The structural components, including the key antigenic components, of human immunodeficiency virus are diagrammed here.Human immunodeficiency virus (HIV) is the causative agent for AIDS. The most common type is known as HIV-1 and is the infectious agent that has led to the worldwide AIDS epidemic. There is also an HIV-2 that is much less common and less virulent, but eventually produces clinical findings similar to HIV-1. The HIV-1 type itself has a number of subtypes (A through H and O) which have differing geographic distributions but all produce AIDS similarly. HIV is a retrovirus that contains only RNA.HIV is a sexually transmitted disease. Infection is aided by Langerhans cells in mucosal epithelial surfaces which can become infected. Infection is also aided by the presence of other sexually transmitted diseases that can produce mucosal ulceration and inflammation. The CD4+ T-lymphocytes have surface receptors to which HIV can attach to promote entry into the cell. The infection extends to lymphoid tissues which contain follicular dendritic cells that can become infected and provide a reservoir for continuing infection of CD4+ T-lymphocytes. HIV can also be spread via blood or blood products, most commonly with shared contaminated needles used by persons engaging in intravenous drug use. Mothers who are HIV infected can pass the virus on to their fetuses in utero or to infants via breast milk. When HIV infects a cell, it must use its reverse transcriptase enzyme to transcribe its RNA to host cell proviral DNA. It is this proviral DNA that directs the cell to produce additional HIV virions which are released. The genome of HIV contains only three major genes: env, gag, and pol. These genes direct the formation of the basic components of HIV. The env gene directs production of an envelope precursor protein gp160 which undergoes proteolytic cleavage to the outer envelope glycoprotein gp120, which is responsible for tropism to CD4+ receptors, and transmembrane glycoprotein gp41, which catalyzes fusion of HIV to the target cell's membrane. The gag gene directs formation of the proteins of the matrix p17, the "core" capsid p24, and the nucleocapsid p7. The pol gene directs synthesis of important enzymes including reverse transcriptase p51 and p66, integrase p32, and protease p11. In addition to the CD4 receptor, a coreceptor known as a chemokine is needed for HIV infection. Chemokines are cell surface fusion-mediating molecules. Such coreceptors include CXCR4 and CCR5. Their presence on cells can aid binding of the HIV envelope glycoprotein gp120, promoting infection. Initial binding of HIV to the CD4 receptor is mediated by conformational changes in the gp120 subunit, but such conformational changes are not sufficient of fusion. The chemokine receptors produce a conformational change in the gp41 subunit which allows fusion of HIV. The differences in chemokine coreceptors that are present on a cell also explains how different strains of HIV may infect cells selectively. There are strains of HIV known as T-tropic strains which selectively interact with the CXCR4 chemokine coreceptor to infect lymphocytes. The M-tropic strains of HIV interact with the CCR5 chemokine coreceptor to infect macrophages. Dual tropic HIV stains have been identified. The presence of a CCR5 mutation may explain the phenomenon of resistance to HIV infection in some cases. Over time, mutations in HIV may increase the ability of the virus to infect cells via these routes. Infection with cytomegalovirus may serve to enhance HIV infection via this mechanism, because CMV encodes a chemokine receptor similar to human chemokine receptors.


A human immunodeficiency viral particle is seen budding from the infected cell surface at the top, with a complete viral particle at bottom in this high magnification electron micrograph.Human immunodeficiency virus (HIV) is the causative agent for AIDS. The most common type is known as HIV-1 and is the infectious agent that has led to the worldwide AIDS epidemic. There is also an HIV-2 that is much less common and less virulent, but eventually produces clinical findings similar to HIV-1. The HIV-1 type itself has a number of subtypes (A through H and O) which have differing geographic distributions but all produce AIDS similarly. HIV is a retrovirus that contains only RNA.HIV is a sexually transmitted disease. Infection is aided by Langerhans cells in mucosal epithelial surfaces which can become infected. Infection is also aided by the presence of other sexually transmitted diseases that can produce mucosal ulceration and inflammation. The CD4+ T-lymphocytes have surface receptors to which HIV can attach to promote entry into the cell. The infection extends to lymphoid tissues which contain follicular dendritic cells that can become infected and provide a reservoir for continuing infection of CD4+ T-lymphocytes. HIV can also be spread via blood or blood products, most commonly with shared contaminated needles used by persons engaging in intravenous drug use. Mothers who are HIV infected can pass the virus on to their fetuses in utero or to infants via breast milk. When HIV infects a cell, it must use its reverse transcriptase enzyme to transcribe its RNA to host cell proviral DNA. It is this proviral DNA that directs the cell to produce additional HIV virions which are released. The genome of HIV contains only three major genes: env, gag, and pol. These genes direct the formation of the basic components of HIV. The env gene directs production of an envelope precursor protein gp160 which undergoes proteolytic cleavage to the outer envelope glycoprotein gp120, which is responsible for tropism to CD4+ receptors, and transmembrane glycoprotein gp41, which catalyzes fusion of HIV to the target cell's membrane. The gag gene directs formation of the proteins of the matrix p17, the "core" capsid p24, and the nucleocapsid p7. The pol gene directs synthesis of important enzymes including reverse transcriptase p51 and p66, integrase p32, and protease p11. In addition to the CD4 receptor, a coreceptor known as a chemokine is needed for HIV infection. Chemokines are cell surface fusion-mediating molecules. Such coreceptors include CXCR4 and CCR5. Their presence on cells can aid binding of the HIV envelope glycoprotein gp120, promoting infection. Initial binding of HIV to the CD4 receptor is mediated by conformational changes in the gp120 subunit, but such conformational changes are not sufficient of fusion. The chemokine receptors produce a conformational change in the gp41 subunit which allows fusion of HIV. The differences in chemokine coreceptors that are present on a cell also explains how different strains of HIV may infect cells selectively. There are strains of HIV known as T-tropic strains which selectively interact with the CXCR4 chemokine coreceptor to infect lymphocytes. The M-tropic strains of HIV interact with the CCR5 chemokine coreceptor to infect macrophages. Dual tropic HIV stains have been identified. The presence of a CCR5 mutation may explain the phenomenon of resistance to HIV infection in some cases. Over time, mutations in HIV may increase the ability of the virus to infect cells via these routes. Infection with cytomegalovirus may serve to enhance HIV infection via this mechanism, because CMV encodes a chemokine receptor similar to human chemokine receptors.


Human immunodeficiency viral particles are seen at medium magnification in this electron micrograph. Note the central core and the outer envelope.Human immunodeficiency virus (HIV) is the causative agent for AIDS. The most common type is known as HIV-1 and is the infectious agent that has led to the worldwide AIDS epidemic. There is also an HIV-2 that is much less common and less virulent, but eventually produces clinical findings similar to HIV-1. The HIV-1 type itself has a number of subtypes (A through H and O) which have differing geographic distributions but all produce AIDS similarly. HIV is a retrovirus that contains only RNA.HIV is a sexually transmitted disease. Infection is aided by Langerhans cells in mucosal epithelial surfaces which can become infected. Infection is also aided by the presence of other sexually transmitted diseases that can produce mucosal ulceration and inflammation. The CD4+ T-lymphocytes have surface receptors to which HIV can attach to promote entry into the cell. The infection extends to lymphoid tissues which contain follicular dendritic cells that can become infected and provide a reservoir for continuing infection of CD4+ T-lymphocytes. HIV can also be spread via blood or blood products, most commonly with shared contaminated needles used by persons engaging in intravenous drug use. Mothers who are HIV infected can pass the virus on to their fetuses in utero or to infants via breast milk. When HIV infects a cell, it must use its reverse transcriptase enzyme to transcribe its RNA to host cell proviral DNA. It is this proviral DNA that directs the cell to produce additional HIV virions which are released. The genome of HIV contains only three major genes: env, gag, and pol. These genes direct the formation of the basic components of HIV. The env gene directs production of an envelope precursor protein gp160 which undergoes proteolytic cleavage to the outer envelope glycoprotein gp120, which is responsible for tropism to CD4+ receptors, and transmembrane glycoprotein gp41, which catalyzes fusion of HIV to the target cell's membrane. The gag gene directs formation of the proteins of the matrix p17, the "core" capsid p24, and the nucleocapsid p7. The pol gene directs synthesis of important enzymes including reverse transcriptase p51 and p66, integrase p32, and protease p11. In addition to the CD4 receptor, a coreceptor known as a chemokine is needed for HIV infection. Chemokines are cell surface fusion-mediating molecules. Such coreceptors include CXCR4 and CCR5. Their presence on cells can aid binding of the HIV envelope glycoprotein gp120, promoting infection. Initial binding of HIV to the CD4 receptor is mediated by conformational changes in the gp120 subunit, but such conformational changes are not sufficient of fusion. The chemokine receptors produce a conformational change in the gp41 subunit which allows fusion of HIV. The differences in chemokine coreceptors that are present on a cell also explains how different strains of HIV may infect cells selectively. There are strains of HIV known as T-tropic strains which selectively interact with the CXCR4 chemokine coreceptor to infect lymphocytes. The M-tropic strains of HIV interact with the CCR5 chemokine coreceptor to infect macrophages. Dual tropic HIV stains have been identified. The presence of a CCR5 mutation may explain the phenomenon of resistance to HIV infection in some cases. Over time, mutations in HIV may increase the ability of the virus to infect cells via these routes. Infection with cytomegalovirus may serve to enhance HIV infection via this mechanism, because CMV encodes a chemokine receptor similar to human chemokine receptors.


Human immunodeficiency virus, viral particles are seen at low magnification adjacent to the cell surface in this electron micrograph.Human immunodeficiency virus (HIV) is the causative agent for AIDS. The most common type is known as HIV-1 and is the infectious agent that has led to the worldwide AIDS epidemic. There is also an HIV-2 that is much less common and less virulent, but eventually produces clinical findings similar to HIV-1. The HIV-1 type itself has a number of subtypes (A through H and O) which have differing geographic distributions but all produce AIDS similarly. HIV is a retrovirus that contains only RNA.HIV is a sexually transmitted disease. Infection is aided by Langerhans cells in mucosal epithelial surfaces which can become infected. Infection is also aided by the presence of other sexually transmitted diseases that can produce mucosal ulceration and inflammation. The CD4+ T-lymphocytes have surface receptors to which HIV can attach to promote entry into the cell. The infection extends to lymphoid tissues which contain follicular dendritic cells that can become infected and provide a reservoir for continuing infection of CD4+ T-lymphocytes. HIV can also be spread via blood or blood products, most commonly with shared contaminated needles used by persons engaging in intravenous drug use. Mothers who are HIV infected can pass the virus on to their fetuses in utero or to infants via breast milk. When HIV infects a cell, it must use its reverse transcriptase enzyme to transcribe its RNA to host cell proviral DNA. It is this proviral DNA that directs the cell to produce additional HIV virions which are released. The genome of HIV contains only three major genes: env, gag, and pol. These genes direct the formation of the basic components of HIV. The env gene directs production of an envelope precursor protein gp160 which undergoes proteolytic cleavage to the outer envelope glycoprotein gp120, which is responsible for tropism to CD4+ receptors, and transmembrane glycoprotein gp41, which catalyzes fusion of HIV to the target cell's membrane. The gag gene directs formation of the proteins of the matrix p17, the "core" capsid p24, and the nucleocapsid p7. The pol gene directs synthesis of important enzymes including reverse transcriptase p51 and p66, integrase p32, and protease p11. In addition to the CD4 receptor, a coreceptor known as a chemokine is needed for HIV infection. Chemokines are cell surface fusion-mediating molecules. Such coreceptors include CXCR4 and CCR5. Their presence on cells can aid binding of the HIV envelope glycoprotein gp120, promoting infection. Initial binding of HIV to the CD4 receptor is mediated by conformational changes in the gp120 subunit, but such conformational changes are not sufficient of fusion. The chemokine receptors produce a conformational change in the gp41 subunit which allows fusion of HIV. The differences in chemokine coreceptors that are present on a cell also explains how different strains of HIV may infect cells selectively. There are strains of HIV known as T-tropic strains which selectively interact with the CXCR4 chemokine coreceptor to infect lymphocytes. The M-tropic strains of HIV interact with the CCR5 chemokine coreceptor to infect macrophages. Dual tropic HIV stains have been identified. The presence of a CCR5 mutation may explain the phenomenon of resistance to HIV infection in some cases. Over time, mutations in HIV may increase the ability of the virus to infect cells via these routes. Infection with cytomegalovirus may serve to enhance HIV infection via this mechanism, because CMV encodes a chemokine receptor similar to human chemokine receptors.


CAPRISA 004  was a clinical trial conducted by  CAPRISA . This particular study was the first to show that a  topical  gel could reduce a person's risk of contracting HIV.  The gel used in the study contained  a microbicide .


A previous study had measured the safety and tolerability of tenofovir in both sexually active and abstinent women.  This study gave support to the idea that tenofovir was a drug which was worth examining as an HIV preventative. [ 1 ]


CAPRISA 004 was a  phase IIb ,  double-blind ,  randomized ,  placebo-controlled study  comparing 1%  tenofovir  gel with a placebo gel. 900 young women who were judged to be at risk of contracting  HIV  volunteered to use a study gel in their  vaginas , with half of those receiving the microbicide gel and the other half getting the placebo (according to their randomization results). The study asked participants to apply a first dose of the gel within 12 hours before having sex and to apply another dose within 12 hours after sex. All study volunteers participated in HIV risk reduction counseling and received  condoms . The study assisted in arranging treatment for any  sexually transmitted infections  that participants contracted. [ 2 ]


The study began in May 2007, was completed in December 2009, and the data collected was published in March 2010. The study design had expected the study to last for 30 months, with about 14 months to recruit study volunteers then with follow-up until 92 participants were observed to have become infected with HIV. The entrance criteria were such that, based on risk factors in the participants' lifestyles, the study expected 92 infections to occur approximately 16 months after they recruited the final volunteer. [ 2 ]


Researchers led by  Quarraisha Karim  found that a microbicide containing 1%  tenofovir  was, for women participating in the trial, 39% effective in reducing risk of contracting HIV during sex and 51% effective in preventing genital herpes infections. [ 3 ] [ 4 ]


The results of CAPRISA 004 were formally released at the 18th  International AIDS Conference . [ 5 ]


Michel Sidibé  of  UNAIDS  described the results of the study as being very encouraging because the treatment "can be controlled by women, and put in 12 hours earlier, and that is empowering. They do not have to ask the man for permission to use it. And the cost of the gel is not high." [ 6 ]


Anthony Fauci  of  NIAID  stated that "This is the first study that has shown a clear-cut positive effect of a microbicide on blocking acquisition of HIV infection." [ 7 ]


Mitchell Warren, head of the  AIDS Vaccine Advocacy Coalition , remarked that "This is a really historic day for HIV prevention research.  For the first time, through the CAPRISA 004 trial, we have seen evidence in a human clinical trial that a microbicide can help to prevent sexual transmission." [ 5 ]


A Phase III study named "FACTS 001", a larger study involving 2,200 women in Africa which is expected to start around the end of July 2011 and last 24 months. [ 8 ]


CAPRISA conducted CAPRISA 004 with the following assistance:


The principal investigators for the study were  Salim Abdool Karim  and  Quarraisha Abdool Karim , both of the  University of KwaZulu-Natal .  The study was conducted at the eThekwini Clinical Research Site in  Durban ,  South Africa  and the Vulindlela Clinical Research Site in  Pietermaritzburg , South Africa. [ 2 ]


The  epidemiology of herpes simplex  is of substantial  epidemiologic  and  public health  interest. Worldwide, the rate of  infection  with  herpes simplex virus —counting both HSV-1 and HSV-2—is around 90%. [ 1 ]   Although many people infected with HSV develop labial or genital lesions ( herpes simplex ), the majority are either undiagnosed or display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having  subclinical  herpes. [ 2 ]


In many infections, the first symptom a person will have of their own infection is the horizontal transmission to a sexual partner or the  vertical transmission  of neonatal herpes to a newborn at term. Since most asymptomatic individuals are unaware of their infection, they are considered at high risk for spreading HSV.  Many studies have been performed around the world to estimate the numbers of individuals infected with HSV-1 and HSV-2 by determining if they have developed antibodies against either  viral species . [ 3 ]


This information provides population prevalence of HSV viral infections in individuals with or without active disease. Note that there are population subgroups that are more
vulnerable for HSV infections, such as  cancer chemotherapy  patients. [ 4 ]


Large differences in HSV-1  seroprevalence  are seen in different  European countries . HSV-1 seroprevalence is high in  Bulgaria  (83.9%) and the  Czech Republic  (80.6%), and lower in Belgium (67.4%), The  Netherlands  (56.7%), and  Finland  (52.4%). [ 7 ]


The typical age at which HSV-1 infection is acquired ranges from 5 to 9 years in  Central  and  Eastern European  countries like Bulgaria and the Czech Republic, to over 25 years of age in  Northern European  countries such as Finland, The Netherlands, Germany, and England and  Wales . Young adults in Northern European countries are less likely to be infected with HSV-1.  European women are more likely to be HSV-1  seropositive  than men. [ 7 ]


HSV-2 seropositivity is widely distributed in Europeans older than 12, although there are large differences in the percentage of the population exposed to HSV-2. Bulgaria has a high (23.9%) HSV-2 seroprevalence relative to other European countries: Germany (13.9%), Finland (13.4%),
Belgium (11.1%), The Netherlands (8.8%), the Czech Republic (6.0%), and England and Wales (4.2%). [ 7 ]


Women are more likely to be seropositive than men, and likely acquire the virus at an earlier age.  In each country of Europe, HSV-2 seropositivity becomes more common from adolescence onwards and increases in the population with age, with a decline in the older age groups in some countries. [ 7 ]


The most recent data for HSV-2 was published in March 2010, based on a  National Health and Nutrition Examination Survey  study performed between 2005 and 2013 by  CDC . About 1 in 6 Americans (16.2%) aged 14 to 49 is infected with HSV-2. HSV-2 prevalence was nearly twice as high among women (20.9%) than men (11.5%), and was more than three times higher among blacks (39.2%) than non-Hispanic whites (12.3%). [ 8 ]


The most affected group was black women, with a prevalence rate of 48%. Prevalence increased with age and number of partners. Only 18.9% of those infected had previously been aware of their infection. [ 8 ]


African Americans and immigrants from  developing countries  typically have an HSV-1 seroprevalance in their adolescent population that is two or three times higher than that of  Caucasian Americans . [ 9 ]  Many white Americans become sexually active while seronegative for HSV-1. The absence of antibodies from a prior oral HSV-1 infection leaves these individuals susceptible to herpes whitlow, herpes gladiatorum, and HSV-1 genital infection. Primary genital infection brings with it the risk of vertical transmission to the neonate, and is highest if the mother contracts a primary infection during the third trimester of pregnancy. In the U.S. the number of genital infections caused by HSV-1 is now thought to be about 50% of first episodes of genital infection. [ 10 ] [ 11 ]


In healthy adults, HSV-2 infection occurs more frequently in the United States than in Europe.


Seroprevalence rates in the United States appeared to be increasing, rising from 16.4% in 1976 to 21.8% in 1994. [ 12 ]
However, this trend seems to have reversed itself in recent years, dropping to 17.2% in 2004. [ 13 ]


The current prevalence of genital herpes caused by HSV-2 in the U.S. is roughly one in four or five adults, with approximately 50 million people infected with genital herpes and an estimated 0.5 million new genital herpes infections occurring each year. [ 9 ]   African Americans  appear more susceptible to HSV-2, although the presence of active genital symptoms is more likely in  Caucasian Americans .  The largest increase in HSV-2 acquisition during the past few years is in white adolescents.  People with many lifetime sexual partners and those who are sexually active from a young age are also at higher-risk for the transmission of HSV-2 in the U.S. [ 14 ] [ 15 ] [ 16 ] [ 17 ]


Due to the anatomical nature of the vagina women are at higher risk than men for acquiring HSV-2 infection, and the chance of being infected increases with age. This is evident despite women on average having a lower number of sexual partners. [ 9 ]   As of 2022, The CDC reports that 48% of African American women and 46% of African American males in the United States are infected with the HSV-2 virus.
 [ 18 ] [ 19 ]


According to a study in  Ontario , of people between the ages of 15 and 16, 26.9% of men, 32% of non-pregnant women, and 55% of pregnant women tested positive for HSV-1 antibodies. Between the ages of 40 and 44, 54.7% of men, 88.7% of women, and 69.2% of pregnant women tested positive for HSV-1 antibodies. The overall age-gender standardized seroprevelance for HSV-1 antibodies was 51.1%. [ 20 ]  Teenagers are less likely to be seropositive for HSV-2—antibodies against this virus are only found in 0–3.8% of 15- and 16-year-olds.  However, 21% of individuals in their early forties have antibodies against HSV-2, reflecting the sexually transmitted nature of this virus. When standardising for age, HSV-2 seroprevalence in Ontario for individuals between the ages of 15 and 44 was 9.1%.   Rates for Canadian people infected with HSV-2  is much lower than estimated levels of HSV-2 seroprevalence in people of a similar age range in the United States. [ 20 ]


HSV-2 seroprevalence in pregnant women between the ages of 15 and 44 in  British Columbia  is similar, with 57% having antibodies for HSV-1 and 13% having antibodies for HSV-2. [ 3 ]  In British Columbia in 1999, the seroprevalence of HSV-2 antibody in leftover serum submitted for antenatal testing revealed a prevalence of 17.3%, ranging from 7.1% in women 15–19 years old to 28.2% in those 40–44 years. [ 21 ]
• In attendees at an Alberta sexually transmitted infection (STI) clinic in 1994 and 1995, the seroprevalence of HSV-1 and -2 in leftover sera was 56% and 19%, respectively. [ 22 ]
In Nova Scotia, 58.1% of 1,790 HSV isolates from genital lesion cultures in women were HSV-1; in men, 36.7% of 468 isolates were HSV-1 [ 23 ]


HSV-2 is more common in  Sub-Saharan Africa  than in Europe or the North America. Up to 82% of women and 53% of men in Sub-Saharan Africa are seropositive for HSV-2.  These are the highest levels of HSV-2 infection in the world, although exact levels vary from country to country in this continent. [ 24 ]


In most African countries, HSV-2 prevalence increases with age. However, age-associated decreases in HSV-2 seroprevalence has been observed for women in  Uganda  and  Zambia , and in men in  Ethiopia ,  Benin , and Uganda. [ 3 ]


Genital herpes appears less common in  Northern Africa  compared to Sub-Saharan Africa.  For example, only 26% of middle-aged women have antibodies for HSV-2 in  Morocco . [ 5 ]   Women are more likely to be infected with HSV-2 once they are over the age of 40. [ 5 ]


Children in  Egypt  with  acute lymphoblastic leukemia  are often infected with HSV from a young age—HSV-1 or HSV-2 antibodies are present in an estimated 54% of children under the age of 5, and 77% in children over 10 years of age. [ 25 ]
 Algerian  children are also likely to acquire HSV-1 infection at a young age (under 6) and 81.25% of the population has antibodies to HSV-1 by the age of 15. [ 26 ]


Relative to rates in Europe and North America, HSV-2 seroprevalency is high in Central and South America. Infection levels are estimated at 20% to 60%. [ 3 ] [ 24 ]
During the mid-1980s, HSV-2 prevalence was 33% in 25- to 29-year-old women and 45% in those aged 40 and over in  Costa Rica . In the early 1990s HSV-2 prevalence was approximately 45% among women over 60 in Mexico. [ 3 ]


The highest HSV-2 prevalence in Central or South America—60%—has been found in  Colombian  middle-aged women, although similar HSV-2 prevalence has been observed in younger women in  Haiti  (54%). [ 3 ]  HSV-2 infects about 30% of women over 30 years old in  Colombia , Costa Rica, Mexico, and  Panama . HSV-2 antibodies were found in more than 41% of women of childbearing age in  Brazil . [ 3 ]


However, no increase in seroprevalence was associated with age in women over 40 years old in Brazil—HSV-2 prevalence was estimated at 50% among women aged 40–49, 33% among women 50–59, and 42% among women over 60. Women in Brazil are more likely to acquire an HSV-2 infection if their male partners had history of anal sex and had many sexual partners in his lifetime. [ 5 ]    In  Peru , HSV-2 prevalence is also high among women in their 30s but is lower in men. [ 3 ]


HSV-1 seroprevalence in some Asian countries is low, relative to other countries worldwide, with only 51% women in  Thailand , and between 50 and 60% in Japan possessing antibodies. [ 3 ] [ 5 ]   HSV-2 seroprevalence in developing  Asian  countries is comparable (10–30%) to that observed in North America and Northern Europe. [ 24 ]  However, estimates of HSV-2 infectivity in Thailand are higher than observed in other  Eastern Asian  countries; total HSV-2 seroprevalence is approximately 37% in this country. [ 5 ]   HSV-2 seroprevalence is low in women in the  Philippines  (9%), although commencing activity while young is associated with an increase risk of acquiring HSV-2 infection; woman starting sexual activity by the time they reach 17 are seven times more likely to be HSV-2 seropositive than those starting sexual activity when over 21. [ 27 ]


In South Korea, incidence of HSV-2 infection in those under the age of 20 is low, only 2.7% in men and 3.0% in women. [ 6 ]   Seroprevalence levels increase in older South Koreans however, such that the population over 20 that has antibodies against HSV-2 is 21.7% of men and 28% of women. [ 6 ]


In India 63% of individuals were seropositive in 2005, within this figure, 33.3% were positive for HSV-1 and 16.6% are seropositive for HSV-2. Those with both HSV-1 and HSV-2 antibodies are estimated at 13.3% of the population. Indian men are more likely to be infected with HSV-2 than women, and increasing seroprevalence of this virus is associated with an increasing age. [ 28 ]


Turkey—
High levels of HSV-1 (97%) and HSV-2 (42%) were found amongst pregnant women in the city of  Erzurum  in  Eastern Anatolia Region, Turkey . [ 3 ]  In  Istanbul  however, lower HSV-2 seroprevalence was observed; HSV-2 antibodies were found in 4.8% of sexually active adults, while HSV-1 antibodies were found in 85.3%. [ 29 ]
Only 5% of pregnant women were infected with HSV-2, and 98% were infected with HSV-1.  Prevalence of these viruses was higher in sex workers of Istanbul, reaching levels of 99% and 60% for HSV-1 and HSV-2 prevalence respectively. [ 29 ]


Jordan—
The prevalence of HSV-2 in  Jordan  is 52.8% for men and 41.5% for women. [ 30 ]


Israel—
HSV-1 seroprevalence is 59.8% in the population of Israel and increases with age in both genders but the adolescent seroprevalence has been declining as in most industrialized nations. [ 31 ]  An estimated 9.2% of Israeli adults are infected with HSV-2. Infection of either HSV-1 or HSV-2 is higher in females; HSV-2 seroprevalence reaches 20.5% in females in their 40s. These values are similar to levels in HSV infection in Europe. [ 32 ]


Antibodies for HSV-1 or HSV-2 are also more likely to be found individuals born outside of Israel, and individuals residing in  Jerusalem  and Southern Israel; people of  Jewish  origin living in Israel are less likely to possess antibodies against herpes. [ 32 ]
Among pregnant women in Israel a small scale cross sectional study found the prevalence of HSV-2 infection was 13.3% and that of HSV-1 was 94.9%. The HSV-2 infection rate was 3-fold higher among immigrants from the former Soviet Union (27.5%) than among
Israeli-born Jewish and Arab women (9%). [ 33 ]  Approximately 78% of HSV-2 infections in Israel are asymptomatic. [ 34 ]  HSV-1 causes 66.3% of genital herpes in the  Tel Aviv  area. [ 35 ]


Syria—
Genital herpes infection from HSV-2 is predicted to be low in  Syria  although HSV-1 levels are high. HSV-1 infections is common (95%) among healthy Syrians over the age of 30, while HSV-2 prevalence is low in healthy individuals (0.15%), and persons infected with other sexually transmitted diseases (9.5%).  High risk groups for acquiring HSV-2 in Syria, include prostitutes and bar girls; they have 34% and 20% seroprevalence respectively. [ 36 ]


In Australia, a study using data from 1999 revealed the seroprevalence of HSV-1 was at 76.5%, with significant differences associated with age, gender and Indigenous status, which were not specified. [ 37 ]   An estimated 12% of Australian adults were seropositive for HSV-2, with higher prevalence in women (16%) than in men (8%). [ 37 ]  Larger cities had higher HSV-2 seroprevalence (13%) than rural populations (9%). Higher prevalence was found in  Indigenous Australians  (18%) than non-Indigenous Australians (12%). [ 37 ]


As in the U.S., HSV-1 is increasingly identified as the cause of   genital herpes in Australians ; HSV-1 was identified in the  anogenital area  of only 3% of the population in 1980, but had risen to 41% in 2001. [ 38 ]  This was most common in females and persons under 25. [ 38 ]
The number of genital herpes infections appears to be rising in New Zealand with three times more cases in 1993 compared to 1977. [ 39 ]  In this country, HSV-2 affects 60% more women than men of similar age. [ 3 ]


Human herpes viruses , also known as  HHV s, are part of a family of  DNA viruses  that cause several diseases in humans. One of the most notable functions of this virus family is their ability to enter a latent phase and lay dormant within animals for extended periods of time. [ 1 ]  The mechanism that controls this is very complex because expression of viral proteins during  latency  is decreased a great deal, meaning that the virus must have transcription of its  genes repressed . There are many factors and mechanisms that control this process and  epigenetics  is one way this is accomplished.  Epigenetics  refers to persistent changes in expression patterns that are not caused by changes to the  DNA sequence . This happens through mechanisms such as  methylation  and  acetylation  of  histones ,  DNA methylation , and  non-coding RNAs  (ncRNA).  Altering the acetylation of histones  creates changes in expression by changing the binding affinity of histones to DNA, making it harder or easier for  transcription  machinery to access the DNA.  Methyl  and  acetyl groups  can also act as binding sites for  transcription factors  and  enzymes  that further modify histones or alter the DNA itself. [ 2 ]


Human herpesviruses are all  double stranded DNA viruses  that enter the  nucleus  of the host cell. HHVs replicate in the nucleus of the infected cells and can enter both a lytic and latent phase. In the lytic phase, the viral genes are being actively transcribed and many times ultimately lead to cell death. In the lytic phase the virus is able to spread to other hosts due to open sores and other such mechanisms. In the latent phase the amount of viral transcript is heavily reduced. In this phase the host will show little to no signs of virus infection. This state can be maintained for very long periods of time and infection with HHVs can last a lifetime. [ 3 ]


Herpes simplex virus 1 and 2  (HSV 1 and HSV 2) are part of the  alpha subfamily  of herpesviruses. The lytic phase of infection occurs within mucoepithelial cells while the latent infection of these cells occurs in neurons. These two viruses are the cause of  oral  and  genital herpes . [ 4 ]


Latency is maintained in a variety of ways, one of which is the  latency-associated transcript , or LAT. This long non-coding RNA accumulates in the latent phase and has been found to suppress the lytic genes. It is also possible that the LAT transcript plays a role in determining which neurons become infected and maintain the lytic phase. LAT manages this suppression of the viral genome through  miRNAs  that block viral  transcription  factors such as  ICP0  and  ICP4  that play a very important role in the lytic phase of infection. Another mechanism that is used to maintain the latent phase is  chromatin remodeling . During the latent phase, researchers have found more methylated chromatin in the lytic genes and less acetylated chromatin, whereas in the LAT region there is less methylation and more acetylation found during latency. This was reversed during the lytic phase, Suggesting that this change of chromatin structure is used to control the [ clarification needed ]  and maintain the lytic and latent phases. [ 5 ]


Varicella zoster virus  (VZV) is a member of the alpha subfamily of herpesviruses and is responsible for the human diseases of the  chicken pox  and  shingles . These viruses have their lytic phase in mucoepithelial cells and are latent in neuronal cells. [ 6 ]


Unlike HSV 1 and 2, there has not been any LAT found in the VZV latent cells. Instead, it appears that the main way that expression of viral transcripts is maintained at a lower level during latency is through  chromatin  structure. There are 5 transcripts identified during latent infection of VZV.  Open reading frames  (ORFs) 21, 29, 62, 63, and 66 are all expressed with 62 and 63 being the most abundant. The  promoters  of these two genes,  ORFs  62 and 63, contain large amounts of acetylated H3K9, which makes these genes  euchromatic . This contrasts other genes normally found in lytic infection that are not associated with acetylated H3K9 histones during latency. This means that these genes are controlled through a mechanism affecting the chromatin structure that allows them to be expressed in the latent phase. The mechanism of how this happens is not clearly understood and research is currently being done in this area. [ 7 ] [ 8 ]


Epstein–Barr virus  (EBV) is a member of the  gammaherpesvirus  subfamily. EBV is responsible for infectious mononucleosis and is linked to several forms of cancer. EBV infects both  B cells  and  epithelial cells  and is able to undergo latency in both of these cells. A remarkable fact concerning the latency of EBV is that different patterns of expression exist while it is latent, known as latency programs. [ 9 ]


One of the ways that latency is achieved and maintained is through histone modification. It is known that  methylation  of histones often serve as marks that cause the formation of heterochromatin, an inactive form of chromatin, while acetylation often marks euchromatin, an active form of  chromatin . In EBV, The amount and location of the histone modifications is different for each latency program. There are several promoter regions which are the key targets of this histone modification in each of these programs.  There are the Cp and  Qp promoter  regions. The Cp promoter promotes the transcription of all the EBNA genes from a  polycistronic mRNA . The Q promoter (Qp) promotes the transcription of  EBNA1 . In type I latency, the Qp is  acetylated  and active while the Cp region is methylated and inactive. The opposite is true in type III latency where the Cp region is active and the Qp region is inactive. In both of these types of latency, H3K27me is slightly enriched in the lytic immediate early promoters. This suggests that facultative heterochromatin interacts with the  polycomb repressive complex  in order to limit lytic reactivation. [ 10 ]


Cytomegalovirus  (CMV) is a member of the  betaherpesvirinae  subfamily. CMV is responsible for a range of diseases, but mainly affects the immunocompromised. The primary targets for infection include  monocytes , lymphocytes, and epithelial cells with the known sites of latency including monocytes and  lymphocytes . [ 11 ]


One epigenetic mechanism employed in the control of latency for CMV is heterochromatization of the viral genome. Studies have shown that during latency the IE promoter is  heterochromatic  while the LUNA promoter is euchromatic. It has also been found that latently infected cells are more enriched for histones relative to the cellular genes. This keeps the transcriptional machinery from being able to access the viral transcripts. [ 12 ]


This control over the chromatin is brought about and maintained by recruited transcriptional repressors. These complexes, which are composed of enzymes such as  histone  deacetylases (HDACs), bind to the major immediate-early promoter (MIEP) of CMV and condense the DNA and prevent any remodeling. HDACs appear to be important for the continued maintenance of latency as HDAC inhibitors induce a lytic infection. It is also of not to mention that while chromatin methylation is utilized in this control mechanism, methylation of the DNA has not been observed. This is important due to the fact that HDACs do not function on their own but instead are part of larger co-repressor complexes that are recruited by methylated DNA or transcription factors which bind to specific sequences on DNA. Since there is no methylated DNA, it is likely that transcription factors are used to recruit these co-repressor complexes. [ 13 ]


Kaposi's sarcoma-associated herpesvirus  (KSHV) is  a part of the gammaherpesvirus subfamily. It undergoes lytic infection in lymphocytes and latency in B cells. It causes  Kaposi's sarcoma  and  primary effusion lymphoma . KSHV is one of eight known human cancer-causing viruses. The control of KSHV latency is most notably controlled by a set of viral miRNAs. During latency there are only a few transcripts that are produced. These transcripts include latency-associated nuclear antigen (LANA), viral cyclin (vCyclin), vFLIP (ORF71), kaposin (K12), and 12 miRNAs. [ 14 ]


One mechanism for this control is that the miRNAs down regulate the lytic activator protein known as Rta or orf50. This down regulation is accomplished through increasing the amount of  methyltransferases  and  CpG  methylation. The main miRNA responsible for this is miR-K12-5 which interacts with orf50 through its  3′ untranslated region  (UTR). These miRNAs also change the methylation of the histones in the viral genome. In the latent phase there is a lot of  H3K9 trimethylation  near the terminal repeats, which is an indication of heterochromatin in these areas. Another of these miRNAs, miR-K12-4-5p, targets  retinoblastoma-like protein 2  (Rbl2). Rbl2 regulates  DNA methyltransferases  (DNMTs), which in turn regulates the amount of DNA methylation. miR-K12-4-5p has been shown to upregulate the amount of DNMTs which increases DNA methylation and allows the latent phase of the infection to continue. [ medical citation needed ]


Herpes simplex research  includes all medical research that attempts to prevent, treat, or cure  herpes , as well as fundamental research about the nature of herpes. Examples of particular herpes research include  drug development , vaccines and genome editing. HSV-1 and HSV-2 are commonly thought of as oral and genital herpes respectively, but other members in the herpes family include  chickenpox  (varicella/zoster),  cytomegalovirus , and  Epstein-Barr virus . There are many more virus members that infect animals other than humans, some of which cause disease in companion animals (e.g., cats, dogs, horses) [ 1 ] [ 2 ] [ 3 ]  or have economic impacts in the agriculture industry (e.g., pigs, cows, sheep, chicken,  oysters ). [ 4 ] [ 5 ] [ 6 ]


Various vaccine candidates have been developed, the first ones in the 1920s, but none has been successful to date. [ 7 ] [ 8 ]


Due to the genetic similarity of both  herpes simplex virus  types (HSV-1 and HSV-2), the development of a prophylactic-therapeutic vaccine that proves effective against one type of the virus would likely prove effective for the other virus type, or at least provide most of the necessary fundamentals. [ citation needed ]  As of 2020 [update] , several vaccine candidates are in different stages of clinical trials.


An ideal herpes vaccine should induce immune responses adequate to prevent infection. Short of this ideal, a candidate vaccine might be considered successful if it (a) mitigates primary clinical episodes, (b) prevents colonization of the  ganglia , (c) helps reduce the frequency or severity of recurrences, and (d) reduces  viral shedding  in actively infected or asymptomatic individuals. [ 9 ]  The fact that a live-attenuated vaccine induced better protection from HSV infection and symptoms is not new, because live-attenuated vaccines account for most of the successful vaccines in use today. However, governmental and corporate bodies seem to support the more recent and safer but possibly less effective approaches such as glycoprotein- and DNA-based vaccines.


Due to the current stigma of the herpes simplex virus, the topic of a cure has always been considered a "taboo" whilst some also consider the symptoms to be mild that a cure or a vaccine is not needed. However, in April 2020, a  subreddit  group,  r/HerpesCureResearch  was formed to advocate for cure research and better treatment of HSV. The "Herpes Cure Research" has grown to 20k members and has raised funds for Fred Hutch's genome editing treatment and UPenn's mRNA vaccine research as well as forming a Herpes Cure Advocacy group in which the group is raising awareness on the health complications associated with HSV.
 [ 10 ]


Vaccine-elicited protection against HSV is challenging to achieve due to the ability of herpesviruses to evade many aspects of the mammalian immune response. As a general principle, the effectiveness of a HSV vaccine design is often inversely proportional to its safety. Subunit vaccines, which consist of individual or small groups of viral antigens, remove all risk of complications resulting from the production of vaccine-associated infectious viral particles but are limited in the degree and scope of immunity that can be produced in vaccinated individuals. Inactivated vaccines, which consist of intact viral particles, dramatically increase the repertoire of viral antigens that engender the immune response but like subunit vaccines are generally constrained to producing humoral immunity. Like inactivated vaccines, replication-defective vaccines expose the immune system to a diverse swath of HSV antigens but can produce both cellular and humoral immunity because they retain the ability to enter cells by HSV-induced membrane fusion. However, replication-defective HSV vaccines are challenging to produce at scale and offer limited immunization due to the lack of vaccine amplification. Live-attenuated vaccines are highly efficacious, potentially eliciting both cell-mediated and humoral immunity against structural and non-structural viral proteins, but their ability to replicate can result in vaccine-related illness particularly in immunocompromised individuals. Whereas subunit vaccines have proven effective against some viruses, immunity produced by subunit HSV vaccines have failed to protect humans from acquiring genital herpes in several clinical trials. In contrast, the success of the live-attenuated  chickenpox vaccine  demonstrates that an appropriately live-attenuated  α-herpesvirus  may be used to safely control human disease. The challenge of achieving vaccines that are both safe and effective has led to two opposing approaches in HSV vaccine development: increasing the efficacy of subunit vaccines (primarily by improving  adjuvant  formulations), and increasing the safety of live-attenuated vaccines (including the development of "non-invasive" vaccines).


The chart below is an attempt to list all known proposed HSV and varicella zoster vaccines and their characteristics. Please update with any missing information on vaccines only.


Ian Frazer


Claudia Kunz, PhD


(Taiwanese Company with a branch in the US.)
N/A


David Knipe [ 17 ]


Gus Kousoulas


Gregory Smith, Gary Pickard, Ekaterina Heldwein


William Jacobs Jr & Betsy Harold


Kevin P. Egan, Harvey Friedman, Sita Awasthi


William Halford [ 39 ]


A recent development in live-attenuated HSV vaccine design is the production of replicative vaccines that are ablated for nervous system infection. These vaccines infect the respiratory mucosa where their replication and localized spread provoke a robust immune response. The safety of these vaccines is based on their inability to invade the nervous system and establish life-long latent infections, as opposed to a general attenuation. Unlike other live-attenuated designs, these vaccines are cleared from the body once the immune response from vaccination has matured. In principle, by avoiding attenuation of HSV replication in the mucosa while removing the capacity to infect the nervous system, non-invasive vaccines have the potential to break the safety-efficacy dilemma by producing the strongest possible immune response while maintaining a high degree of safety.


The VC2 non-invasive vaccine was developed by Dr. Gus Kousoulas at  Louisiana State University . VC2 encodes two attenuating mutations that together reduce HSV entry into neurons. The establishment of latency is prevented in animal models such as mice, guinea pig, and rhesus monkeys. [ 21 ] [ 22 ] [ 23 ]


The R2 non-invasive vaccine was developed by Drs. Gregory Smith ( Northwestern University Feinberg School of Medicine ), Patricia Sollars & Gary Pickard ( University of Nebraska-Lincoln ), and Ekaterina Heldwein ( Tufts University School of Medicine ). R2 vaccines retain native replication in epithelial cells but are incapable of retrograde axonal transport and invasion of the nervous system. [ 25 ]  A single dose of the R2 vaccine passively introduced on mucosal tissues protects the nervous system from future infections and affords protection against lethal encephalitic infections in mice and rats. This vaccine strategy is noted for its effectiveness against both veterinary and clinical neuroinvasive herpesviruses . [ 47 ]  Thyreos Inc was founded to develop a herpesvirus  vaccine platform  based on the R2 design with targeted applications in human health, companion animal health, and livestock productivity.


Dr. William Halford at the  Southern Illinois University (SIU) School of Medicine  tested a live-attenuated HSV-2 ICP0∆NLS vaccine in 2016, before his death in June, 2017. [ 48 ] [ 49 ] [ 50 ]  Vaccine attenuation is achieved by a mutation in ICP0 (ICP0∆NLS) that increases the vaccine strain's sensitivity to interferon responses and limits its replication. Already proven as safe and effective in rodents and eliciting 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine, Halford's vaccine was tested outside of the United States, in St. Kitts in 20 human volunteers. All 20 of the participants self-reported an improvement in symptoms, but only 17 received and completed all three dosages. [ 51 ]   Blot tests showed a clear antibody response, which cannot be instigated by a placebo effect. However, the human trial was conducted without approval from the FDA or from the SIU Institutional Review Board. [1]


David M. Knipe , a professor at  Harvard Medical School  has developed  dl 5-29. The  dl 5-29 vaccine is also known under the name ACAM-529 [ 52 ]  or HSV-529, a replication-defective vaccine that has proved successful in preventing both HSV-2 and HSV-1 infections and in combating the virus in already-infected hosts, in animal models. [ 53 ]  The HSV-529 is a leading vaccine candidate which has been investigated in numerous research publications, and is endorsed by many researchers in the field (i.a. Lynda A. Morrison and Jeffrey Cohen). [ 54 ]   The vaccine induces strong HSV-2-specific  antibody  and  T-cell  responses, protects against challenge with a wild-type HSV-2 virus, reduces the severity of recurrent disease, and provides cross-protection against HSV-1. [ 55 ]  The ongoing trials would prove if a durable immune response in humans is to be successfully achieved or if the vaccine is too over attenuated to do the same. The vaccine was being researched and developed by  Sanofi Pasteur . [ 56 ]


On 28 April 2022, Sanofi announced it had discontinued a trial evaluating four HSV-2 vaccines. [ 57 ]  The pipeline section of the Sanofi website no longer lists any HSV vaccine candidate in active development. [ 58 ]


Professor  Ian Frazer  developed an experimental vaccine with his team at  Coridon , a biotechnology company he founded in 2000. [ 59 ]  The company, now known under the name  Admedus Vaccines , is researching DNA technology for vaccines with prophylactic and therapeutic potential. What's different about this vaccine is the way that response is being created. Instead of introducing a weakened version of the herpes virus or protein subunit, this vaccine uses a small section of DNA to produce T-cells and stimulate the immune response. [ 60 ]  The new vaccine candidate is designed to prevent new infections, and to treat those who already have the infection. In February 2014, it was announced that Frazer's vaccine against genital herpes passed human safety trials in a trial of 20 Australians. [ 61 ]  In October 2014, Admedus announced success in creating a positive T-cell response in 95% of participants. [ 62 ]  Further research is required to determine if the vaccine can prevent transmission. In July 2014, Admedus increased its stake in Frazer's vaccines by 16.2%. In addition, $18.4 million was posted as funds raised towards Phase II vaccine testing and research. [ 63 ]


The HSV-2 Phase II trial began in April 2015. [ 64 ]   Interim results were published on March 4, 2016, and based on the results of a scheduled, blinded, pooled analysis of data from the first 20 patients to receive at least three vaccinations in the randomised, placebo controlled Phase II study with the following results:


On 19 October 2016, Admedus released interim results from the ongoing HSV-2 Phase IIa study.  The unblinded data demonstrated a 58% reduction in viral shedding compared to baseline and a reduction in outbreaks of 52% post vaccination and 81% overall reduction post-booster. [ 65 ]


On 1 June 2020, Admedus announced it had changed its name to Anteris Technologies Ltd., and would become a "dedicated structural heart company". [ 66 ]  No vaccines are listed in the company's most recent research report [ 67 ]  and the vaccine is likely discontinued.


Vitaherpavac - In patients with monotonously recurrent genital herpes infection and history of failure of standard vaccination, anti-relapse efficacy of Vitaherpavac vaccine was demonstrated after allergometry-based tailored choice of vaccine administration regimen. The used approach was associated with lower antigenic load and sensitization, more than three-fold increase in relapse-free period in 85% of treated patients and improvement of Th1-dependent immunity. The Russian vaccine Vitagerpavak — the only polyvalent vaccine in the world for treatment of the chronic gerpesvirusny infection (CGI) І and ІІ types. It is developed in scientific research institute of virology of D.I. Ivanovsky of the Russian Academy of Medical Science. More than 15 years are applied in the Russian Federation. [ 68 ]


A study from the  Albert Einstein College of Medicine , where glycoprotein D (gD-2) was deleted from the herpes cell, showed positive results when tested in mice. [ 69 ]  Researchers deleted gD-2 from the herpes virus, which is responsible for herpes microbes entering in and out of cells. The vaccine is still in early stages of development and more research needs to be conducted before receiving FDA approval for clinical trials. [ 70 ]


Research conducted by the  NanoBio Corporation  indicates that an enhanced protection from HSV-2 is a result of mucosal immunity which can be elicited by their intranasal nanoemulsion vaccine. NanoBio published results showing efficiency in studies conducted in both the prophylactic and the therapeutic guinea pig model. This included preventing infection and viral latency in 92% of animals vaccinated and a reduction in recurrent legions by 64% and viral shedding by 53%. NanoBio hopes to raise funds in 2016 to enter into Phase I clinical testing. [ 71 ]


Profectus BioSciences  intends to use its PBS Vax therapeutic vaccine technology to engineer a vaccine for HSV-2. [ 72 ]  The vaccine is in early development and much is unknown about its viability.


Biomedical Research Models , a  Worcester -based biopharmaceutical company has been awarded a fund for the development of a novel vaccine platform to combat mucosally transmitted pathogens such as HSV-2. [ 73 ]


The company  Tomegavax  (recently acquired by  Vir Biotechnology ) is researching to utilize  cytomegalovirus  vectors in the development of a therapeutic vaccine against herpes simplex virus 2 (HSV-2), the causative agent of genital herpes. It has been awarded a grant by the NIH for this purpose. [ 74 ]


Redbiotec , a privately held Swiss biopharmaceutical company, based in  Zurich  as a spin-off of the  ETH Zurich , is focusing on the development of a therapeutic vaccine against HSV-2. Redbiotec's preclinical vaccine shows over 90% of lesion score (vs. approx. 50% for GEN-003 of Genocea) in early findings. [ 75 ]


Sanofi Pasteur and the clinical-stage immunotherapy company  Immune Design  have entered a broad collaboration, which will explore the potential of various combinations of agents against HSV-2, including an adjuvanted trivalent vaccine candidate G103, consisting of recombinantly-expressed viral proteins. [ 76 ]


Below is a list of vaccines that are no longer being pursued.


One vaccine that was under trial was Herpevac, a vaccine against HSV-2. The  National Institutes of Health  (NIH) in the  United States  conducted  phase III trials  of Herpevac. [ 95 ]   In 2010, it was reported that, after 8 years of study in more than 8,000 women in the United States and Canada, there was no sign of positive results against the sexually transmitted disease caused by HSV-2 [ 80 ]  (and this despite earlier favorable interim reports [ 95 ] ).


PaxVax , a specialty vaccine company, partnered with Spector Lab at the  UC San Diego  Department of Cellular and Molecular Medicine regarding the development of a genital herpes  viral vector  vaccine. The vaccine was in the pre-clinical stage. [ 96 ]  The vaccine is no longer listed on their website as a present endeavour and has likely been discontinued. [ 84 ]


A private company called  BioVex  began Phase I clinical trials for  ImmunoVEX , another proposed vaccine, in March 2010. [ 97 ]  The company had commenced clinical testing in the UK with its vaccine candidate for the prevention and potentially the treatment of genital herpes. The biopharmaceutical company  Amgen  bought BioVex [ 98 ]  and their proposed ImmunoVEX vaccine appears to have been discontinued, furthermore it has been removed from the company's research pipeline. [ 86 ]


A live, attenuated vaccine (which was proven very effective in clinical trials in Mexico) by the company  AuRx  has failed to proceed to a Phase III trial in the year 2006, due to financial reasons. The AuRx therapy was shown to be safe and decrease the occurrence of lesions by 86% after one year. [ 99 ]


Mymetics  is developing a pre-clinical preventative vaccine for HSV 1 and 2 using its virosome technology. [ 91 ]  There has not been any recent announcement by the company regarding their vaccine, which seems to have been taken off from the company's research product pipeline.


HerpV , a genital herpes vaccine candidate manufactured by the company  Agenus , announced Phase II clinical trial results in June 2014. Results showed up to a 75% reduction in viral load and a weak reduction in viral shedding by 14%. [ 100 ]  These results were achieved after a series of vaccinations and a booster dose after six months, signalling the vaccine may take time to become effective. Further testing results are to show if the vaccine is a viable candidate against genital herpes. [ 101 ]  There has not been any recent announcement by Agenus regarding the vaccine HerpV, which seems to have been taken off from the company's research product pipeline. [ 102 ]


Genocea Biosciences  has developed GEN-003, a first-in-class protein subunit T cell-enabled therapeutic vaccine, or immunotherapy, designed to reduce the duration and severity of clinical symptoms associated with moderate-to-severe HSV-2, and to control transmission of the infection. GEN-003 includes the antigens  ICP4  and  gD2 , as well as the proprietary adjuvant Matrix-M. GEN-003 had concluded  Phase IIa clinical trials . In December 2015, Genocea announced  interim data  showing a 58% decrease in viral shedding and a 69% decrease in genital lesions. They also showed one of the doses stopped outbreaks for at least 6 months. [ 103 ]  GEN-003 was  undergoing a Phase IIb clinical trial  in the United States. Genocea has announced it would shift their strategic efforts to cancer vaccines while at the same time heavily cutting down on research and development of GEN-003 vaccine against genital herpes. [ 104 ]  Being unable to secure funding or partnering with another company, Genocea's further vaccine development remains to be determined.


Vical  had been awarded grant funding from the National Institute of Allergy and Infectious Diseases division of the NIH to develop a   plasmid  DNA-based vaccine to inhibit recurring lesions in patients latently infected with herpes simplex virus type 2 (HSV-2). The plasmid DNA encoding the HSV-2 antigens was formulated with  Vaxfectin , Vical's proprietary cationic lipid adjuvant. Vical is concluding  Phase I clinical trials , while reporting data showing the vaccine candidate failed to meet the primary endpoint. [ 105 ]  The San Diego-based company was forced to concede that their herpes strategy had misfired, with their vaccine failing to perform as well as a placebo. [ 106 ]   However, that seemed to may have changed, since 20 June 2016, when Vical released phase I/II results at  ASM . [ 107 ]  Their vaccine (named VCL-HB01) was involved in a  Phase II clinical trial . The recent trial, similarly to a past trial again missed the primary endpoint and therefore the company is discontinuing the vaccine and moving to other pipeline products. [ 94 ]


Another area of research for HSV treatment or a potential cure is the use of  genome editing . It is thought that by cleaving the DNA of HSV that infects neurons, thereby causing destruction or mutational inactivation of the HSV DNA, the virus can be greatly treated or even cured. [ 108 ]


The  Jerome Lab  run by  Keith R. Jerome  at the  Fred Hutchinson Cancer Research Center  has looked at using  zinc finger nuclease  as well as  endonuclease  to prevent HSV from replicating. Most recently Jerome and his lab were able to demonstrate cleavage of latent HSV in a living organism, which is vital to disabling the virus. [ 109 ]  On August 18, 2020, the team led by Jerome and Martine Aubert published a paper in Nature Communications showing that, through a series of incremental improvements on their original method, they had destroyed up to 95% of herpes virus lurking in certain nerve clusters of mice, with 3 years of work expected before clinical trials are considered. [ 110 ]


Editas Medicine , that previously collaborated with the Cullen Lab, [ 111 ]  are researching  CRISPR-Cas9  for its use in  Herpes Simplex Keratitis .


Researchers at  Temple University  have been researching how to disrupt HSV from replicating that could eventually lead to a cure. [ 112 ] [ 113 ]  Some members of research team at Temple University have also joined forces to create Excision BioTherapeutics. The company intends to begin clinical trials in 2022. [ 114 ]


Researchers at the  University Medical Center Utrecht , using the  CRISPR-Cas9  system, have showed promising results in clearing HSV-1 infection by simultaneously targeting multiple essential vital genes in vitro. [ 115 ]  The researchers are now looking at targeting latent HSV-1 genomes and are investigating in vivo model systems to assess the potential therapeutic application. [ 116 ]


In 2021, scientists in China described a CRISPR-Cas9 genome editing approach which could be used to treat HSV-1 in  corneal stroma : injection of  engineered lentiviruses  into the affected anatomical regions for transient editing without inducing  off-target edits . [ 117 ] [ 118 ]


Johnston, Gottlieb & Wald 2016 published an overview of the state of research. [ 119 ]


Since the introduction of the nucleoside analogs decades ago, treatment of herpes simplex virus (HSV) infections has not seen much innovation, except for the development of their respective prodrugs (Aciclovir, Famciclovir, Valacilovir..). Drawbacks such as poor bioavailability or limited effectiveness of these drugs require further research effort of new pharmaceutical drugs against the herpes simplex disease. The inhibitors of the  Helicase-primase complex  of HSV represent a very innovative approach to the treatment of herpesvirus disease. [ 120 ]


Researchers have made a  Hammerhead ribozyme  that targets and cleaves the mRNA of essential genes in HSV-1. The hammerhead, which targets the mRNA of the UL20 gene, greatly reduced the level of HSV-1 ocular infection in rabbits, and reduced the viral yield in vivo. [ 126 ]  The gene-targeting approach uses a specially designed RNA enzyme to inhibit strains of the herpes simplex virus. The enzyme disables a gene responsible for producing a protein involved in the maturation and release of viral particles in an infected cell. The technique appears to be effective in experiments with mice and rabbits, but further research is required before it can be attempted in people infected with herpes. [ 127 ]


In 2016, researchers showed that the  genome editing  technology known as  CRISPR /Cas can be used to limit viral replication in multiple strains of herpesviruses, in some cases even eliminating the infection altogether. [ 128 ]  The researchers tested three different strains of herpesviruses:  Epstein-Barr virus , the cause of  mononucleosis  and some cancers;  Herpes simplex viruses  (HSV-1) and (HSV-2), which cause cold sores and genital herpes respectively; and  human cytomegalovirus , which causes congenital herpes. The results indicated that CRISPR can be used to eliminate replication in all three strains of the virus, but that the technology was so far only successful in actually eradicating Epstein-Barr virus. The authors think this may be because the Epstein-Barr virus genome is located in dividing cells that are easily accessible to CRISPR. Comparatively, the HSV-1 genome targeted by CRISPR is located in closed-off, non-replicating neurons, which makes reaching the genome much more challenging. [ 129 ]


Another possibility to eradicate the HSV-1 variant is being pursued by a team at  Duke University . By figuring out how to switch all copies of the virus in the host from latency to their active stage at the same time, rather than the way the virus copies normally stagger their activity stage, leaving some dormant somewhere at all times, it is thought that immune system could kill the entire infected cell population, since they can no longer hide in the nerve cells.  This is a potentially risky approach especially for patients with widespread infections as there is the possibility of significant tissue damage from the immune response.  One class of drugs called  antagomir  could trigger reactivation. These are chemically engineered oligonucleotides or short segments of RNA, that can be made to mirror their target genetic material, namely herpes microRNAs. They could be engineered to attach and thus 'silence' the microRNA, thus rendering the virus incapable of keeping latent in their host. [ 130 ]  Professor Cullen believes a drug could be developed to block the microRNA whose job it is to suppress HSV-1 into latency. [ 131 ]


Herpes has been used in research with  HeLa cells  to determine its ability to assist in the treatment of  malignant   tumors . A study conducted using suicide gene transfer by a cytotoxic approach examined a way to eradicate malignant tumors. [ 132 ]  Gene therapy is based on the cytotoxic genes that directly or indirectly kill tumor cells regardless of its gene expression. In this case the study uses the transfer of the Herpes simplex virus type I thymidine kinase (HSVtk) as the cytotoxic gene. Hela cells were used in these studies because they have very little ability to communicate through  gap junctions . [ 133 ]  The Hela cells involved were grown in a monolayer culture and then infected with the HSV virus. The HSV mRNA was chosen because it is known to share characteristics with normal eukaryotic mRNA. [ 134 ]


The HSVtk expression results in the  phosphorylation  of drug  nucleoside  analogues; in this case the drug ganciclovir, an antiviral medication used to treat and prevent cytomegaloviruses, converts it into the nucleoside analogue triphosphates. Once granciclovir is phosphorylated through HSV-tk it is then incorporating DNA strands when the cancer cells are multiplying. [ 133 ]  The nucleotide from the ganciclovir is what inhibits the DNA polymerization and the replication process. This causes the cell to die via  apoptosis . [ 132 ]


Apoptosis is regulated with the help of  miRNAs , which are small non-coding RNAs that negatively regulate gene expression. [ 135 ]  These miRNAs play a critical role in developing the timing, differentiation and death of cells. The miRNAs effect on apoptosis has affected cancer development by the regulation of cell proliferation, as well as cell transformation.  Avoidance of apoptosis is critical for the success of malignant tumors, and one way for miRNAs to possibly influence cancer development is to regulate apoptosis. In order to support this claim, Hela cells were used for the experiment discussed.


The cytotoxic drug used, ganciclovir, is capable of destroying via apoptosis transduced cells and non-transduced cells from the cellular gap junction. This technique is known as the "bystander effect," which has suggested to scientists that the effect of some therapeutic agents may be enhanced by  diffusion  through gap junctional  intercellular  communication (GJIC) or cell coupling. GJIC is an important function in the maintaining of tissue homeostasis and it is a critical factor in balance of cells dying and surviving.


When Hela cells were  transfected  with the HSV-tk gene, and were then put in a culture with nontransfected cells, only the HSV-tk transfected Hela cells were killed by the granciclovir, leaving the nonviral cells unharmed. [ 133 ]    The Hela cells were transfected with the encoding for the gap junction protein  connexin  43 (Cx43) to provide a channel that permits ions and other molecules to move between neighboring cells. Both Hela cells with the HSV-tk and without the HSV-tk were destroyed. This result has led to the evidence needed to state that the bystander effect in the HSV-tk gene therapy is possibly due to the Cx-mediated GJIC.


Research from 1964 into amino acid requirements of  herpes simplex virus  in human cells indicated that "...the lack of  arginine  or  histidine , and possibly the presence of  lysine , would interfere markedly with virus synthesis", but concludes that "no ready explanation is available for any of these observations". [ 136 ]


Further medical evidence indicates that "absorbing more arginine may indirectly cause cold sores by disrupting the body's balance of arginine and another amino acid called lysine." [ 137 ] [ 138 ]


Further reviews conclude that "lysine's efficacy for  herpes labialis  may lie more in prevention than treatment." and that "the use of lysine for decreasing the severity or duration of outbreaks" is not supported, while further research is needed. [ 139 ]


HSV is found to be susceptible to many essential oils and their constituents, however there is concern with the cutaneous use of essential oils is the degree of skin and mucous membrane irritation. [ 140 ] [ 141 ] [ 142 ]


Herpesvirus glycoprotein B  is a  viral   glycoprotein  that is involved in the  viral cell entry  of  Herpes simplex virus  (HSV).  Herpesviruses  have a  lipid bilayer , called the  envelope , which contains twelve surface glycoproteins. For  infectivity  to be attained, the double stranded  DNA  genome of HSV must enter the host cell through means of fusion of its envelope with the  cellular membrane  or via  endocytosis . Other viral glycoproteins involved in the process of viral cell entry include gC, gB, gD, gH, and gL, but only gC, gB, gD, and gH are required for the fusion of the HSV's envelope with the cellular membrane. It can be noted that all herpesviruses have glycoproteins gB, gH, and gL. [ 2 ]


The herpesvirus glycoprotein B is a  type-1 transmembrane protein  with a signal sequence at its N terminus. [ 2 ]  The  crystal structure  of herpes simplex virus (HSV) type-1 and  Epstein–Barr virus  glycoprotein B  ectodomains  were solved as a trimer, revealing five structural domains (I-V). [ 3 ] [ 4 ]  Domain I contains two internal fusion loops, thought to insert into the cellular membrane during virus-cell fusion. [ 5 ]  In HSV, domain II is hypothesized to interact with another herpesvirus glycoprotein, gH/gL, during the fusion process. [ 6 ]  Domain III consists of a structurally important elongated alpha helix, while domain IV is hypothesized to interact with cellular receptors. [ 7 ]   Finally, domain V acts in conjunction with domain I during protein-lipid interactions. In HSV, neutralizing  monoclonal antibodies  map to structural domains I, II, IV and V. [ 7 ]  Due to its unique structure, herpesvirus glycoprotein B (along with vesicular stomatitis virus glycoprotein G and baculovirus gp64) belongs to a new class of viral membrane fusion glycoproteins, class III. [ 3 ]


The herpesvirus glycoprotein B is the most highly conserved of all surface glycoproteins and acts primarily as a  fusion protein . The precise functions of gB and gH/gL are unknown but they are required for viral entry into the cell and constitute the core fusion machinery. The claim that gB is involved in fusion comes from the notable syncytial phenotype caused by certain mutations within the  cytoplasmic  domain of glycoprotein B, [ 8 ]  as well as its structural homology to other viral fusion proteins. [ 3 ]


This  membrane protein –related article is a  stub . You can help Wikipedia by  expanding it .


Martin v. Ziherl , 607  S.E.2d  367 (Va. 2005), was a decision by the  Supreme Court of Virginia  holding that the  Virginia  criminal law against  fornication  (sexual acts between unmarried people) was unconstitutional.  The court's decision followed the 2003 ruling of the  U.S. Supreme Court  in  Lawrence v. Texas , which established the constitutionally-protected right of adults to engage in private, consensual sex.


Virginia's law against fornication was repealed on March 4, 2020. [ 1 ]


Muguet Martin and Kristopher Ziherl were an unmarried couple who had been in a sexually active relationship for two years when Martin's doctor diagnosed her with  herpes .  She then filed a  lawsuit  against Ziherl in the  Richmond  Circuit Court, alleging that he knew he was infected with herpes when they had unprotected sex, knew it was contagious, and failed to inform her.  Her  complaint  claimed  negligence , intentional  battery  and  intentional infliction of emotional distress , for which she sought compensatory and  punitive damages .


The Supreme Court of Virginia had ruled in  Zysk v. Zysk , 404 S.E.2d 721 (Va. 1990), that  plaintiffs  could not recover damages for injuries suffered while participating in illegal conduct.  As sex between unmarried persons was criminalized under Virginia's anti-fornication statute, [ 2 ]  Ziherl filed a  demurrer  in response to Martin's suit.  Judge Theodore J. Markow rejected Martin's argument that the statute was no longer valid after  Lawrence v. Texas , in which the U.S. Supreme Court found unconstitutional a  Texas  law criminalizing  homosexual   sodomy  as an infringement upon the liberty of adults to engage in private and consensual intimate conduct under the  due process  clause of the  Fourteenth Amendment to the United States Constitution .  Judge Markow instead believed the fornication prohibition satisfied the  rational basis review  that  Lawrence  ruled the Texas statute failed, because the fornication law was reasonably related to the legitimate government goals of protecting public health and encouraging marriage for procreation.  Ziherl's demurrer was sustained, resulting in the dismissal of Martin's suit.  She subsequently appealed to the Virginia Supreme Court.


On appeal, Ziherl argued that Martin lacked  standing  to challenge the constitutionality of the statute because she was under no threat of prosecution, as the law had not been enforced against consenting adults since the mid-19th century. [ 3 ]  Invalidation would therefore not impact her liberty but would only allow her to pursue her lawsuit.  The court refused to consider this argument,  because of the longstanding rule that it would not consider a standing argument that was not first made at the trial court level.


The Virginia Supreme Court unanimously ruled on January 14, 2005, that the Virginia fornication law violated the  Fourteenth Amendment . [ 4 ]  Because the conduct by which Martin was allegedly injured could not be considered illegal,  Zysk  did not apply and she could proceed with her suit against Ziherl in the Richmond Circuit Court.


Lawrence v. Texas  was the sole foundation for the court's ruling, and so the majority of its opinion was an interpretation of that decision.  The U.S. Supreme Court in  Lawrence  had stated that it was adopting the reasoning of  Justice   John Paul Stevens  in his dissent to  Bowers v. Hardwick , which  Lawrence  overruled.  The Stevens rationale, as the Virginia Supreme Court presented it, was that "decisions by married or unmarried persons regarding their intimate physical relationship are elements of their personal relationships that are entitled to due process protection."  The Virginia Supreme Court stated that  sexual intercourse  was clearly part of the personal relationship of an unmarried couple, and that criminalizing intercourse clearly infringed upon their constitutionally protected right to make intimate choices.


Regarding Ziherl's argument that the statute served valid public interests, the court stated that in  Lawrence , the U.S. Supreme Court had ruled that the Texas sodomy statute furthered "no legitimate state interest" that could justify infringing the right to intimate contact.  The Virginia Supreme Court interpreted this to mean that  all  state interests must be insufficient to justify a prohibition on private, consensual sexual conduct, rather than only those advanced by Texas to support its statute in  Lawrence .  The court was careful to note that this did not pertain to laws involving minors, non-consensual or public sexual activity, or  prostitution , all of which the  Lawrence  Court also distinguished.


MPWH  (Meeting People With Herpes) is an American-based international  Herpes   dating community . MPWH offers an exclusive platform for positive singles who are living with Herpes (HSV-1 and HSV-2) to find support, friendship and love. [ 2 ]


In 2015, MPWH launched its apps for iOS and Android devices, which provide full functionality as its pc site and mobile site. Currently Michelle Lee is MPWH APP co-founder.


MPWH app was announced by  Cosmopolitan UK  as a dating app for people with Herpes in September, 2015. [ 3 ]


MPWH started to charge its members from March, 2016 PT (Pacific time) for providing a serious and meaningful dating environment. [ 4 ]


In 2018, MPWH was incorporated into SuccessfulMatch.com. [ 1 ]


The MPWH business frame is based on a membership system, people with Herpes create profiles with anonymous usernames and join in free of charge. Members have the options to hide or open their profiles or photos to others. [ 5 ] [ 4 ]


The community supports features, such as Latest Activities, Browse, SPARK, Private Album, Winks, Connections, Messages, Blog, etc.


The MPWH uses Tinder-style matching function called "SPARK" for members finding their matches. [ 6 ]  "SPARK" offers members' photos with age, gender, location to swipe and encourage members upload photos to enjoy swiping. Members swipe left 'pass' and swipe right to 'like'. If members like each other, MPWH will let them know. [ 7 ]


The  Recurrent Genital Herpes Quality of Life  (RGHQoL) measure is a  patient-reported outcome  measure which determines the impact that recurrent genital herpes has on a patient’s quality of life. It is a 20 item  questionnaire [ 1 ]  with items such as “Herpes makes it difficult for me to plan ahead” and “I worry that sex will trigger an outbreak.”. [ 2 ]  Lower scores on the RGHQoL indicate a higher negative impact on quality of life. [ 3 ]


The RGHQoL was published in 1998 by Galen Research and was funded by  Glaxo Wellcome  Research & Development. The content of the measure was taken from qualitative interviews conducted with patients with recurrent genital herpes. The initial interviews were conducted in the UK and then an international panel was assembled in order to translate and validate the measure for the UK, USA, Italy, France, Germany and Denmark. Items were translated and then field tested with up to 20 RGH patients in each country. The test-retest correlations for each language version was found to be in excess of 0.85, meaning every version had good reliability. [ 4 ]


The RGHQoL has been used in numerous clinical studies worldwide as a tool for assessing new treatments and measuring quality of life. It has been utilized in studies investigating suppressive  antiviral therapy , [ 5 ]   famciclovir [ 6 ]  and  quality of life . [ 7 ]


Valaciclovir , also spelled  valacyclovir , is an  antiviral medication  used to treat outbreaks of  herpes simplex  or  herpes zoster  (shingles). [ 2 ]  It is also used to prevent  cytomegalovirus  following a  kidney transplant  in high risk cases. [ 2 ]  It is taken  by mouth . [ 2 ]


Common side effects include  headache  and  vomiting . [ 2 ]  Severe side effects may include  kidney problems . [ 2 ]  Use in  pregnancy  appears to be safe. [ 2 ]  It is a  prodrug , which works after being converted to  aciclovir  in a person's body. [ 2 ]


Valaciclovir was patented in 1987 and came into medical use in 1995. [ 3 ] [ 4 ]  It is on the  World Health Organization's List of Essential Medicines . [ 5 ]  It is available as a  generic medication . [ 6 ]  In 2022, it was the 113th most commonly prescribed medication in the United States, with more than 5   million prescriptions. [ 7 ] [ 8 ]


Valaciclovir is used for the treatment of HSV and VZV infections, including: [ 9 ]


It has shown promise as a treatment for  infectious mononucleosis [ 12 ] [ 13 ] [ 14 ]  and is preventively administered in suspected cases of herpes B virus exposure. [ 15 ]


Bell's palsy  does not seem to benefit from using valaciclovir as its only treatment. [ 16 ] [ 17 ]


Common  adverse drug reactions  (≥1% of people) associated with valaciclovir are the same as for  aciclovir , its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation,  vertigo , confusion, dizziness,  edema ,  arthralgia , sore throat, constipation, abdominal pain, rash, weakness and/or  renal impairment . Rare adverse effects (<0.1% of patients) include: coma, seizures,  neutropenia ,  leukopenia , tremor,  ataxia ,  encephalopathy , psychotic symptoms,  crystalluria ,  anorexia , fatigue,  hepatitis ,  Stevens–Johnson syndrome ,  toxic epidermal necrolysis  and/or  anaphylaxis . [ 9 ]


Valaciclovir is a prodrug, an  esterified  version of  aciclovir  that has greater oral  bioavailability  (about 55%) than aciclovir. [ 1 ]  It is converted by  esterases  to the active drug,  aciclovir , and the  amino acid   valine  via  hepatic   first-pass metabolism .  Aciclovir  is selectively converted into a monophosphate form by viral  thymidine kinase , which is more effective (3000 times) in  phosphorylation  of  aciclovir  than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo- GTP , by cellular  kinases . [ 1 ]


Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of  viral   DNA replication . Aciclo-GTP competitively inhibits and inactivates the  viral   DNA polymerase . [ 1 ]  Its monophosphate form also incorporates into the viral DNA, resulting in  chain termination . It has also been shown that the viral enzymes cannot remove aciclo- GMP  from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular  phosphatases . [ 18 ]


Aciclovir is active against most species in the  herpesvirus  family. In descending order of activity: [ 19 ]


The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valaciclovir has been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms. [ 12 ] [ 13 ] [ 14 ]  Valaciclovir and acyclovir act by inhibiting viral DNA replication, but as of 2016 there was little evidence that they are effective against Epstein–Barr virus. [ 20 ]  Acyclovir therapy does prevent  viral latency , but has not proven effective at eradicating latent viruses in  nerve ganglia . [ 19 ]


As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity. [ 21 ]


It also is used for  herpes B virus  postexposure prophylaxis. [ 15 ] [ 22 ]


Details of the synthesis of valaciclovir were first published by scientists from the  Wellcome Foundation .


Aciclovir was esterified with a  carboxybenzyl   protected   valine , using  dicyclohexylcarbodiimide  as the  dehydrating agent . In the final step, the protecting group was removed by  hydrogenation  using a palladium on alumina catalyst. [ 23 ] [ 24 ]


Valaciclovir was patented in 1987 and came into medical use in 1995. [ 3 ] [ 4 ]  It is available as a  generic medication . [ 6 ]  In 2022, it was the 113th most commonly prescribed medication in the United States, with more than 5   million prescriptions. [ 7 ] [ 8 ]


It is marketed by  GlaxoSmithKline  under the brand names Valtrex [ 1 ]  and Zelitrex. Valaciclovir has been available as a  generic drug  in the US since November 2009. [ 25 ]


Bacterial vaginosis  ( BV ) is an  infection  of the  vagina  caused by excessive growth of  bacteria . [ 6 ] [ 12 ]  Common symptoms include increased  vaginal discharge  that often smells like fish. [ 2 ]  The discharge is usually white or gray in color. [ 2 ]   Burning with urination  may occur. [ 2 ]  Itching is uncommon. [ 2 ] [ 6 ]  Occasionally, there may be no symptoms. [ 2 ]  Having BV approximately doubles the risk of infection by a number of  sexually transmitted infections , including  HIV/AIDS . [ 11 ] [ 13 ]  It also increases the risk of  early delivery  among pregnant women. [ 3 ] [ 14 ]


BV is caused by an imbalance of the naturally occurring bacteria in the vagina. [ 4 ] [ 5 ]  There is a change in the most common type of bacteria and a hundred to thousandfold increase in total numbers of bacteria present. [ 6 ]  Typically, bacteria other than  Lactobacilli  become more common. [ 15 ]  Risk factors include  douching , new or  multiple sex partners ,  antibiotics , and using an  intrauterine device , among others. [ 5 ]  However, it is not considered a sexually transmitted infection and, unlike  gonorrhoea  and  chlamydia , sexual partners are not treated. [ 16 ]  Diagnosis is suspected based on the symptoms, and may be verified by testing the vaginal discharge and finding a higher than normal vaginal  pH , and large numbers of bacteria. [ 6 ]  BV is often confused with a  vaginal yeast infection  or  infection with  Trichomonas . [ 7 ]


Usually treatment is with an antibiotic, such as  clindamycin  or  metronidazole . [ 9 ] [ 6 ]  These medications may also be used in the second or third trimesters of  pregnancy . [ 6 ]  The  antiseptic   boric acid  can also be effective. [ 10 ]  BV often recurs following treatment. [ 6 ]   Probiotics  may help prevent re-occurrence. [ 6 ] [ 8 ]  It is unclear if the use of probiotics or antibiotics affects pregnancy outcomes. [ 6 ] [ 17 ]


BV is the most common vaginal infection in women of reproductive age. [ 5 ]  The percentage of women affected at any given time varies between 5% and 70%. [ 11 ]  BV is most common in parts of Africa and least common in Asia and Europe. [ 11 ]  In the United States about 30% of women between the ages of 14 and 49 are affected. [ 18 ]  Rates vary considerably between  ethnic groups  within a country. [ 11 ]  While BV-like symptoms have been described for much of  recorded history , the first clearly documented case occurred in 1894. [ 1 ]


Although about 50% of women with BV are asymptomatic, [ 19 ]  common symptoms include increased  vaginal discharge  that usually smells like fish. The discharge is often white or gray in color. There may be  burning with urination . Occasionally, there may be no symptoms. [ 2 ]


The discharge coats the walls of the vagina, and is usually without significant irritation, pain, or  erythema  (redness), although mild  itching  can sometimes occur. By contrast, the normal vaginal discharge will vary in consistency and amount throughout the  menstrual cycle  and is at its clearest at  ovulation —about two weeks before the  period  starts. Some practitioners claim that BV can be asymptomatic in almost half of affected women, [ 20 ]  though others argue that this is often a misdiagnosis. [ 21 ]


Although previously considered a mere nuisance infection, untreated bacterial vaginosis may cause increased susceptibility to sexually transmitted infections, including HIV, and  pregnancy complications . [ 22 ] [ 23 ]


It has been shown that HIV-infected women with bacterial vaginosis (BV) are more likely to transmit HIV to their sexual partners than those without BV. [ 13 ]
There is evidence of an association between BV and increased rates of sexually transmitted infections such as HIV/AIDS. [ 22 ]  BV is associated with up to a six-fold increase in HIV shedding. BV is a risk factor for viral shedding and  herpes simplex virus  type 2 infection. BV may increase the risk of infection with or reactivation of  human papillomavirus  (HPV). [ 22 ] [ 24 ]


In addition, bacterial vaginosis as either  pre-existing , or acquired, may increase the risk of pregnancy complications, most notably  premature birth  or  miscarriage . [ 25 ] [ 26 ]
Pregnant women with BV have a higher risk of  chorioamnionitis , miscarriage, preterm birth,  premature rupture of membranes , and postpartum  endometritis . [ 27 ]  Women with BV who are treated with  in vitro fertilization  have a lower implantation rate and higher rates of early pregnancy loss. [ 22 ] [ 24 ]


Healthy vaginal microbiota consists of species that neither cause symptoms or infections, nor negatively affect pregnancy. It is dominated mainly by Lactobacillus species. [ 15 ] [ 28 ]  BV is defined by the disequilibrium in the  vaginal microbiota , with decline in the number of  lactobacilli . While the infection involves a number of bacteria, it is believed that most infections start with  Gardnerella vaginalis   creating a  biofilm , which allows other  opportunistic bacteria , such as  Prevotella  and  Bacteroides , to thrive. [ 29 ] [ 12 ] [ 30 ]


One of the main risks for developing BV is  douching , which alters the vaginal microbiota and predisposes women to developing BV. [ 31 ]  Douching is strongly discouraged by the  U.S. Department of Health and Human Services  and various medical authorities, for this and other reasons. [ 31 ]


BV is a risk factor for  pelvic inflammatory disease , HIV, sexually transmitted infections (STIs), endometriosis, and reproductive and obstetric disorders or negative outcomes. Although BV can be associated with  sexual activity , there is no clear evidence of sexual transmission. [ 29 ] [ 32 ] [ 33 ]  It is possible for sexually inactive persons to develop bacterial vaginosis. [ 32 ] [ 12 ]


Also, subclinical iron deficiency may correlate with bacterial vaginosis in early pregnancy. [ 34 ]  A longitudinal study published in February 2006, in the  American Journal of Obstetrics and Gynecology , showed a link between psychosocial stress and bacterial vaginosis persisted even when other risk factors were taken into account. [ 35 ]  Exposure to the spermicide  nonoxynol-9  does not affect the risk of developing bacterial vaginosis. [ 36 ]


The cause of the fishy smell of BV is mainly due to reduction of  trimethylamine oxide  (TMAO) to  trimethylamine  (TMA) by bacteria in vaginal secretion. [ 37 ] [ 38 ] [ 39 ]  TMA is the same compound that is predominantly responsible for the smell of decomposing fish. [ 37 ] [ 38 ]  The  diamines   putrescine  and  cadaverine , which are the  decarboxylation  products of  arginine  and  lysine   amino acid   metabolism , respectively, are also present in BV and may contribute to the fishy smell of the condition as well. [ 37 ]


To make a diagnosis of bacterial vaginosis, a swab from inside the vagina should be obtained. These swabs can be tested for:


Differential diagnosis for bacterial vaginosis includes the following: [ 42 ]


The Center for Disease Control (CDC) defines STIs as "a variety of clinical syndromes and infections caused by pathogens that can be acquired and transmitted through sexual activity." [ 44 ]  But the CDC does not specifically identify BV as sexually transmitted infection. [ 16 ]


In clinical practice BV can be diagnosed using the Amsel criteria: [ 45 ]


At least three of the four criteria should be present for a confirmed diagnosis. [ 46 ]
A modification of the Amsel criteria accepts the presence of two instead of three factors and is considered equally diagnostic. [ 47 ]


An alternative is to use a Gram-stained vaginal smear, with the Hay/Ison [ 48 ]  criteria or the Nugent [ 27 ]  criteria. The Hay/Ison criteria are defined as follows: [ 46 ]


Gardnerella vaginalis  is the main culprit in BV.  Gardnerella vaginalis  is a short, Gram-variable rod (coccobacillus). Hence, the presence of clue cells and gram variable coccobacilli are indicative or diagnostic of bacterial vaginosis. [ 49 ]


The  Nugent score  is now rarely used by physicians due to the time it takes to read the slides and requires the use of a trained microscopist. [ 4 ]  A score of 0–10 is generated from combining three other scores.  The scores are as follows: [ 27 ]


At least 10–20 high power (1000× oil immersion) fields are counted and an average determined. [ 50 ]


Lactobacillus morphotypes – average per high powered (1000× oil immersion) field. View multiple fields.


Gardnerella  /  Bacteroides  morphotypes – average per high powered (1000× oil immersion) field. View multiple fields.


Curved Gram variable rods – average per high powered (1000× oil immersion) field. View multiple fields (note that this factor is less important – scores of only 0–2 are possible)


DNA hybridization  testing with Affirm VPIII was compared to the Gram stain using the Nugent criteria. [ 51 ]  The Affirm VPIII test may be used for the rapid diagnosis of BV in symptomatic women but uses expensive proprietary equipment to read results, and does not detect other pathogens that cause BV, including  Prevotella  spp,  Bacteroides  spp, and  Mobiluncus  spp. [ 52 ]  The cervicovaginal microbiome measured using 16S rRNA sequencing has the capacity to increase throughput of the Nugent Score and has demonstrate to be directly comparable to clinical Nugent Score measurement. [ 53 ]


Screening during pregnancy is not recommended in the United States as of 2020 because " the US Preventive Services Task Force concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for bacterial vaginosis in pregnant persons at increased risk for preterm delivery". [ 54 ]


Some steps suggested to lower the risk include: not  douching , avoiding sex, or limiting the number of sex partners. [ 55 ]


Systematic reviews  and  meta-analyses  from 2022 to 2023 have concluded that  probiotics  may help prevent re-occurrence. [ 8 ] [ 56 ] [ 57 ]


Early evidence suggested that antibiotic treatment of male partners could re-establish the normal microbiota of the male urogenital tract and prevent the recurrence of infection. [ 22 ]  However, a 2016 Cochrane review found high-quality evidence that treating the sexual partners of women with bacterial vaginosis had no effect on symptoms, clinical outcomes, or recurrence in the affected women. It also found that such treatment may lead treated sexual partners to report increased adverse events. [ 22 ]


Treatment is typically with the  antibiotics   metronidazole  or  clindamycin . [ 58 ]  They can be either given  by mouth  or  applied inside the vagina  with similar efficacy. [ 19 ] [ 58 ]  Other antibiotics related to metronidazole, including  tinidazole  and the newer  secnidazole , are also approved and used to treat BV. [ 9 ] [ 59 ] [ 60 ]  When clindamycin is given to pregnant women symptomatic with BV before 22 weeks of gestation the risk of pre-term birth before 37 weeks of gestation is lower. [ 61 ]  Additional antibiotics that are not approved for treatment of BV but might work include  macrolides ,  lincosamides , and  penicillins . [ 22 ]


Although antibiotics are effective, about 10% to 15% of people do not improve with the first course of antibiotics and recurrence rates of up to 80% have been documented. [ 24 ]  Recurrence rates are increased with sexual activity with the same pre-/post-treatment partner and inconsistent condom use. [ 62 ]   Estrogen-containing contraceptives  have been found to decrease recurrence. [ 62 ]


BV is not considered a  sexually transmitted infection , and treatment of a male sexual partner of a woman with BV is not recommended. [ 63 ] [ 64 ]


A 2009 Cochrane review found tentative but insufficient evidence for probiotics as a treatment for BV. [ 24 ]  A 2014 review reached the same conclusion. [ 65 ]  A 2013 review found some evidence supporting the use of probiotics during pregnancy. [ 66 ]  The preferred probiotics for BV are those containing high doses of lactobacilli (around 10 9   CFUs Tooltip Colony-forming units ) given  in the vagina . [ 67 ]  Intravaginal administration is preferred to  taking them by mouth . [ 67 ]  Prolonged repetitive courses of treatment appear to be more promising than short courses. [ 67 ]


The lack of effectiveness of commercially available  Lactobacillus  probiotics may be because most do not actually contain vaginal lactobacilli strains. [ 68 ]   LACTIN-V  is a  live biopharmaceutical  medication containing the vaginally important  Lactobacillus crispatus  which is under development for the treatment of bacterial vaginosis and recurrent  urinary tract infections . [ 68 ] [ 69 ] [ 70 ]  It has shown initial effectiveness in considerably reducing recurrence of bacterial vaginosis following antibiotic treatment. [ 68 ] [ 70 ]  LACTIN-V is not yet  Food and Drug Administration  (FDA)-approved or commercially available. [ 70 ] [ 69 ]