Herpes Simplex virus type 2 (HSV-2) is a virus that belongs to the alpha herpes viridae subfamily and causes genital ulcer diseases. The transmission of HSV-2 occurs most often due to a sexual intercourse in humans, although it can disseminate through physical contact with the lesions and saliva from the patients. Medical professionals may contract the infection and lesions on their fingers, if they inadvertently contact the patient’s vaginal mucosa or mouth, without using appropriate gloves. The HSV-2 infection is known to be asymptomatic in 80 % of the cases . Genital herpes is a frequent infection acquired during pregnancy and about 5 % of the women could pass on the infection to their neonatal infants . Vertical transmission of HSV-2 is possible during vaginal delivery and may result in congenital defects and neonatal lesions of the mouth, skin or eyes of the newborn infants .
Viral entry and Pathogenesis. The HSV-2 virus infects the host cell and replicates in the cytoplasm and nucleus of the infected cell. The virus has the potential of remaining latent in the host cell nucleus, where the genome is stable and produces very few viral proteins . The factors which contribute to the virulence of the virus are its ability to evade the immune surveillance, long term latency, reactivation and replication in the host cell. HSV-2 can traverse from one cell to another, innervating nerves, and subsequently reach sacral dorsal root ganglia . Physical or emotional stress could trigger the reactivation of the latent virus, and causes the virus to travel from the sacral ganglion down the nerve root, resulting in mucocutaneous lesions and asymptomatic shedding . The initial infection may or may not be symptomatic and the antibodies appear in the circulatory system, 4-6 weeks after infection.
Disease and Virulence Factors
Of the herpes virus family, eight viruses including the HSV-2 virus are known to infect humans. The herpes virus family is further divided into subgroups alpha, beta and gamma. All viruses of this family contain double stranded DNA genome, packaged into an icosahedral capsid that is encapsulated by a tegument protein layer. The attachment of the glycoproteins of the virions to the heparin sulfate domains on the infected mucocutaneous host cell surface initiates the primary infection . These primary molecular interactions further facilitate the binding of viral proteins to the host cell surface receptors and result in penetration of the viral nucleocapsid and the tegument protein layer into the host cell cytoplasm. The viral nucleocapsid is then carried into the cytoplasm and the viral DNA is released.
According to a national survey in the US, the prevalence of HSV-2 has increased from to 21.7% in the adults from 1976 to 1994, whereas in Europe the prevalence rates range between 4% and 24 % . The age-adjusted prevalence of HSV-2 in the sub-Sahara regions of Africa is much higher, compared to the developing countries. In the Asian populations, the rates are comparatively low, ranging from 10% to 30% . Factors such as increased sensitivity of laboratory techniques used for detection of HSV-2, effective management and increased antibiotic usage, contribute to the changes in the prevalence rates over many years. Epidemiological evidence suggests that HSV-2 infection increases the susceptibility to HIV and vice versa. HIV infection may increase the risk of acquisition of HSV-2, HSV-2 shedding or reactivation of latent infection . Spontaneous mutations in the HSV enzyme thymidine kinase, occurring during viral replication, can facilitate its resistance to drugs such as aciclovir and penciclovir and result in HSV evolution .
Viral culture of samples from ulcers and lesions of the infected patients is a highly specific method of detection of HSV-2, although Polymerase chain reaction (PCR) has a greater sensitivity of almost 11-71% higher than viral culture . Seroconversion or appearance of antibodies in the blood of the patients occurs about 12 weeks after the initial infection with HSV-2. Presence of HSV-2 can be detected by the examination of specific antibodies against glycoproteins G (gG1 and gG2). Western Blot is a standard technique, although not very widely used for detection of the virus, because it is expensive and laborious.
According to a study conducted on immunocompetent, heterosexual, monogamous couples, the administration of once-daily dose of valaciclovir decreased the occurrence of symptomatic genital herpes among uninfected individuals by 77% and reduced the risk of transmission of HSV-2 by 50 % . Primary prevention strategies, including deferring of sexual advent among adolescents, decreasing the number of sexual partners, and use of condoms are the most cost effective intervention methods of prevention of HSV-2 .
Prevention of neonatal transmission. Antiviral treatment is generally considered safe in pregnancy with no significant birth defects as demonstrated by the pregnancy registries collected on prenatal exposure to drugs. Caesarean section is generally recommended if the first episode genital lesions appear in the women in the last few weeks of pregnancy, since the risk of viral shedding is very high at the time of vaginal delivery.
Two kinds of treatment are commonly administered for treatment of HSV-2. Short and episodic treatment reduces the severity and duration of symptoms such as pain and time of healing of the lesions during the infection, whereas long suppressive treatment lowers the symptomatic recurrences and asymptomatic viral shedding. Suppressive treatment with drugs such as aciclovir (ACV) prevents or delays about 80 % of the recurrence rates . ACV is a thymidine nucleoside analogue, which has been used to treat the mucosal HSV-2 infection for the last 30 years. It serves as a substrate for the viral enzyme thymidine kinase which phosphorylates ACV. Phosphorylated ACV then terminates the DNA synthesis and replication of HSV-2. Although efficient, its poor bioavailability and short half-life entails its frequent dosing. The phosphorylated active forms of valaciclovir, a pro-drug of ACV and famciclovir, a pro-drug of guanosine nucleoside analog, penciclovir, function as competitive inhibitors of the viral DNA polymerase, thereby inhibiting viral DNA synthesis .
The parameters such as the complexity of the HSV-2 viral lifecycle, latency of the virus and the immune evasion strategies employed by the virus in the infected host have imposed various hurdles in the development of successful prophylactic vaccines for the virus . The complexity and large size of the viral proteome with about 80 proteins have made identification of immunodominant proteins in the virus more challenging. While the animal studies conducted to develop vaccines are successful, human clinical studies have proven to be futile and inefficacious .
Owing to the lower efficacy of vaccines for HSV-2 and intricacies involved in the management of the genital herpes caused by the virus, scientists and researchers are gearing towards the development of molecular therapeutic strategies to treat HSV-2 infections. Preclinical research on microbicides containing topically applied small inhibitory RNA molecules (siRNAs) shows promising effects on inhibition of viral transmission, although they are yet to be approved for their efficacy and practical use.
Genital Herpes caused by HSV-2 has become a challenging disease to handle, considering the complexity of the viral life cycle and its latency. Nevertheless, with appropriate preventive measures the transmission of the HSV from lesions can be curbed and use of suitable treatment regimen can enable effective management of the disease. The new insights in the molecular targets of HSV-2 also lend a potential for development of novel vaccines and immunotherapeutic strategies to combat HSV-2 infection.
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