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Herpes Simplex Virus type 2 (HSV-2) is the causative agent of genital herpes and is a fairly common virus around the world that affects about 40 to 60 million people in the USA ("Initiative for Vaccine Research"). It is a double stranded DNA virus and it has an envelope. It has the ability to establish a lifelong latency in neural ganglia and be reactivated when conditions are appropriate. While the virus can never be cleared from the body, there are antiviral medications that can be used to help lessen the length and amount of outbreaks a person endures. Since it is a sexually transmitted disease (STD), people most at risk of infection are people that participate in unprotected sex with infected individuals and people with multiple sex partners. The virus is highly prevalent, so it can be useful to know the important details of the virus.
HSV-2 is a group 1 Baltimore class (Shors 76). It is in the family Herpesviridae and subfamily Alphaherpesvirinae. HSV-2 is a large, complex dsDNA virus with an outer lipid envelope that contains at least ten viral glycoproteins. It has a tegument layer that has at least fifteen viral proteins, and an icosahedral capsid ("Initiative for Vaccine Research"). Viral glycoproteins found on the envelope that are involved in fusion to host cells include gB, gC, gD, gH, and gL. These proteins are used to facilitate viral fusion to host cells so they are very important to the virus life cycle (Shors 419).
HSV-2 fuses to cells of the epidermis and dermis of the skin when it makes contact with mucosal surfaces or skin abrasions such as genital areas. The virus depends on cell-surface receptors, coreceptors, and the many proteins on the viral envelope to fuse with the host cell. Coreceptors include HVEM and nectin-1 and nectin-2. The envelope fuses with the host cell membrane and the nucleocapsid is released into the cytoplasm. The tegument is also released in the cytoplasm and begins to shut down cellular protein synthesis. The nucleocapsid binds to the cell's nuclear membrane and the viral genome is delivered to the nucleus. When the virus enters the cell, either a productive (lytic infection) or a lifelong latent infection occurs. In the productive infection, the viral genome is transcribed by cellular DNA-dependent RNA polymerase in the nucleus. Cellular and viral proteins are responsible for regulating transcription (Shors 419-421). Transcription occurs in a temporal manner. Immediate-early gene transcription depends on a virally-encoded protein named VP16 that encodes for viral alpha proteins. Alpha proteins are important or transcription because the encode for DNA binding proteins. The alpha proteins are early genes, and their products are beta proteins which are involved in DNA replication. Gamma proteins are known as late genes and they are the products of beta proteins. Gamma protein products are viral structural proteins and other proteins necessary for virus particle assembly and release. Many viral gene products are virulence genes that are known to prevent apoptosis, block production of interferons, or downregulate the presentation of viral antigens on MHCI cells ("Initiative for Vaccine Research"). To begin replication a viral protein named UL9 will bind to the origins of replication on the DNA and unwind the DNA. RNA primers will be made next by a helicase/primase that is composed of UL5, UL8, and UL52 proteins binding to the single stranded DNA. DNA synthesis is initiated when UL30 (a viral DNA polymerase) and a UL42 protein binds to the RNA primers. Rolling circle replication is used by HSV-2 to form linear concatemers of DNA. Since HSV-2 can infect neurons which are nondividing cells, the virus needs a way to replicate no matter the state of the cell. The way the virus can replicate in slowly or nondividing cells is it encodes most of the enzymes that are required to have a high amount of nucleotides in a cell so it can replicate its genome (Shors 421).
The monomers of newly synthesized DNA are packaged into capsids and the tegument proteins collect around the nucleocapsid. Viral glycoproteins will also collect in the inner membrane of the nucleus and these proteins will promote the budding of the nucleocapsids through the nuclear membrane. It is believed that it de-envelops in the cytoplasm and then goes through Golgi-derived vesicles. The virus matures and buds through the vesicles acquiring an envelope, and cell lysis occurs (Shors 421-422).
In latent infections, HSV-2 infects the sensory neurons in the primary site of infection. The virus will remain in the sensory neurons even after a productive infection, but it typically moves down the axon and into the cell body of the sacral ganglion in the CNS. HSV-2 does not integrate into the host genome, it stays as an episome in the nucleus. During latency, very few viral genes are expressed except LATs (latency associated transcripts). These are believed to prevent viral gene expression so the neurons will not undergo apoptosis while the virus is present. Since no replication occurs during latency, no virus particles can be detected so it is able to hide from the immune system. Reactivation can occur due to changes in temperature or weather, stress, hormones, and many other factors. During reactivation, the virus travels down the nerve pathway and shows symptoms on the skin surface (Shors 422-423).
HSV-2 tends to stay latent in the sacral ganglion so symptoms are shown in the nearby genital areas. While cells do not survive lytic infections, no noticeable changes can be observed on the outside of the cell and only viral LATs are produced during latent infections. Cell function is not altered during latency, but in lytic infections the cell's transcription is shut down so the virus can use the cellular replication machinery and the cell is eventually killed when the virus is released. In the laboratory, CPEs can be a way to determine if a cell is actively infected with HSV-2. In vitro, the CPE of infected diploid and HEp-2 cells is swelling and rounding of cells. In late CPE, infected HEp-2 cells tend to cluster together ("Effect of Viruses"). Sometimes CPEs in vivo can cause symptoms that can be seen in humans.
HSV-2 lytic infections can be asymptomatic for some people. Symptoms can include flu-like symptoms, or tingling and itching before any physical outbreaks occur. Other symptoms include sores, blisters, bumps, pimples, redness, and pains in the genital area. These symptoms will usually go away in two to twelve days, although the first outbreak is typically the longest display of symptoms. Symptoms can reappear during reactivation of the virus in the neurons. As stated before, factors that weaken the immune system can cause reactivation. These factors can include stress, hormones, poor sleep or diet, and any type of illness ("Frequently Asked Questions").
Long term consequences are usually not very severe. The most a person normally has to deal with is recurring outbreaks throughout their life, although there can be emotional distress from having the lifelong virus. Occasionally more severe problems can develop. These problems can include herpes encephalitis, herpes meningitis, eczema herpeticum, ocular herpes and vision loss, and gingivostomatitis. Encephalitis and eczema herpeticum can be fatal if they are not treated quickly. The other problems are usually not fatal and go away without treatment. In severely immunocompromised patients problems can include pneumonia, inflammation of the esophagus, encephalitis, destruction of the adrenal glands, disseminated herpes, and liver damage. These problems can be fatal and need to be treated promptly. It has also been shown that people with herpes have a much higher risk of contracting HIV. If a person has HIV and herpes, it has been shown to have a synergistic effect between them ("Herpes simplex").
The immune system can work to clear the virus during lytic infections. It is believed that CD4+ Th1 T-cells are very important to the clearing of the productive virus. It is also believed that IFN-gamma secretions and CD8+ CTLs play an important role in preventing recurring outbreaks ("Initiatives for Vaccine Research"). While the virus can never be fully cleared from the immune system, there are medicinal ways to treat it and make the outbreaks less severe.
Antiviral medications are the only way to currently treat herpes. The medications cannot clear the virus from the system, but it can reduce the amount and severity of the outbreaks. Suppressive therapy is used to reduce the amount of outbreaks and is done by taking antivirals daily. Taking the medications only when outbreaks occur to reduce the severity and length of the outbreak is called episodic therapy. It can shorten the length of the outbreak by a few days ("Frequently Asked Questions"). Antivirals typically prescribed are Valtrex and acyclovir. HSV-2 vaccines are in progress right now, but none are available yet. HSV-2 subunit and live attenuated vaccines are being experimented with currently. DNA vaccines and whole inactivated virus vaccines were shown to be ineffective and their development was halted. One version of the subunit vaccine was developed by Chiron. It produced antibody titres but was not very efficient for long in women and was not effective for men. Another version of the subunit vaccine shows more promise, but it seems to be ineffective for people seropositive for HSV-1. It does produce good Th1 immunity in mice, but in countries where HSV-1 is very prevalent, the vaccine will not be useful. Two of the possible live vaccines use a replication-impaired virus. The live vaccine made by Xenova/GSK is being refocused towards being used as a prophylactic vaccine. The other replication-impaired vaccine is under development by Avant Immunotherapeutics but it is at a preclinical stage. The last live vaccine is able to replicate but has a mutation with ICP10, and it is in Phase II clinical study ("Initiatives for Vaccine Research"). Having a vaccine available could affect the current prognosis of the disease.
This disease has the same prognosis whether it is treated or not. It can never be cleared from the system so any treatments that are done will just shorten or lessen the outbreaks. A vaccine may be available sometime soon, and that would prevent the disease if the person has received the vaccine. The best way to prevent contracting the virus now, is to abstain from sexual contact with anyone. Using condoms can reduce the risk of infection, but it will not always prevent it. Since skin contact is a way it is spread, if virus is being released from a part of the body not covered by a condom, the partner could contract the virus. Infected persons that are not showing any symptoms can still infect sex partners ("Genital Herpes"). It does not matter who the partner is, both need to be careful since HSV-2 does not discriminate against who it can infect.
The demographic of infection is extremely broad. The virus will infect any human it comes in contact with. Everyone is susceptible to the virus although it is more common in females than males. Approximately one out of five women aged 14 to 49 in the US are infected, while one out of nine men aged 14 to 49 are infected. Even though more women are infected than men, transmission from infected males to females is more common than transmission from infected females to males. Nationwide, one out of six people aged 14 to 49 are infected in the US ("Genital Herpes").
Generally, HSV-2 can only be attained while having sexual contact with an infected person. Uninfected people that are having sexual contact with an infected person are the most susceptible to the virus. Since HSV-2 is an STD that is spread from skin-to-skin contact, it can be transmitted by genital to genital or genital to anal contact with an infected person. A person can have no symptoms and not realize that they are infected and pass the virus through unprotected sex. Condoms can reduce the risk of passing the virus to the partner, but if the virus is being released from a place not covered by the condom then it can easily be spread. The possibility of becoming infected with the virus increases as the number of sexual partners increases. The virus can have an economic impact as well as a personal impact.
Economically, it can be a little expensive to keep up suppressive therapy. Valtrex is a commonly prescribed medication to treat HSV-2. It recently went generic so it is cheaper now than the brand was, but it can still be somewhat expensive for some people to take daily. Without insurance, most people would not be able to afford a monthly prescription since it can cost over one hundred dollars for a month supply. Acyclovir is a cheaper substitution that the doctor could choose for the patient. With the right tools, suppressive and episodic therapies can make life with HSV-2 less dramatic.
The common virus that causes genital herpes is HSV-2. When the virus is not lying latent in the sacral ganglion, it is causing symptoms that include tingling, itching, and sores. Antiviral medications can be used to lessen the length of these symptoms or decrease the amount of outbreaks a person has in a lifetime. While anyone having sexual contact with an infected person is at risk for contracting the virus, women commonly have the virus more than men. The virus can never be cleared from the system, and it has the potential to cause more severe problems so hopefully a vaccine will be successfully approved by the FDA soon.
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