Information about Herpes Simplex Virus

Herpes simplex virus
TEM micrograph of a 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 (HSV-1) Herpes simplex virus 2 (HSV-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 strains of the herpesvirus family, Herpesviridae, which cause infections in humans.^[1] HSV-1 and 2 are also referred to as Human Herpes Virus 1 and 2 (HHV-1 and HHV-2).

After an initial, or primary, infection, HSV establishes latency, during which the virus is present in the cell bodies of nerves which innervate the area of original outbreak. During reactivation, the virus is produced in the cell and transported outwardly via the nerve cell's axon to the skin.^[2] The ability of HSV to become latent leads to the chronic nature of Herpes infection; after the initial infection subsides, Herpes symptoms may periodically recur in the form of outbreaks of herpetic sores near the site of original infection.

Herpes infections are marked by painful, watery blisters in the skin or mucous membranes (such as the mouth or lips) or on the genitals.^[2] The blisters resemble those seen in chickenpox — an infection caused by a third member of the alpha-Herpesviridae subfamily, Varicella Zoster Virus (VZV), also known as Human Herpes Virus 3 (HHV-3). Lesions heal with a crudescent scab, the hallmark of herpetic disease. Herpes is contagious if the carrier is producing and releasing ("shedding") virus. This is particularly likely during an outbreak, although individuals may shed virus between outbreaks. Although no cure is yet available, treatments exist which reduce the likelihood of viral shedding. An HSV infection on the lips is commonly known as a "cold sore" or "fever blister" and should not to be confused with a canker sore; canker sores are not caused by the HSV virus.

Transmission

HSV is generally transmitted by direct contact of lips or genitals when the sores are present, or also when no sores are present (known as viral shedding). HSV can be present in semen, vaginal fluids, and saliva. In addition, herpes may be transmitted during childbirth, which can be fatal to the infant. The immature immune system of the child is unable to defend against the virus and even if treated, infection can result in brain damage. Transmission occurs while passing through the birth canal and the risk of infection is minimal 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 also carries a low (~1%) risk of developing aseptic meningitis.^[2]

Infectious Cycle

Cellular entry

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

The sequential stages of HSV entry are analagous to those of other viruses. At first, complementary receptors on the virus and cell surface bring the two 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.^[3]

In the case of Herpes virus, initial interactions occur when glycoprotein C, on the surface of the viral envelope, binds to a cell surface particle, heparan sulfate. Glycoprotein D binds specifically to the herpesvirus entry mediator receptor (HVEM), thus providing a strong, fixed attachment to the host cell. These interactions bring the membrane surfaces into mutual proximity and allow for other surface glycoproteins to interact.

Once bound to the HVEM, glycoprotein D changes its conformation and interacts with glycoproteins H and L, which form a complex. The interaction of these membrane proteins results in the hemifusion state. Afterward, glycoprotein B interaction with the glycoprotein H and L complex creates an entry pore.^[3] Glycoprotein B interacts with host cell surface glycosaminoglycans.

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 Herpes capsid portal is a ring containing twelve (12) of the same protein, Herpes Capsid Portal Protein, produced by the herpes gene UL6.^[4] The DNA exits the capsid in a single linear segment. ^[5] The viral DNA enters the nucleus via the pore. Once the DNA has entered the nucles, replication may begin to go though the cell and then they eat the nucleus.

Replication

Consequent to a cell being infected, groups of Herpes virus proteins, termed immediate-early, early, and late proteins, are produced following specific time periods. Research using a new flow cytometry methodology in KSHV indicates the possibility of an additional lytic stage, delayed-late.^[6] These stages of lytic infection, particularly late lytic, are distinct from the latency stage. For example, in the case of HSV-1, no protein products are detected during latency.

Upon entering the cell, an α-TIF protein also joins the viral particle and aids in immediate-early Transcription. The virion host shutoff protein (VHF-UL41) is very important to viral replication. This enzyme shuts off protein synthesis in the host, degrades host mRNA, helps in viral replication, and regulates gene expression of viral proteins. While the viral genome immediately travels to the nucleus, the VHF protein remains in the cytoplasm. The packaging of the viral particles, which include the genome, core and the capsid, occur in the nucleus. In the nucleus, cleavage of genome concatemers occurs and these are placed into pre-formed capsids. The viral envelope is acquired from the nuclear envelope, more specifically the inner lamellae of the membrane.^[7]

Latent infection

HSV may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia.^[2] 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 for the virus, which allows later recurrences to produce further infections.

A protein found in neurons may bind to Herpes DNA and regulate latency. Recent studies have found that the Herpes DNA contains a sequence that is involved in silencing the expression of a gene associated with lytic infection, ICP4. The sequence contains elements which bind to human nerve cell protein factors: the human neuronal protein Neuronal Restrictive Silencing Factor (NRSF), and human Repressor Element Silencing Transciption Factor (REST). When the proteins are able to bind to the viral DNA elements, histone deacytalization occurs atop the ICP4 gene sequence. ^[8][9]

Reactivation

The virus can be reactivated due to the effects of other illnesses such as cold and influenza, menstruation, emotional and physical stress, exposure to bright sunlight, gastric upset, fatigue or injury, consequently resulting in the appearance of surface sores.

Anti-virals

Nucleoside analogs

Treatment is available in the form of antiviral medications such as nucleoside analog, which reduce the duration of symptoms and accelerate healing.

Nucleoside analogs are molecules which possess a similarity to natural nucleotides - the building-blocks of DNA and RNA. Because the replicating virus incorporates these analogs into viral DNA, the genetic material produced contains defects and mutations. As a result, the subsequent generation of virus produced is damaged and reduced in number.

Oral Prodrug	Drug	Analog of Nucleoside	Nucleoside Family
Famciclovir[10] (bioavailability: 75% oral) (trade names: Famvir)	Penciclovir (1.5% oral, IV, locally topical) (Denavir, Fenistil)	guanosine	purine
Valaciclovir (55% oral) (Valtrex)	Aciclovir (10-20% oral) (Zovirax, Zovir)
Valganciclovir (60% oral) (Valcyte)	Ganciclovir (5% oral, IV, locally intraocular) (Cytovene, Cymevene)
Brivudine[11] (BVDU)		thymidine	pyrimidine

Treatment should begin at the first symptoms of an outbreak for best results as far as duration and healing; should treatment begin before the lesions appear, it is possible that the outbreak can be averted. Another option is the use of daily suppressive therapy, in which antivirals are taken every day over the course of years. Suppressive therapy reduces frequency of symptoms and recurrence of outbreaks. In addition, suppressive therapy reduces subclinical shedding, lowering the risk of transmission through sexual contact or kissing.

Of these, Ganciclovir is known to have cytotoxic effects on infected cells, while Acyclovir is not known to have this effect.^[12]

Fusion inhibitors

Fusion inhibitors prevent "fusion" of the viral envelope with the cell membrane. This prevents viral entry to the cell.

• Docosanol

Helicase-primase inhibitors

One of three key protein structures involved in HSV DNA replication is the Helicase-Primase structure. New research compounds which bind to this megamolecule show remarkable effectiveness against HSV. In particular, BAY 57-1293 has been used to treat infant HSV-2 encephalitis, and has also shown positive results in animal models of HSV infection.^[13] However, naturally-occurring strains resistant to BAY 57-1293 have been found in 2 of 10 HSV samples from clinical settings.^[14]

Dietary supplements

The amino acid lysine has demonstrated the ability to reduce the duration of infection through inhibiting the replication of the HSV. When foods high in lysine (such as cheese) are consumed in preference to foods high in arginine, HSV replication may be inhibited; conversely, consuming foods high in arginine (such as nuts or peanuts) may interfere with the therapeutic use of lysine.^[15][16] However, according to the American Social Health Association: "While some studies have suggested that lysine supplements can reduce the frequency of recurrences or healing time, other trials have been unable to replicate those results. Therefore, there is not sufficient information to discern how effective it may be, in addition to what the effective dosages or frequency of L-lysine may be."^[16]

Other

Undecylenic acid (Castor oil derivative) is also proven to have anti-bacterial and anti-viral properties that are effective on viral skin infections such as the herpes simplex virus (HSV).

Butylated Hydroxytoluene (BHT), commonly available as a food preservative, has been shown in vitro to inactivate enveloped viruses including herpes.^[17][18] In-vivo studies of topical application to animals confirmed the anti-viral activity of BHT during outbreaks.^[19] BHT has not been clinically tested and approved to treat herpes in humans.

Vaccine research

Herpevac, a vaccine for HSV-2 is currently (as of February 2007) undergoing clinical testing in women in the United States and Canada.^[20][21] Previous studies have determined that this vaccine is approximately 70% effective in women, but does not prevent the disease in men. ^[22]

References

External links

• Mayo Clinic on Cold Sores
• Genital Herpes - Public Health Agency of Canada
• Infected for Life: How Herpes Simplex Virus Uses MicroRNA to Hide Out in Cells
• UK Genital Herpes Resource Site