1.
Primary infection is often asymptomatic but many painful lesions can
develop on the glans or shaft of the penis in men and on the vulva,
vagina, cervix and perianal region of women. In both sexes, the urethra
can be involved. In women, the infection may be accompanied by vaginal
herpes on the penile shaft. CDC
herpes on the vagina. HSV-2 typically causes one or more blisters to
form on or around the genitals or rectum, which break, leaving tender
ulcers which may take 2-4 weeks to heal after their initial appearance.
Primary infections involve a transient viremia and can be accompanied
by a variety of symptoms including fever, myalgia, and glandular
inflammation of the groin area.
Secondary episodes of genital herpes, which occur as a result of
reactivation of virus in the sacral ganglion, are frequently less
severe and of shorter duration than the first. Some people have only
infrequent recurrences but others experience recurrences as often as
every 14-21 days. Whether there is an apparent active disease or not,
an infected person remains infectious and may be a source of
herpes in its spread and maintenance in the population.
Encephalitis. This is usually the result of an HSV-1 infection
and is the most common sporadic viral encephalitis. HSV encephalitis is
a febrile disease and may result in damage to one of the temporal
lobes. As a result there is blood in the spinal fluid and the patient
experiences neurological symptoms such as seizures. The disease can be
fatal, but in the US there are fewer than 1000 cases per year.
This is the result of an HSV-2 infection. The symptoms seem to resolve
HSV Infection of Neonates
This results from HSV-2 and is often fatal, although such infections
are rare. Infection is especially possible if the mother is shedding
virus at the time of delivery. Thus, prospective mothers should avoid
contracting herpes during pregnancy.
A primary HSV-2 infection during pregnancy creates a greater risk of
transmission to the newborn. If a woman has active genital herpes at
delivery, a cesarean-section delivery is usually performed. The virus
can either be obtained in utero
or during birth with
the latter being more common. Because the neonate has an underdeveloped
immune system, the virus can spread rapidly to many peripheral organs
(e.g. lungs and liver) and can infect the central nervous system.
Treatment of HSV
There are a variety of
nucleoside analog drugs used to treat herpes infections, though the
person still harbors the virus for life. Some of these drugs are very
specific and are only activated by specific viral enzymes, meaning that
these drugs show few side effects.
The best known of the
nucleoside analogs is acyclovir. Other approved drugs including
famciclovir and valacyclovir. These drugs act against the replicating
virus (they are incorporated into the DNA as it is copied) and
therefore they are ineffective against latent virus.
The best way to avoid HSV infection is by not coming in contact with
virus. However, this is not always possible as many people experiencing
viral replication are asymptomatic. Needless to say, people with active
genital herpes or cold sores should avoid intercourse, oral sex and
kissing during such episodes in order to prevent transmission of the
Varicella-Zoster Virus (VZV)
Zoster means "girdle" from the
characteristic rash that forms a belt
around the thorax in many patients. The structure of Varicella virus is
very similar to Herpes Simplex virus although the genome is somewhat
This virus causes two major diseases, chickenpox
in childhood, and shingles,
later in life. Shingles (Zoster) results from
reactivation of an earlier varicella infection.
Varicella is highly infectious. More than 90% of the population of the
States have antibodies against varicella proteins. In the household of
an infected patient, 90% of contacts who lack immunity (from previous
disease or vaccination) will contract
the disease. It is spread by respiratory aerosols or direct contact
with skin lesions. Infection is via the mucosa of the respiratory tract.
The average period between the initial infection and the occurrence
of the chickenpox lesions is about two weeks, with a range of 10 to 23
days. The virus is spread by respiratory secretions (by
a cough) or from contact with ruptured vesicles on the skin containing
chickenpox lesions. The blister-like lesions
appearing on the face scalp and trunk, have a pus-filled
The disease is more severe in older children and adults. This is
particularly the case in immunocompromised patients (AIDS,
transplantation, etc.) where the disease may linger for several weeks
the fever may be more pronounced. The spread of the virus may lead to
problems in the lungs or liver, or to meningitis. In these cases, the
mortality rate may be 20%. In about 15% of adult patients, pneumonia
can be a complication and may be fatal. Although most children recover
rapidly from the disease, there may be some complications, including
fulminant encephalitis and cerebellar ataxia. Reye syndrome may be
caused by aspirin used in
Major problems may be caused by infection in utero during the first
trimester. This is congenital varicella syndrome (CVS) which leads to
scarring of the skin of the limbs, damage to the lens, retina and
brain, and microphthalmia.
Infection of the mother, at around the time of birth can lead to
infection of the infant. Since the infant will not have maternal
antibodies against varicella and has immature cell-mediated immunity,
it may succumb to the disease with a mortality rate of up to 35%.
After the infectious period of chickenpox,
the virus may migrate to the ganglia associated with areas in which the
virus is actively replicated. The virus may then be reactivated under
stress or with immune suppression. This usually occurs later in life.
The recurrence of varicella replication is accompanied by severe
radicular pain in areas innervated by the nerve in
which latent infection has occurred. A few days later, chickenpox-like
lesions occur in restricted areas (dermatome) that are innervated by a
The skin lesions are somewhat different from chickenpox, being
restricted to small areas of the skin. They are small and close
together and usually heal in about two weeks. Chronic burning or
itching pain called post-herpetic
neuralgia may occur in the elderly.
The pain may last well after the rash has healed, sometimes months or
herpes outbreak (shingles) due to VZV. CDC
Virus Epstein-Barr virus is the
causative agent of Burkitt's lymphoma
in Africa, nasopharyngeal cancer
in the orient and infectious mononucleosis in the west. It was first
discovered as the causative agent of Burkitt's lymphoma and it was
later found that patients with infectious mononucleosis have antibodies
that react with Burkitt's lymphoma cells.
Virus attached to its CD21 receptor on a B lymphocyte.
EBV only infects a small number of cell types that express the
receptor for complement C3d component (CR2 or CD21). These are certain
epithelial cells (oro- and naso-pharynx) and B lymphocytes. This
explains the cellular tropism of the virus.
The virus is replicated in pharyngeal epithelial cells, shed into the
saliva and is taken up by CD21+ B lymphocytes. These cells are normally
short-lived. Although B cells do not show any histological alterations
as a result
of EBV infection, they are stimulated to divide and are protected from
undergoing apoptosis (cell death). They become transformed cells and
they begin to
appear in high levels as monocytes in the bloodstream. T cell
responses are inhibited while growth of B cells and antibody secretion
are stimulated. The virus also causes the cells to produce other
cytokines including IL-5 and
Burkitt's lymphoma is a tumor of the jaw and face found in children.
The tumor cells show evidence of EBV DNA and tumor antigens, and
patients show a much higher level of anti-EBV antibodies than other
members of the population. The tumor cells display a particular
chromosomal abnormality. Burkitt's lymphoma is endemic in equatorial
Africa and only occurs rarely elsewhere. There is thought to be a
genetic explanation possibly involving an association with malaria.
This disease occurs in a number of areas in south China, as well as
Alaska, Tunisia and east Africa. It is also associated with EBV. There
may be a genetic predisposition to the development of EBV cancers in
these populations or there may be an environmental cofactor involved.
The disease is a tumor of the epithelium of the upper respiratory tract
the tumor cells contain EBV DNA.
The disease is characterized by malaise, lymphadenopathy, tonsillitis,
enlarged spleen and liver, and fever. The fever may persist for more
than a week. There may also be a rash. The severity of disease often
depends on age (with younger patients resolving the disease more
quickly) and resolution usually occurs in 1 to 4 weeks. The primary
infection is often asymptomatic, but a person may shed
infectious virus for many years. Sometimes infectious
mononucleosis is not developed until 1- 2 months after primary
mononucleosis is usually benign, there may be complications. These
include neurological disorders such as meningitis encephalitis,
myelitis and Guillain-Barrè syndrome. A chronic syndrome
may also occur, the symptoms of which are similar to those reported for
fatigue syndrome (headaches, sore throat and low fever).
However, EBV is
probably not the cause of chronic fatigue syndrome.
In infectious mononucleosis, infected B cells are also transformed. The
infected B cells proliferate and activate suppressor CD8 T cells. The T
cells increase in number in the circulation and may account for up to
80% of the white blood cells. This T cell response results in enlarged
lymph glands (and enlarged liver and spleen). It is the
activation of the T
cells that limits the proliferation of B cells, so that the disease
A large proportion of the
population (90-95%) is infected with Epstein-Barr virus, and these
people, although usually asymptomatic, will shed the virus from time to
time throughout life. The virus is spread by close
contact (kissing). Up to 80% of students entering college in the U.S.
are seropositive for the virus, and many of those that are negative
become positive while at college. The virus can also be spread by blood
infection involves two types of cells: (1) B cells, where infection is
predominantly latent and has the potential to induce
growth-transformation of infected cells; and (2) epithelial cells,
where infection is predominantly replicative. The B-cell acts as the
main mediator of primary as well as persistent infection. Following
primary infection of B cells, a chronic virus carrier state is
established in which the outgrowth of EBV-transformed B cells is
controlled by an EBV-specific cytotoxic T lymphocytes. Latently
infected B cells can become permissive for lytic EBV infection.
Infectious virus released from these cells can be shed directly into
the saliva or might infect epithelial cells and other B cells. In this
way a virus-carrier state is established that is characterized by
persistent, latent infection in circulating B cells and occasional EBV
replication in B cells and epithelial cells.
Cytomegalovirus has the largest genome of all herpes viruses and
appears only to replicate in human cells. Some cells such as
macrophages and fibroblasts support productive (virulent)
infection, while latent infection is set up in other cell types,
including T lymphocytes and stromal cells of the bone marrow. There is
only one serotype of CMV.
infection of cell in urine. CDC.
Cytomegalovirus infection is found in s significant
proportion of the
population. Seropositivity increases with age. By college age, about
15% of the US population is infected and this rises to about 50% by 35
years of age. The virus is spread in most secretions, particularly
saliva, urine, vaginal secretions and semen. Cytomegalovirus infection
is therefore transmitted by sexual contact, as well as kissing . It can
spread to a fetus in a pregnant woman and to the newborn via lactation.
In the hospital, the virus can spread via blood transfusions
and transplants. In developing countries with more crowded conditions,
the virus is found in a much higher proportion of the population than
in western countries.
The virus first infects the upper respiratory tract and then local
lymphocytes. Circulating lymphocytes then spread the virus to other
lymphocytes and monocytes in spleen and lymph nodes. The virus finally
spreads to a variety of epithelial cells including those of salivary
glands, kidney tubules, testes, epididymis and cervix.
Infection is usually asymptomatic (sub-clinical) but glandular fever is
sometimes seen in young adults. The virus can inhibit T cell responses.
The virus elicits both humoral antibodies and cell-mediated immunity
but the infection is not cleared. Although suppressed, the virus may
later reactivate, particularly in cases of immunosuppression.
There are two instances in which cytomegalovirus can cause serious
1. During a primary infection of the mother, the virus can spread via
the placenta to the fetus and congenital abnormalities can occur; in
fact, this virus is the most common viral cause of congenital disease.
2. In immunosuppressed patients who have received an organ transplant
or have an immunosuppressive disease (e.g. AIDS), cytomegalovirus can
be a major problem. Particularly important is
cytomegalovirus-retinitis in the eye, which occurs in up to 15% of all
AIDS patients. In addition, interstitial pneumonia, colitis,
esophagitis and encephalitis are seen in some
Ganciclovir, which inhibits the replication of all human herpes
viruses, is usually used in treatment, especially for retinitis.
Foscarnet is also approved, but Acyclovir is not effective. A vaccine
is being developed, but the best way to avoid the virus is to restrict
contact between infected children and pregnant women. Also, since
cytomegalovirus is sexually transmitted, condoms can limit spread.
Human herpes virus
This herpes virus is found worldwide
and is found in the saliva of the majority (90%) of adults. It
infects almost all children by the age of two
and the infection is life-long. It replicates in B and T lymphocytes in
the oropharynx. It can set up a latent infection in T cells which can
later be activated when the cells are stimulated to divide.
Human herpes virus-6 has two forms, HHV-6A and
HHV-6B. The latter causes exanthem
subitum, otherwise known as roseola
infantum. This a common disease
of young children. Symptoms include fever and sometimes upper
respiratory tract infection and lymphadenopathy. The symptoms last a
few days after an incubation period of around 14 days. The fever
subsides leaving a macropapular rash on the trunk and neck that last a
few days longer.
In adults, primary infection by HHV is associated with a
mononucleosis. It has also been associated with a number of
neurological disorders, including encephalitis and seizures. It has
been postulated to play a role in multiple sclerosis and chronic
This virus is also known as
Kaposi's sarcoma associated herpes
virus (KSHV) and is found in the saliva of many AIDS patients.
It infects peripheral blood lymphocytes. The distribution of the virus
may explain why some populations of HIV-infected people come down with
Kaposi's sarcoma while others do not.
HHV-8 is an opportunist and generally does not cause disease in
healthy hosts. Immunosuppression or AIDS is usually required before
disease is manifested.
The virus infects CD19+ B cells and endothelial-derived spindle
cells of Kaposi's sarcoma lesions. In addition to its
role in Kaposi's sarcoma, it is known to cause a primary lymphoma and a
B cell lymphoproliferative disorder.
Epstein-Barr Virus and Infectious Mononucleosis
Herpes (Fact Sheet)
Department of Health
and Human Services - Genital Herpes
Views in Molecular Medicine: Epstein-Barr Virus (EBV) infections in
normal healthy virus carriers
Herpes, NIAID Fact Sheet
Genome News Network: Small Genes May Help Mono Virus
Hide in Humans
- Minnesota Dept. of Health
News Online.: New studies suggest how Epstein Barr virus infects and
of South Carolina School of Medicine: Herpes Viruses
Written and Edited by Kenneth Todar. All rights
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