Herpes simplex virus

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Herpes simplex virus

TEM micrograph of a herpes simplex virus.

Virus classification
Group: Group I (dsDNA)
Family: Herpesviridae
Subfamily: Alphaherpesvirinae
Genus: Simplexvirus
Species
Herpes simplex virus 1 (HWJ-1)
Herpes simplex virus 2 (HWJ-2)
This article is about the virus. For information about the disease, see Herpes simplex.

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are two species of the herpes virus
family, Herpesviridae, which cause infections in humans.[1] Eight members of herpes
virus infect humans to cause a variety of illnesses including cold sores, chickenpox or
varicella, shingles or herpes zoster (VZV), cytomegalovirus (CMV), and various cancers,
and can cause brain inflammation (encephalitis). All viruses in the herpes family produce
life-long infections.

They are also called Human Herpes Virus 1 and 2 (HHV-1 and HHV-2) and are
neurotropic and neuroinvasive viruses; they enter and hide in the human nervous system,
accounting for their durability in the human body. HSV-1 is commonly associated with
herpes outbreaks of the face known as cold sores or fever blisters, whereas HSV-2 is
more often associated with genital herpes.
An infection by a herpes simplex virus is marked by watery blisters in the skin or mucous
membranes of the mouth, lips or genitals.[1] Lesions heal with a scab characteristic of
herpetic disease. However, the infection is persistent and symptoms may recur
periodically as outbreaks of sores near the site of original infection. After the initial, or
primary, infection, HSV becomes latent in the cell bodies of nerves in the area. Some
infected people experience sporadic episodes of viral reactivation, followed by
transportation of the virus via the nerve's axon to the skin, where virus replication and
shedding occurs.[2]

Herpes is contagious if the carrier is producing and shedding the virus. This is especially
likely during an outbreak but possible at other times. There is no cure yet, but there are
treatments which reduce the likelihood of viral shedding.

Contents
[hide]

• 1 Transmission
• 2 Microbiology
o 2.1 Viral structure
o 2.2 Cellular entry
o 2.3 Genetic inoculation
o 2.4 Replication
o 2.5 Latent infection
• 3 Alzheimer's disease
• 4 References

• 5 External links

[edit] Transmission
Main article: Herpes simplex

HSV is transmitted during close contact with an infected person who is shedding virus
from the skin, in saliva or in secretions from the genitals. This horizontal transmission of
the virus is more likely to occur when sores are present, although viral shedding, and
therefore transmission, does occur in the absence of visible sores.[3] In addition, vertical
transmission of HSV may occur between mother and child during childbirth, which can
be fatal to the infant.[4] The immature immune system of the child is unable to defend
against the virus and even if treated, the infection can result in inflammation of the brain
(encephalitis) that may cause brain damage. Transmission occurs when the infant passes
through the birth canal, but the risk of infection is reduced if there are no symptoms or
exposed blisters during delivery. The first outbreak after exposure to HSV is commonly
more severe than future outbreaks, as the body has not had a chance to produce
antibodies; this first outbreak carries a low (~1%) risk of developing aseptic meningitis.[1]
[edit] Microbiology
[edit] Viral structure

Animal herpes viruses all share some common properties. The structure of herpes viruses
consists of a relatively large double-stranded, linear DNA genome encased within an
icosahedral protein cage called the capsid, which is wrapped in a lipid bilayer called the
envelope. The envelope is joined to the capsid by means of a tegument. This complete
particle is known as the virion.[5] HSV-1 and HSV-2 each contain at least 74 genes (or
open-reading frames, ORFs) within their genomes,[6] although speculation over gene
crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.[7]
These genes encode a variety of proteins involved in forming the capsid, tegument and
envelope of the virus, as well as controlling the replication and infectivity of the virus.
These genes and their functions are summarized in the table below.

The genomes of HSV-1 and HSV-2 are complex, and contain two unique regions called
the long unique region (UL) and the short unique region (US). Of the 74 known ORFs, UL
contains 56 viral genes, whereas US contains only 12.[6] Transcription of HSV genes is
catalyzed by RNA polymerase II of the infected host.[6] Immediate early genes, which
encode proteins that regulate the expression of early and late viral genes, are the first to
be expressed following infection. Early gene expression follows, to allow the synthesis of
enzymes involved in DNA replication and the production of certain envelope
glycoproteins. Expression of late genes occurs last; this group of genes predominantly
encode proteins that form the virion particle.[6]

Five proteins from (UL) form the viral capsid; UL6, UL18, UL35, UL38 and the major
capsid protein UL19.[5]
A simplified diagram of HSV replication

Entry of HSV into the host cell involves interactions of several glycoproteins on the
surface of the enveloped virus, with receptors on the surface of the host cell. The
envelope covering the virus particle, when bound to specific receptors on the cell surface,
will fuse with the host cell membrane and create an opening, or pore, through which the
virus enters the host cell.

The sequential stages of HSV entry are analogous to those of other viruses. At first,
complementary receptors on the virus and the cell surface bring the viral and cell
membranes into proximity. In an intermediate state, the two membranes begin to merge,
forming a hemifusion state. Finally, a stable entry pore is formed through which the viral
envelope contents are introduced to the host cell.[12] In the case of a herpes virus, initial
interactions occur when a viral envelope glycoprotein called glycoprotein C (gC) binds to
a cell surface particle called heparan sulfate. A second glycoprotein, glycoprotein D (gD),
binds specifically to a receptor called the herpesvirus entry mediator receptor (HVEM)
and provides a strong, fixed attachment to the host cell. These interactions bring the
membrane surfaces into mutual proximity and allow for other glycoproteins embedded in
the viral envelope to interact with other cell surface molecules. Once bound to the
HVEM, gD changes its conformation and interacts with viral glycoproteins H (gH) and L
(gL), which form a complex. The interaction of these membrane proteins results in the
hemifusion state. Afterward, gB interaction with the gH/gL complex creates an entry pore
for the viral capsid.[12] Glycoprotein B interacts with glycosaminoglycans on the surface
of the host cell.

[edit] Genetic inoculation

After the viral capsid enters the cellular cytoplasm, it is transported to the cell nucleus.
Once attached to the nucleus at a nuclear entry pore, the capsid ejects its DNA contents
via the capsid portal. The capsid portal is formed by twelve copies of portal protein, UL6,
arranged as a ring; the proteins contain a leucine zipper sequence of amino acids which
allow them to adhere to each other.[13] Each icosahedral capsid contains a single portal,
located in one vertex.[14][15] The DNA exits the capsid in a single linear segment.[16]

[edit] Replication

Following infection of a cell, herpes virus proteins, called immediate-early, early, and
late, are produced. Research using flow cytometrys on another member of the herpes
virus family, KSHV, indicates the possibility of an additional lytic stage, delayed-late.[17]
These stages of lytic infection, particularly late lytic, are distinct from the latency stage;
in the case of HSV-1, no protein products are detected during latency whereas, they are
detected during the lytic cycle.

The early proteins transcribed are used in the regulation of genetic replication of the
virus. On entering the cell, an α-TIF protein joins the viral particle and aids in immediate-
early transcription. The virion host shutoff protein (VHS or UL41) is very important to
viral replication.[9] This enzyme shuts off protein synthesis in the host, degrades host
mRNA, helps in viral replication, and regulates gene expression of viral proteins. The
viral genome immediately travels to the nucleus but the VHS protein remains in the
cytoplasm.[18][19]

The late proteins are used in to form the capsid and the receptors on the surface of the
virus. Packaging of the viral particles — including the genome, core and the capsid -
occurs in the nucleus of the cell. Here, concatemers of the viral genome are separated by
cleavage and are placed into pre-formed capsids. HSV-1 undergoes a process of primary
and secondary envelopment. The primary envelope is acquired by budding into the inner
nuclear membrane of the cell. This then fuses with the outer nuclear membrane releasing
a naked capsid into the cytoplasm. The virus acquires its final envelope by budding into
cytoplasmic vesicles.[20]

[edit] Latent infection

HSV may persist in a quiescent but persistent form known as latent infection, notably in
neural ganglia.[1] During latent infection of a cell, HSV express Latency Associated
Transcript (LAT) RNA. LAT is known to regulate the host cell genome and interferes
with natural cell death mechanisms. By maintaining the host cells, LAT expression
preserves a reservoir of the virus, which allows later recurrences to produce further
infections.

A protein found in neurons may bind to herpes virus DNA and regulate latency. Herpes
virus DNA contains a gene for a protein called ICP4, which an important transactivator of
genes associated with lytic infection in HSV-1.[21] Elements surrounding the gene for
ICP4 bind a protein known as the human neuronal protein Neuronal Restrictive Silencing
Factor (NRSF) or human Repressor Element Silencing Transcription Factor (REST).
When bound to the viral DNA elements, histone deacytalization occurs atop the ICP4
gene sequence to prevent initiation of transcription from this gene, thereby preventing
transcription of other viral genes involved in the lytic cycle.[22][23] Another HSV protein
reverses the inhibition of ICP4 protein synthesis. ICP0 dissociates NRSF from the ICP4
gene and thus prevents silencing of the viral DNA.[24]

The virus can be reactivated by other illnesses such as cold and influenza, eczema,
emotional and physical stress, exposure to bright sunlight, gastric upset, fatigue or injury,
and menstruation.
[edit] Alzheimer's disease
Scientists discovered a link between HSV-1 and Alzheimer’s disease in 1979.[25] In the
presence of a certain gene variation (APOE-epsilon4 allele carriers), HSV-1 appears to be
particularly damaging to the nervous system and increases one’s risk of developing
Alzheimer’s disease. The virus interacts with the components and receptors of
lipoproteins, which may lead to the development of Alzheimer's disease.[26] This research
identifies HSVs as the pathogen most clearly linked to the establishment of
Alzheimer’s.[27] Without the presence of the gene allele, HSV type 1 does not appear to
cause any neurological damage and thus increase the risk of Alzheimer’s.[28]

A 2008 study published in The Journal of Pathology, [29] has shown a striking localization
of herpes simplex virus type 1 DNA within the beta-amyloid plaques that characterize
Alzheimer's disease, and suggests that this virus is a major cause of the plaques and
hence probably a significant aetiological factor in Alzheimer's disease.
Herpes simplex virus
Introduction:

Herpes simplex virus (HSV) infections are very common worldwide. HSV-1 (usually
known as a cold sore) is transmitted through kissing or sharing drinking utensils, and
HSV-2 (usually known as genital herpes) through sexual contact. You may be infected
and not show symptoms for a long time. Often symptoms are triggered by exposure to the
sun, fever, menstruation, emotional stress, a weakened immune system, or an illness.

There is not cure for herpes, and once you have it, it is likely to recur; however, some
people may have one outbreak and then never have another one. In between herpes
outbreaks, the virus lies dormant (as if it is hibernating or sleeping) in nerve cells.

While exposure to HSV-1 is extremely common – as many as 90% of American adults

have been exposed to the virus – and there is no stigma to having a cold sore, HSV-2 or
genital herpes can cause embarrassment. Although there is no cure for genital herpes, an
infected person can take steps to preventing spreading the disease and can continue to
have a sex life.

While most herpes infections do not cause serious complications, infections in infants
and in people with weakened immune systems or herpes infections that affect the eyes
can be life-threatening.

Signs and Symptoms:

HSV-1

• Small, painful blisters filled with fluid around the lips or edge of the mouth
• Tingling or burning around the mouth or nose (often a few days before blisters
appear)
• Fever
• Sore throat
• Swollen lymph nodes in neck
HSV-2

• Small red blisters or open sores on genitals or inner thighs; in women, often occur
inside the vagina
• May be painful or not
• In women, vaginal discharge
• Fever, muscle aches
• Headache Painful urination
• Swollen lymph glands in the groin

Causes:

HSV-1 is transmitted through saliva. Kissing, using the same eating utensils, sharing
personal items (such as a razor), and receiving oral sex from someone who has HSV-1
can cause you to contract the virus.

HSV-2 is a sexually transmitted disease.

Both herpes viruses can be contagious even if the infected person does not have active
symptoms or visible blisters.

Also, a mother can pass the infection to her baby during vaginal birth, especially if there
are active blisters around the vagina at the time of delivery.

Risk Factors:

Oral herpes (cold sores)

Everyone is at risk for oral herpes from HSV-1. In fact, studies suggest that by
adolescence 62% of Americans are infected with HSV-1 and by the time people are in
their 40s, 90% have been infected.

Genital herpes

All sexually active people are at risk for genital herpes. Having multiple sexual partners
puts you at even greater risk. Women have a greater risk of being infected after sex with
an unprotected partner than men do. Estimates of how many Americans are infected
range from 20% to 30%.

Other factors

People with weakened immune systems, such as people with HIV/AIDS or those who
take immunosuppressant drugs to treat an autoimmune disease or because of organ
transplant, are at increased risk for severe cases of herpes.
Diagnosis:

In many instances, your doctor is able to make the diagnosis of herpes from examining
you and no tests are required. If your doctor is not 100% certain, however, then he or she
make take a sample from the blisters to test for the virus. Finally, there is a blood test that
may be helpful for making a diagnosis, especially if your doctor suspects herpes but you
don't have an active infection.

Preventive Care:

HSV-1

• Avoiding kissing people with visible core sores

• Don't share personal items
• Wash your hands frequently
• If you have HSV-1, be careful touching your eyes and genitals; don't perform oral
sex on your partner
• Use sunscreen
• Reduce stress

HSV-2

• Avoid having sex if you or your partner has an outbreak (active infection) of
herpes. Herpes outbreaks are not always obvious and your partner may be
contagious without you knowing it. Anyone involved in an ongoing sexual
relationship with a partner infected with HSV-2 should get counseling from a
healthcare practitioner on how to best keep yourself safe.
• Avoid touching the sores
• Use or have your partner use a latex condom (even when sores are not visible)
• Limit the number of sex partners

Treatment Approach:

Herpes cannot be cured, so the goals of treatment are to reduce the number of outbreaks
and to lessen symptoms when you do have an outbreak.

Cold sores usually go away by themselves in no more than 1 to 2 weeks. Using

medications may shorten the outbreak and decrease discomfort.

Antiviral medications for genital herpes can reduce outbreaks and help speed recovery
when an outbreak does occur. They can also lessen the chances of spreading the virus.

Coping with the emotional and social aspects of having genital herpes is part of
treatment. Relaxation techniques and support groups can help.
Lifestyle
For cold sores, applying either heat or cold to blisters may help relieve pain. Try ice or
warm compresses.

For genital herpes, wear cotton underwear and avoid tight fitting clothes as they can
restrict air circulation and slow the healing of lesions.

Be sure to tell your partner or potential partner that you have herpes.

Medications
Antiviral medicines — may help shorten the duration of a herpes outbreak and suppress
recurring outbreaks. For genital herpes, there are two types of therapy: episodic and
suppressive. With episodic therapy, you take medication at the first sign of an outbreak
and for several days to shorten the duration or prevent a full outbreak. With suppressive
therapy, you may take medication daily to keep outbreaks from occurring. Antiviral
medications include:

• Acyclovir (Zovirax)
• Famciclovir (Famvir)
• Valacyclovir (Valtrex)

Topical medications (for oral herpes) — include the antiviral cream Penciclovir (Denavir)
and an over-the-counter cream, docosanol (Abreva).

Nutrition and Dietary Supplements

Because supplements may have side effects or interact with medications, they should be
taken only under the supervision of a knowledgeable healthcare provider.

• Lysine (1 to 3 g per day) — Although not all studies agree, several studies suggest
that lysine may help reduce the number of recurring outbreaks of cold sores and
possibly genital herpes. Most of the studies have involved people with cold sores
or with both cold sores and genital herpes. A few studies also suggest that lysine
may help shorten the duration of an outbreak. The evidence is somewhat stronger
for cold sores: the research to date is not entirely conclusive, lysine supplements
have been used to help treat or prevent mouth and genital lesions caused by
herpes. Taking lysine supplements or increasing lysine in your diet (from foods
like fish, chicken, eggs, and potatoes) may speed recovery time and reduce the
chance of recurrent breakouts of the herpes infection. If you have high
cholesterol, heart disease, or high triglycerides (type of fatty material in the blood,
 generally measured when you have your cholesterol checked), it is best, at this
point, not to use lysine because animal studies suggest that this supplement may
raise cholesterol and triglyceride levels.
• Propolis — A resin made by bees, propolis is loaded with flavonoids (antioxidants
that help fight infection and boost immune function). Test tube studies show it can
stop HSV-1 and HSV-2 from reproducing. One small study of people with genital
herpes compared an ointment made from propolis to Zovirax ointment. People
using propolis saw the lesions heal faster than those using topical Zovirax. More
studies are needed to say for sure whether propolis works.
• Zinc — In test tubes, zinc is effective against HSV-1 and HSV-2. In one small
study in people, those who applied zinc oxide cream to cold sores saw them heal
faster than those who applied a placebo cream.

Herbs
The use of herbs is a time-honored approach to strengthening the body and treating
disease. Herbs, however, can trigger side effects and can interact with other herbs,
supplements, or medications. For these reasons, herbs should be taken with care, under
the supervision of a healthcare practitioner.

• Lemon balm (Melissa officinalis) — Several studies suggest that topical

ointments containing lemon balm may help heal cold sores. In one study, for
example, those who applied lemon balm cream to their lip sores saw a reduction
in redness and swelling after two days.
• Aloe (Aloe vera) — Preliminary evidence suggests that aloe gel used topically
may improve the symptoms of genital herpes in men. In two studies, men who
used the aloe vera cream (0.5% aloe) saw lesions heal faster than those who used
a placebo cream. It isn't know whether aloe vera would also help heal cold sores.
• Rhubarb cream (Rheum palmatum) — In one Swiss study, a cream made from
sage (Salvia officinalis) and rhubarb was as effective as Zovirax in healing cold
sores. Sage by itself was not beneficial. More research is needed.
• Eleutherococcus or Siberian ginseng (Eleutherococcus senticosus/Acanthopanax
senticosus) —Although not all studies agree, one 6-month study of 93 people with
genital herpes found that Siberian ginseng reduced the frequency, severity, and
duration of outbreaks. This herb should not be taken if you have high blood
pressure, obstructive sleep apnea (repeated, prolonged periods when breathing
stops while sleeping), narcolepsy (frequent day time sleeping), are pregnant or
breastfeeding.
• Peppermint oil (Mentha x piperita ) — In test tubes, peppermint oil has stopped a
number of viruses from reproducing, including herpes. However, it isn't known
whether peppermint oil would have any effect on the herpes virus in humans.
Homeopathy
Although few studies have examined the effectiveness of specific homeopathic therapies,
professional homeopaths may consider the remedies described below for the treatment of
herpes based on their knowledge and experience. One study of 53 people with genital
herpes did show that the majority had improvement in their symptoms and were less
likely to have recurrent outbreaks when treated with homeopathy. Participants in this
study were followed for up to 4 years.

Before prescribing a remedy, homeopaths take into account a person's constitutional type.
A constitutional type is defined as a person's physical, emotional, and psychological
makeup. An experienced homeopath assesses all of these factors when determining the
most appropriate remedy for each individual.

For cold sores:

• Natrum muriaticum — for eruptions at the corners of the mouth that occur during
periods of emotional stress and tend to worsen in the daytime
• Rhus toxicodendron — for eruptions consisting of many small blisters that itch
intensely at night
• Mercurius — for children who drool and may have a fever
• Sepia — for outbreaks that do not improve with other homeopathic remedies; this
remedy is most appropriate for individuals who tend to have a lack of energy and
don't tolerate cold weather

For genital lesions:

• Graphites — for large, itchy lesions in individuals who are overweight

• Natrum muriaticum — for eruptions that occur during periods of emotional stress
and symptoms that tend to worsen in the daytime
• Petroleum — for lesions that spread to anus and thighs; symptoms tend to worsen
in winter and improve in summer
• Sepia — for outbreaks that do not improve with other homeopathic remedies; this
remedy is most appropriate for individuals who tend to have a lack of energy and
don't tolerate cold weather

Mind/Body Medicine
• Support groups — Having genital herpes can impact your social and emotional
life. In fact, if you have herpes, it is quite common to feel depressed, angry, and
even guilty. Worrying about possible rejection by someone with whom you are
hoping to become intimate is also typical. Joining a support group where
members share experiences and problems can help relieve the stresses associated
with having genital herpes. If you are in a committed relationship, seeing a
couples' therapist with your partner may also be helpful.
 •

Relaxation techniques — Using relaxation techniques, such as yoga, guided imagery,

and meditation, on a daily basis may help you feel better overall and cope with
stresses related to having herpes.

• Self-hypnosis — Self-hypnosis using guided imagery may also help relieve stress.
In one 6-week training program, participants with frequently recurring genital
herpes were able to reduce outbreaks by nearly 50% and improve their mood,
including reducing feelings of depression and anxiety.
• Other — Individual therapy with a psychiatrist, psychologist, or social worker;
and techniques such as biofeedback can help reduce emotional symptoms
associated with herpes.

Other Considerations:

Pregnancy
Herpes viruses can be transmitted to a newborn during vaginal delivery, especially if the
mother has active lesions in the vagina at the time of delivery. Herpes infections in
newborns can be life-threatening or cause disability. Delivery by cesarean section (C-
section) will be recommended to avoid infecting the baby.

Special Populations
Newborns – herpes infections contracted during delivery from the mother can lead to
meningitis, herpes infection in the blood, chronic skin infection, and may even be fatal.

You are more likely to have severe, frequent outbreaks and to experience complications
from herpes if your immune system is suppressed from:

• HIV or AIDS
• Chemotherapy for cancer
• Long-term use of high doses of corticosteroids
• Medications that intentionally suppress the immune system

Warnings and Precautions

If you are diagnosed with genital herpes, you should be tested for other sexually
transmitted diseases such as chlamydia and gonorrhea.
Prognosis and Complications
Herpes is a chronic, recurrent infection. The initial symptoms usually appear within 1 to 3
weeks of exposure to the virus and last 7 to 10 days (for cold sores) or 7 to 14 days (for
genital lesions). Usually the number of outbreaks is greatest in the first year and higher
for HSV-2 genital lesions than HSV-1 cold sores. Each year after that, the number of
outbreaks usually goes down and they become less severe. But you can never completely
get rid of the virus.

Complications of herpes include:

• Herpetic keratitis – herpes infection of the eye leading to scaring within the
cornea and possible blindness
• Persistent herpes infection, without lesion-free periods
• Herpes infection in the esophagus
• Herpes infection of the liver which can lead to cirrhosis (liver failure)
• Encephalitis and/or meningitis (serious brain infections)
• Lung infection
• Eczema herpetiform – widespread herpes across the skin