The  genome  of HBV is made of circular  DNA , but it is unusual because the DNA is not fully  double-stranded . One end of the full length strand is linked to the  HBV DNA polymerase . The genome is 3020–3320  nucleotides  long (for the full-length strand) and 1700–2800 nucleotides long (for the short length-strand). [ 44 ]  The negative-sense (non-coding) is complementary to the viral  mRNA . The viral DNA is found in the  nucleus  soon after infection of the  cell . The partially double-stranded DNA is rendered fully double-stranded by completion of the (+) sense strand and removal of a  protein   molecule  from the (−) sense strand and a short sequence of  RNA  from the (+) sense strand. Non-coding bases are removed from the ends of the (−) sense strand and the ends are rejoined. There are four known genes encoded by the genome, called C, X, P, and S. The core protein is coded for by gene C (HBcAg), and its start  codon  is preceded by an upstream in-frame AUG start codon from which the pre-core protein is produced. HBeAg is produced by  proteolytic  processing of the pre-core protein. In some rare strains of the virus known as  hepatitis B virus precore mutants , no HBeAg is present. [ 45 ]
The DNA  polymerase  is encoded by gene P. Gene S is the gene that codes for the surface  antigen  (HBsAg). The HBsAg gene is one long  open reading frame  but contains three in frame "start" (ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S. Because of the multiple start codons,  polypeptides  of three different sizes called large (the order from surface to the inside: pre-S1, pre-S2, and S ), middle (pre-S2, S), and small (S) [ 46 ]  are produced. [ 47 ]  There is a myristyl group, which plays an important role in infection, on the amino-terminal end of the preS1 part of the large (L) protein. [ 48 ]  In addition to that, N terminus of the L protein have virus attachment and capsid binding sites. Because of that, the N termini of half of the L protein molecules are positioned outside the membrane and the other half positioned inside the membrane. [ 49 ]


The function of the protein coded for by gene X is not fully understood but it is associated with the development of liver cancer. It stimulates genes that promote cell growth and inactivates growth regulating molecules. [ 50 ]


The life cycle of  hepatitis B  virus is complex.  Hepatitis B  is one of a few known  pararetroviruses : non- retroviruses  that still use  reverse transcription  in their replication process. The virus gains entry into the cell by binding to  NTCP [ 51 ]  on the surface and being  endocytosed . Because the virus multiplies via RNA made by a host enzyme, the viral genomic DNA has to be transferred to the cell nucleus by host proteins called chaperones. The partially double-stranded, circular viral DNA is then made fully double stranded by HBV DNA polymerase, transforming the genome into  covalently closed circular DNA  (cccDNA). This cccDNA serves as a template for transcription of four viral  mRNAs  by host RNA polymerase. The largest mRNA, (which is longer than the viral genome), is used to make the new copies of the genome and to make the  capsid  core protein and the viral  DNA polymerase . These four viral transcripts undergo additional processing and go on to form progeny virions that are released from the cell or returned to the nucleus and re-cycled to produce even more copies. [ 47 ] [ 52 ]  The long mRNA is then transported back to the cytoplasm where the virion P protein (the DNA polymerase) synthesizes DNA via its reverse transcriptase activity.


The virus is divided into four major  serotypes  (adr, adw, ayr, ayw) based on antigenic  epitopes  presented on its envelope proteins, and into eight major genotypes (A–H). The genotypes have a distinct geographical distribution and are used in tracing the evolution and transmission of the virus. Differences between genotypes affect the disease severity, course and likelihood of complications, and response to treatment and possibly vaccination. [ 53 ] [ 54 ]  There are two other genotypes I and J but they are not universally accepted as of 2015. [ 55 ]  The diversity of genotypes is not shown equally in the world. For example, A, D, and E genotypes have been seen in Africa prevalently while B and C genotypes are observed in Asia as widespread. [ 56 ]


Genotypes differ by at least 8% of their sequence and were first reported in 1988 when six were initially described (A–F). [ 57 ]  Two further types have since been described (G and H). [ 58 ]  Most genotypes are now divided into subgenotypes with distinct properties. [ 59 ]


Hepatitis B  virus primarily interferes with the functions of the liver by replicating in  hepatocytes . A functional  receptor  is  NTCP . [ 51 ]  There is evidence that the receptor in the closely related  duck hepatitis B virus  is  carboxypeptidase D . [ 60 ] [ 61 ]  The virions bind to the host cell via the preS domain of the viral surface antigen and are subsequently internalized by endocytosis. HBV-preS-specific receptors are expressed primarily on hepatocytes; however, viral DNA and proteins have also been detected in extrahepatic sites, suggesting that cellular receptors for HBV may also exist on extrahepatic cells. [ 62 ]


During HBV infection, the host  immune response  causes both hepatocellular damage and viral clearance. Although the innate immune response does not play a significant role in these processes, the adaptive immune response, in particular virus-specific  cytotoxic T lymphocytes (CTLs), contributes to most of the liver injury associated with HBV infection. CTLs eliminate HBV infection by killing infected cells and producing antiviral  cytokines , which are then used to purge HBV from viable hepatocytes. [ 63 ]  Although liver damage is initiated and mediated by the CTLs,  antigen -nonspecific  inflammatory cells  can worsen CTL-induced immunopathology, and  platelets  activated at the site of infection may facilitate the accumulation of CTLs in the liver. [ 64 ]


The tests, called  assays , for detection of  hepatitis B  virus infection involve  serum  or  blood tests  that detect either viral antigens (proteins produced by the virus) or  antibodies  produced by the host. Interpretation of these assays is complex. [ 65 ]


The  hepatitis B  surface antigen ( HBsAg ) is most frequently used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host. The infectious virion contains an inner "core particle" enclosing viral genome. The icosahedral core particle is made of 180 or 240 copies of the core protein, alternatively known as  hepatitis B  core antigen, or  HBcAg . During this 'window' in which the host remains infected but is successfully clearing the virus,  IgM  antibodies specific to the  hepatitis B  core antigen ( anti-HBc IgM ) may be the only serological evidence of disease.  Therefore, most  hepatitis B  diagnostic panels contain HBsAg and total anti-HBc (both IgM and IgG). [ 66 ]


Shortly after the appearance of the HBsAg, another antigen called  hepatitis B  e antigen ( HBeAg ) will appear. Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication and enhanced infectivity; however, variants of the  hepatitis B  virus do not produce the 'e' antigen, so this rule does not always hold true. [ 67 ]  During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen ( anti-HBe ) will arise immediately afterwards. This conversion is usually associated with a dramatic decline in viral replication.


If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by  IgG  antibodies to the  hepatitis B  surface antigen and core antigen ( anti-HBs  and  anti HBc IgG ). [ 39 ]  The time between the removal of the HBsAg and the appearance of anti-HBs is called the  window period . A person negative for HBsAg but positive for anti-HBs either has cleared an infection or has been vaccinated previously.


Individuals who remain HBsAg positive for at least six months are considered to be  hepatitis B  carriers. [ 68 ]  Carriers of the virus may have chronic hepatitis B, which would be reflected by elevated serum  alanine aminotransferase  (ALT) levels and inflammation of the liver, if they are in the immune clearance phase of chronic infection. Carriers who have seroconverted to HBeAg negative status, in particular those who acquired the infection as adults, have very little viral multiplication and hence may be at little risk of long-term complications or of transmitting infection to others. [ 69 ]  However, it is possible for individuals to enter an "immune escape" with HBeAg-negative hepatitis.


PCR  tests have been developed to detect and measure the amount of HBV DNA, called the  viral load , in clinical specimens. These tests are used to assess a person's infection status and to monitor treatment. [ 70 ]  Individuals with high  viral loads , characteristically have  ground glass hepatocytes  on biopsy.


Vaccines for the prevention of hepatitis B have been routinely recommended for babies since 1991 in the United States. [ 71 ]  The first dose is generally recommended within a day of birth. [ 72 ]  The hepatitis B vaccine was the first vaccine capable of preventing cancer, specifically liver cancer. [ 73 ]


Most vaccines are given in three doses over a course of days. A protective response to the vaccine is defined as an anti-HBs antibody concentration of at least 10 mIU/ml in the recipient's serum. The vaccine is more effective in children and 95 percent of those vaccinated have protective levels of antibody. This drops to around 90% at 40 years of age and to around 75 percent in those over 60 years. The protection afforded by vaccination is long lasting even after antibody levels fall below 10 mIU/ml. For newborns of HBsAg-positive mothers: hepatitis B vaccine alone, hepatitis B immunoglobulin alone, or the combination of vaccine plus hepatitis B immunoglobulin, all prevent hepatitis B occurrence. [ 74 ]  Furthermore, the combination of vaccine plus hepatitis B immunoglobulin is superior to vaccine alone. [ 74 ]  This combination prevents HBV transmission around the time of birth in 86% to 99% of cases. [ 75 ]


Tenofovir  given in the second or third trimester can reduce the risk of mother to child transmission by 77% when combined with hepatitis B immunoglobulin and the hepatitis B vaccine, especially for pregnant women with high hepatitis B virus DNA levels. [ 76 ]  However, there is not sufficient evidence that the administration of hepatitis B immunoglobulin alone during pregnancy, might reduce transmission rates to the newborn infant. [ 77 ]  No randomized control trial has been conducted to assess the effects of hepatitis B vaccine during pregnancy for preventing infant infection. [ 78 ]


All those with a risk of exposure to body fluids such as blood should be vaccinated, if not already. [ 71 ]  Testing to verify effective immunization is recommended and further doses of vaccine are given to those who are not sufficiently immunized. [ 71 ]


In 10- to 22-year follow-up studies there were no cases of hepatitis B among those with a normal immune system who were vaccinated. Only rare chronic infections have been documented. [ 79 ]  Vaccination is particularly recommended for high risk groups including: health workers, people with chronic  kidney failure , and men who have sex with men. [ 80 ] [ 81 ] [ 82 ]


Both types of the hepatitis B vaccine, the plasma-derived vaccine (PDV) and the recombinant vaccine (RV) are of similar effectiveness in preventing infection in both healthcare workers and chronic kidney failure groups. [ 80 ] [ 81 ]  One difference was noticed among the health worker group: the RV intramuscular route was significantly more effective compared with the RV intradermal route of administration. [ 80 ]


In  assisted reproductive technology ,  sperm washing  is not necessary for males with hepatitis B to prevent transmission, unless the female partner has not been effectively vaccinated. [ 83 ]  In females with hepatitis B, the risk of transmission from mother to child with IVF is no different from the risk in spontaneous conception. [ 83 ]


Those at high risk of infection should be tested as there is effective treatment for those who have the disease. [ 84 ]  Groups that screening is recommended for include those who have not been vaccinated and one of the following: people from areas of the world where hepatitis B occurs in more than 2%, those with HIV, intravenous drug users, men who have sex with men, and those who live with someone with hepatitis B. [ 84 ]  Screening during  pregnancy  is recommended in the United States. [ 85 ]


Acute  hepatitis B  infection does not usually require treatment and most adults clear the infection spontaneously. [ 86 ] [ 87 ]  Early antiviral treatment may be required in fewer than 1% of people, whose infection takes a very aggressive course (fulminant hepatitis) or who are  immunocompromised . On the other hand, treatment of chronic infection may be necessary to reduce the risk of  cirrhosis  and liver cancer. Chronically infected individuals with persistently elevated serum  alanine aminotransferase , a marker of liver damage, and HBV DNA levels are candidates for therapy. [ 88 ]  Treatment lasts from six months to a year, depending on medication and genotype. [ 89 ]  Treatment duration when medication is taken by mouth, however, is more variable and usually longer than one year. [ 90 ]


Although none of the available medications can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. As of 2024, there are seven medications licensed for the treatment of  hepatitis B  infection in the United States. [ 91 ]  These include  antiviral  medications  lamivudine ,  adefovir ,  tenofovir disoproxil ,  tenofovir alafenamide ,  telbivudine , and  entecavir , and the two  immune system  modulators  interferon alpha-2a  and  PEGylated interferon alpha-2a . In 2015, the World Health Organization recommended tenofovir or entecavir as first-line agents. [ 92 ]  Those with current cirrhosis are in most need of treatment. [ 92 ]


The use of interferon, which requires injections daily or thrice weekly, has been supplanted by long-acting  PEGylated   interferon , which is injected only once weekly. [ 93 ]  However, some individuals are much more likely to respond than others, and this might be because of the  genotype  of the infecting virus or the person's heredity. The treatment reduces viral replication in the liver, thereby reducing the  viral load  (the amount of virus particles as measured in the blood). [ 94 ]  Response to treatment differs between the genotypes.  Interferon  treatment may produce an e antigen seroconversion rate of 37% in genotype A but only a 6% seroconversion in type D. Genotype B has similar seroconversion rates to type A while type C seroconverts only in 15% of cases. Sustained e antigen loss after treatment is ~45% in types A and B but only 25–30% in types C and D. [ 95 ]


It seems unlikely that the disease will be eliminated by 2030, the goal set in 2016 by WHO. However, progress is being made in developing therapeutic treatments. In 2010, the Hepatitis B Foundation reported that 3 preclinical and 11 clinical-stage drugs were under development, based on largely similar mechanisms. In 2020, they reported that there were 17 preclinical- and 32 clinical-stage drugs under development, using diverse mechanisms. [ 15 ]


Hepatitis B  virus infection may be either acute (self-limiting) or chronic (long-standing). Persons with self-limiting infection clear the infection spontaneously within weeks to months.


Children are less likely than adults to clear the infection. More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus. However, this drops to 30% for younger children, and only 5% of newborns that acquire the infection from their mother at birth will clear the infection. [ 96 ]  This population has a 40% lifetime risk of death from  cirrhosis  or  hepatocellular carcinoma . [ 93 ]  Of those infected between the age of one to six, 70% will clear the infection. [ 97 ]


Hepatitis D  (HDV) can occur only with a concomitant  hepatitis B  infection, because HDV uses the HBV surface antigen to form a  capsid . [ 98 ]  Co-infection with hepatitis D increases the risk of liver cirrhosis and liver cancer. [ 99 ]   Polyarteritis nodosa  is more common in people with  hepatitis B  infection.


A number of different tests are available to determine the degree of cirrhosis present.  Transient elastography  (FibroScan) is the test of choice, but it is expensive. [ 92 ]   Aspartate aminotransferase to platelet ratio index  may be used when cost is an issue. [ 92 ]


Hepatitis B  virus DNA remains in the body after infection, and in some people, including those that do not have detectable HBsAg, the disease recurs. [ 100 ] [ 101 ]  Although rare, reactivation is seen most often following alcohol or drug use, [ 102 ]  or in people with impaired immunity. [ 103 ]  HBV goes through cycles of replication and non-replication. Approximately 50% of overt carriers experience acute reactivation. Males with baseline ALT of 200 UL/L are three times more likely to develop a reactivation than people with lower levels. Although reactivation can occur spontaneously, [ 104 ]  people who undergo  chemotherapy  have a higher risk. [ 105 ]   Immunosuppressive drugs  favor increased HBV replication while inhibiting  cytotoxic T cell  function in the liver. [ 106 ]  The risk of reactivation varies depending on the serological profile; those with detectable HBsAg in their blood are at the greatest risk, but those with only antibodies to the core antigen are also at risk. The presence of antibodies to the surface antigen, which are considered to be a marker of immunity, does not preclude reactivation. [ 105 ]  Treatment with prophylactic antiviral drugs can prevent the serious morbidity associated with HBV disease reactivation. [ 105 ]


Approximately 254 million people had chronic HBV infection as of 2022. Another 1.2 million cases of acute HBV infection also occurred that year. [ 108 ]  Regional prevalences across the globe range from around 7.5% in Africa to 0.5% in the Americas. [ 19 ]


The primary method of HBV transmission and the prevalence of chronic HBV infection in specific regions often correspond with one another. In populations where HBV infection rates are 8% or higher, which are classified as high prevalence, vertical transmission (usually occurring during birth) is most common, though rates of early childhood transmission can also be significant among these populations. [ 109 ]  In 2021, 19 African countries had infection rates ranging between 8-19%, placing them in the high prevalence category. [ 110 ]  High prevalence of HBV also exists in  Mongolia . [ 111 ] [ 112 ]


In moderate prevalence areas where 2–7% of the population is chronically infected, the disease is predominantly spread horizontally, often among children, but also vertically. [ 113 ]  China's HBV infection rate is at the higher end of the moderate prevalence classification with an infection rate of 6.89% as of 2019. [ 114 ]  HBV prevalence in India is also moderate, with studies placing India's infection rate between 2-4%. [ 115 ]


Countries with low HBV prevalence include Australia (0.9%), [ 116 ]  those in the WHO European Region (which average 1.5%), [ 19 ]  and most countries in North and South America (which average 0.28%). [ 117 ] [ 118 ]
In the United States, an estimated 0.26% of the population was living with HBV infection as of 2018. [ 119 ]


Findings of HBV DNA in ancient human remains have shown that HBV has infected humans for at least ten millennia, both in Eurasia and in the Americas. [ 120 ] [ 121 ] [ 122 ]  This disproved the belief that hepatitis B originated in the New World and spread to Europe around 16th century. [ 122 ]  Hepatitis B virus subgenotype C4 is exclusively present in Australian aborigines, suggesting an ancient origin as much as 50,000 years old. [ 123 ] [ 124 ] [ 125 ]  However, analyses of ancient HBV genomes suggested that the most recent common ancestor of all known human HBV strains was dated to between 20,000 and 12,000 years ago, [ 120 ]  pointing to a more recent origin for all HBV genotypes. The evolution of HBV in humans was shown to reflect known events of human history such as the first peopling of the Americas during the late Pleistocene and the Neolithic transition in Europe. [ 120 ]  Ancient DNA studies have also showed that some ancient hepatitis viral  strains  still infect humans, while other strains became extinct. [ 120 ] [ 121 ]


The earliest record of an epidemic caused by  hepatitis B  virus was made by Lurman in 1885. [ 126 ]  An outbreak of  smallpox  occurred in  Bremen  in 1883 and 1,289 shipyard employees were  vaccinated  with  lymph  from other people. After several weeks, and up to eight months later, 191 of the vaccinated workers became ill with  jaundice  and were diagnosed with serum hepatitis. Other employees who had been inoculated with different batches of lymph remained healthy. Lurman's paper, now regarded as a classical example of an  epidemiological  study, proved that contaminated lymph was the source of the outbreak. Later, numerous similar outbreaks were reported following the introduction, in 1909, of  hypodermic needles  that were used, and, more importantly, reused, for administering  Salvarsan  for the treatment of  syphilis .


The largest recorded outbreak of hepatitis B was the infection of up to 330,000 American soldiers during World War II. The outbreak has been blamed on a yellow fever vaccine made with contaminated human blood serum, and after receiving the vaccinations about 50,000 soldiers developed jaundice. [ 127 ]


The virus was not discovered until 1966 when  Baruch Blumberg , then working at the  National Institutes of Health  (NIH), discovered the  Australia antigen  (later known to be  hepatitis B  surface antigen, or HBsAg) in the blood of Aboriginal Australian people. [ 128 ]  Although a virus had been suspected since the research published by Frederick MacCallum in 1947, [ 129 ]   David Dane  and others discovered the virus particle in 1970 by  electron microscopy . [ 130 ]  In 1971, the FDA issued its first-ever blood supply screening order to blood banks. [ 131 ]  By the early 1980s the  genome  of the virus had been sequenced, [ 132 ]  and the first vaccines were being tested. [ 133 ]


World Hepatitis Day , observed 28 July, aims to raise global awareness of  hepatitis B  and  hepatitis C  and encourage prevention, diagnosis, and treatment. It has been led by the World Hepatitis Alliance since 2007 and in May 2010, it received global endorsement from the  World Health Organization . [ 134 ]


Genital herpes  is a  herpes  infection of the  genitals  caused by the  herpes simplex virus  (HSV). [ 1 ]  Most people either have no or mild symptoms and thus do not know they are infected. [ 1 ]  When symptoms do occur, they typically include small  blisters  that break open to form painful  ulcers . [ 1 ]   Flu-like symptoms , such as fever, aching, or swollen  lymph nodes , may also occur. [ 2 ]  Onset is typically around 4 days after exposure with symptoms lasting up to 4 weeks. [ 1 ]  Once infected further outbreaks may occur but are generally milder. [ 1 ]


The disease is typically spread by direct genital contact with the skin surface or secretions of someone who is infected. [ 1 ]  This may occur during  sex , including  anal ,  oral , and  manual sex . [ 1 ] [ 5 ]  Sores are not required for transmission to occur. [ 1 ]  The risk of spread between a couple is about 7.5% over a year. [ 6 ]  HSV is classified into two types, HSV-1 and HSV-2. [ 1 ]  While historically HSV-2 was more common, genital HSV-1 has become more common in the  developed world . [ 1 ] [ 7 ]  Diagnosis may occur by testing lesions using either  PCR  or  viral culture  or  blood tests  for specific  antibodies . [ 1 ]


Efforts to prevent infection include  not having sex , using  condoms , and only having sex with someone who is not infected. [ 2 ]  Once infected, there is no cure. [ 2 ]   Antiviral medications  may, however, prevent outbreaks or shorten outbreaks if they occur. [ 1 ]  The long-term use of antivirals may also decrease the risk of further spread. [ 1 ]


In 2015, about 846 million people (12% of the world population) had genital herpes. [ 4 ]  In the United States, more than one in six people between the ages of 14 and 49 have the disease. [ 8 ]  Women are more commonly infected than men. [ 1 ]  Rates of disease caused by HSV-2 have decreased in the United States between 1990 and 2010. [ 1 ]  Complications may rarely include  aseptic meningitis , an increased risk of  HIV/AIDS  if exposed to  HIV-positive  individuals, and spread to the baby during  childbirth  resulting in  neonatal herpes . [ 1 ]


In males, the lesions occur on the  glans penis , shaft of the penis or other parts of the genital region, on the inner thigh, buttocks, or  anus . In females, lesions appear on or near the  pubis ,  clitoris  or other parts of the  vulva , buttocks or anus. [ 2 ]


Other common symptoms include pain, itching, and burning. Less frequent, yet still common, symptoms include discharge from the penis or  vagina ,  fever ,  headache , muscle pain ( myalgia ), swollen and enlarged lymph nodes and  malaise . [ 9 ]  Women often experience additional symptoms that include painful urination ( dysuria ) and  cervicitis . Herpetic  proctitis  (inflammation of the anus and rectum) is common for individuals participating in  anal intercourse . [ 9 ]


After 2–3 weeks, existing lesions progress into ulcers and then crust and heal, although lesions on mucosal surfaces may never form crusts. [ 9 ]  In rare cases, involvement of the  sacral  region of the  spinal cord  can cause acute  urinary retention  and one-sided symptoms and signs of  myeloradiculitis (a combination of  myelitis  and  radiculitis ): pain, sensory loss, abnormal sensations ( paresthesia ) and rash. [ 10 ] [ 11 ]  Historically, this has been termed Elsberg syndrome, although this entity is not clearly defined. [ 10 ]


After a first episode of herpes genitalis caused by  HSV-2 , there will be at least one recurrence in approximately 80% of people, while the recurrence rate for herpes genitalis caused by  HSV-1  is approximately 50%. [ 12 ]  Herpes genitalis caused by HSV-2 recurs on average four to six times per year, while that of HSV-1 infection occurs only about once per year. [ 12 ]


People with recurrent genital herpes may be treated with  suppressive therapy , which consists of daily antiviral treatment using acyclovir, valacyclovir or famciclovir. [ 13 ]  Suppressive therapy may be useful in those who have at least four recurrences per year but the quality of the evidence is poor. [ 13 ]  People with lower rates of recurrence will probably also have fewer recurrences with suppressive therapy. [ 14 ]  Suppressive therapy should be discontinued after a maximum of one year to reassess recurrence frequency. [ 14 ]


Genital herpes can be spread by  viral shedding  prior to and following the formation of ulcers. The risk of spread between a couple is about 7.5% over a year (for unprotected sex). [ 6 ]  The likelihood of transferring genital herpes from one person to another is decreased by external  condom  use by 50%, by  internal condom  by 50%, and refraining from sex during an active outbreak. [ 6 ]  The longer a partner has had the infection, the lower the transmission rate. [ 6 ]  An infected person may further decrease transmission risks by maintaining a daily dose of antiviral medications. [ 6 ]  Infection by genital herpes occurs in about 1 in every 1,000 sexual acts. [ 6 ]


Because herpes simplex virus (HSV) infection is common and not routinely screened for in the general population, complete prevention of the transmission of genital herpes is difficult. To reduce the chance of contracting herpes simplex virus, external  condoms  for the penis may be used during  oral sex ,  vaginal sex , and  anal sex . [ 15 ]  Internal condoms for the vagina may be used during oral sex or vaginal sex. [ 15 ]  Internal condoms and external condoms should not be used simultaneously. [ 15 ]   Dental dams  may be used during oral sex involving the vagina or anus. [ 15 ]  Decreasing the number of sexual partners a person has may also decrease the chance of contracting HSV. [ 16 ]  People who have sexual relations with others may get tested for HSV. In people who have been diagnosed with genital herpes, transmission to others may be prevented through suppressive  antiviral  drugs. [ 17 ]  This option is 90% effective in preventing the transmission of HSV and is a commonly used option for sexual and/or romantic partners or those who plan on becoming pregnant. [ 17 ]  Those who are aware that they have genital herpes should notify their partner(s). [ 17 ]


Genital herpes may be diagnosed through a  physical examination  by a doctor or through a herpes simplex virus (HSV) test by sampling fluid within a genital  blister  or blood for HSV  antibodies . [ 17 ]  Herpes simplex virus testing is recommended for those who have symptoms of herpes or who have a sexual partner who has a herpes infection. [ 8 ]  There is currently no recommendation for  asymptomatic  screening for genital herpes. [ 8 ]


False negative  test results may occur if the test is performed late in the course of the illness or if the test sample is not appropriately acquired. [ 17 ]  Testing people for HSV when they are asymptomatic is not recommended due to the high  false-positivity  rate. [ 18 ]  A false positive test may cause relationship difficulties. [ 18 ]


Women who have genital herpes before pregnancy have a very low risk of transmitting herpes simplex virus to the baby during  delivery . In the United States, 20-25% of pregnant women have genital herpes; however, fewer than 0.1% of babies born get  neonatal herpes  during delivery. [ 19 ]


Per the U.S. Preventive Services Task Force, routine screening for pregnant women without a history of genital herpes is not recommended. Serologic (blood) antibody testing in asymptomatic patients without history has been shown to frequently have false positive and false negative test results which may lead to anxiety, labeling, or false reassurance with minimal improvements in health outcomes of reducing neonatal herpes transmission. [ citation needed ]


Pregnant women should notify their doctor if they show symptoms of genital herpes. At the time of delivery, women should be physically examined for signs of genital herpes. [ 19 ]  If a pregnant woman is symptomatic during delivery, a  Cesarean section  is the safest method of preventing contact and transmission of herpes simplex virus between the mother and the baby. [ 19 ]  Alternatively, some physicians use the drug  acyclovir  to treat pregnant women with genital herpes at 36 weeks until delivery to prevent the recurrence of symptoms and reduce the risk of transmission during delivery. [ 19 ]  Acyclovir is not approved for this purpose by the FDA; however, acyclovir's manufacturer has tracked pregnant women who have taken the drug during pregnancy, and there is no evidence that shows any risks for the infant. [ 19 ]


Acyclovir may help reduce the frequency of symptomatic recurrence near term but may not definitively protect against transmission in all cases. This may be favorable particularly for women who prefer to have a vaginal delivery instead of cesarean section. [ citation needed ]


There is no cure for the disease. Skin lesions disappear without treatment within a few weeks, but treatment accelerates the healing of lesions, reduces symptoms, and helps prevent or reduce recurrent outbreaks of the disease.
 Antiviral medications  provide clinical benefits to those who are symptomatic and is the primary means of management once infected. The main goal for the use of antiviral medications is to treat the first outbreak or to prevent genital herpes recurrences, improve quality of life, and help suppress the virus to sexual transmission to partners.  Three FDA-approved antiviral medications have clinical benefits in controlling the signs and symptoms of genital herpes when used for first clinical symptoms and recurrent episodes or when used as daily suppressive therapy. [ 20 ]  These medications are acyclovir, valacyclovir, and famciclovir and have been shown to be safe with long-term use.


Acyclovir is an  antiviral medication  and reduces the pain and the number of lesions in the initial case of genital herpes. Furthermore, it decreases the frequency and severity of recurrent infections. It comes in  capsules ,  tablets , and  ointment . However, topical ointment with acyclovir is discouraged since it offers minimal clinical benefits.


Valacyclovir is a prodrug that is converted to acyclovir once in the body. It helps relieve the pain and discomfort and speeds healing of sores. It only comes in caplets and its advantage is that it has a longer duration of action than acyclovir. [ 21 ]


Famciclovir is another antiviral drug that belongs to the same class. Famciclovir is a  prodrug  that is converted to penciclovir in the  body . The latter is the one active against the viruses. It has a longer duration of action than acyclovir and it only comes in tablets. [ 22 ]


The first time an individual experiences genital herpes, they may have prolonged clinical illness with severe genital ulceration. [ 20 ]  Furthermore, for those who have mild clinical symptoms initially may experience severe recurrent infections later. Typical recommended regimens for first clinical episodes of genital herpes may be something like: [ 20 ]


A treatment longer than 10 days may be recommended if the genital ulcers have not fully healed.


Most individuals who experience a symptomatic first episode of genital herpes will experience recurrence of genital lesions at some point in the future.  Asymptomatic shedding can also occur where an individual may not have genital ulcerations present but still possibly transmit the virus to other partners. It is important for patients to have a discussion with their primary care doctor for options of receiving either episodic treatment or long-term suppressive therapies. [ 20 ]


Suppressive therapy has been shown effective in reducing recurrent genital herpes in as high as 80% which can tremendously help in improving quality of life since patients claim having minimal symptomatic episodes. [ 23 ] [ 24 ]  Long-term use of anti-virals like acyclovir, valacyclovir, and famciclovir have been shown to be safe and effective. Furthermore, long-term treatment of genital herpes with valacyclovir daily has shown to decrease the rates of transmission. [ 25 ]  It is important for patients to continue suppressive therapy in conjunction to consistent condom use and sexual abstinence during recurrent episodes to decrease transmission as well. [ 20 ]


To decrease symptoms during an outbreak of genital herpes, people can use an ice pack on the affected areas, take a warm bath, keep the genitals dry when not bathing, and take  over-the-counter  pain relief medication such as  ibuprofen  or  acetaminophen . [ 17 ]


About 16 percent of Americans between the ages of 14 and 49 are infected with genital herpes, making it one of the most common sexually transmitted infections. [ 26 ]   More than 85% of those with HSV-2 are unaware of their infection. [ 27 ]  Approximately 776,000 people in the United States get new herpes infections every year. [ 27 ]


Tests for herpes are not routinely included among STI screenings. Performers in the  pornography industry  are screened for HIV,  chlamydia , and gonorrhea with an optional panel of tests for hepatitis B, hepatitis C and syphilis, but not herpes. Testing for herpes is controversial since the results are not always accurate or helpful. [ 28 ]  Most  sex workers  and performers will contract herpes at some point in their careers whether they use protection or not. [ 29 ]


Early 20th century public health legislation in the United Kingdom required compulsory treatment for sexually transmitted infections but did not include herpes because it was not serious enough. [ 30 ]  As late as 1975, nursing textbooks did not include herpes as it was considered no worse than a common cold. [ 30 ]  After the development of  acyclovir  in the 1970s, the drug company  Burroughs Wellcome  launched an extensive marketing campaign that publicized the illness, including creating victim's support groups. [ 30 ]


There are efforts to develop a  vaccine  for active outbreaks of the virus—despite most cases being asymptomatic—but the results thus far have not been able to do so or eliminate transmission. [ 31 ]


Herpes simplex , often known simply as  herpes , is a  viral infection  caused by the  herpes simplex virus . [ 5 ]  Herpes infections are categorized by the area of the body that is infected. The two major types of herpes are  oral herpes  and  genital herpes , though  other forms  also exist.


Oral herpes involves the face or mouth. It may result in small  blisters  in groups, often called cold sores or fever blisters, or may just cause a sore throat. [ 2 ] [ 6 ]  Genital herpes involves the  genitalia . It may have minimal symptoms or form blisters that break open and result in small  ulcers . [ 1 ]  These typically heal over two to four weeks. [ 1 ]  Tingling or shooting pains may occur before the blisters appear. [ 1 ]


Herpes cycles between periods of active disease followed by periods without symptoms. [ 1 ]  The first episode is often more severe and may be associated with fever, muscle pains, swollen  lymph nodes  and headaches. [ 1 ]  Over time, episodes of active disease decrease in frequency and severity. [ 1 ]


Herpetic whitlow  typically involves the fingers or thumb, [ 7 ]   herpes simplex keratitis  involves the eye, [ 8 ]   herpesviral encephalitis  involves the brain, [ 9 ]  and  neonatal herpes  involves any part of the body of a newborn, among others. [ 10 ]


There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2). [ 1 ]  HSV-1 more commonly causes infections around the mouth while HSV-2 more commonly causes genital infections. [ 2 ]  They are transmitted by direct contact with body fluids or lesions of an infected individual. [ 1 ]  Transmission may still occur when symptoms are not present. [ 1 ]  Genital herpes is classified as a  sexually transmitted infection . [ 1 ]  It may be spread to an infant during childbirth. [ 1 ]  After infection, the viruses are transported along  sensory nerves  to the nerve cell bodies, where they  reside lifelong . [ 2 ]  Causes of recurrence may include  decreased immune function , stress, and sunlight exposure. [ 2 ] [ 3 ]  Oral and genital herpes is usually diagnosed based on the presenting symptoms. [ 2 ]  The diagnosis may be confirmed by  viral culture  or detecting herpes DNA in fluid from blisters. [ 1 ]  Testing the blood for  antibodies  against the virus can confirm a previous infection but will be negative in new infections. [ 1 ]


The most effective method of avoiding genital infections is by avoiding vaginal, oral, manual, and anal sex. [ 1 ] [ 11 ]   Condom  use decreases the risk. [ 1 ]  Daily  antiviral medication  taken by someone who has the infection can also reduce spread. [ 1 ]  There is no available  vaccine [ 1 ]  and once infected, there is no cure. [ 1 ]   Paracetamol  (acetaminophen) and topical lidocaine may be used to help with the symptoms. [ 2 ]  Treatments with antiviral medication such as  aciclovir  or  valaciclovir  can lessen the severity of symptomatic episodes. [ 1 ] [ 2 ]


Worldwide rates of either HSV-1 or HSV-2 are between 60% and 95% in adults. [ 4 ]  HSV-1 is usually acquired during childhood. [ 1 ]  Since there is no cure for either HSV-1 or HSV-2, rates of both inherently increase as people age. [ 4 ]  Rates of HSV-1 are between 70% and 80% in populations of low socioeconomic status and 40% to 60% in populations of improved socioeconomic status. [ 4 ]  An estimated 536 million people worldwide (16% of the population) were infected with HSV-2 as of 2003 with greater rates among women and those in the developing world. [ 12 ]  Most people with HSV-2 do not realize that they are infected. [ 1 ]


The name is from  Ancient Greek :  ἕρπης   herpēs , which is related to the meaning 'to creep', referring to spreading blisters. [ 13 ]  The name does not refer to latency. [ 14 ]


HSV infection causes several distinct medical  disorders .  Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands ( herpetic whitlow ).  More serious disorders occur when the virus infects and damages the eye ( herpes keratitis ), or invades the central nervous system, damaging the brain (herpes encephalitis).  People with immature or suppressed immune systems, such as newborns, transplant recipients, or people with AIDS,  are prone to severe complications from HSV infections. HSV infection has also been associated with cognitive deficits of  bipolar disorder , [ 15 ]  and  Alzheimer's disease , although this is often dependent on the  genetics  of the infected person.


In all cases, HSV is never removed from the body by the  immune system .  Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the  cell body  of the neuron, and becomes latent in the  ganglion . [ 16 ]  As a result of primary infection, the body produces antibodies to the particular type of HSV involved, which can help reduce the odds of subsequent infection of that type at a different site. In HSV-1-infected individuals,  seroconversion  after an oral infection helps prevent additional HSV-1 infections such as whitlow, genital herpes, and herpes of the eye. Prior HSV-1 seroconversion seems to reduce the symptoms of a later HSV-2 infection, although HSV-2 can still be contracted.


Many people infected with HSV-2 display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having  subclinical  herpes. [ 17 ]  However, infection with herpes can be fatal. [ 18 ]


Neonatal herpes simplex  is an HSV infection in an infant. It is a rare but serious condition, usually caused by  vertical transmission  of HSV-1 or -2 from mother to newborn. During immunodeficiency, herpes simplex can cause unusual lesions in the skin.  One of the most striking is the appearance of clean linear erosions in skin creases, with the appearance of a knife cut. [ 23 ]   Herpetic sycosis  is a recurrent or initial herpes simplex infection affecting primarily the hair follicles. [ 24 ] : 369    Eczema herpeticum  is an infection with herpesvirus in patients with chronic  atopic dermatitis  may result in spread of herpes simplex throughout the eczematous areas. [ 24 ] : 373


Herpetic keratoconjunctivitis , a primary infection, typically presents as swelling of the  conjunctiva  and eyelids ( blepharoconjunctivitis ), accompanied by small white itchy lesions on the surface of the  cornea .


Herpetic sycosis is a recurrent or initial herpes simplex infection affecting primarily the  hair follicle . [ 24 ] : 369  [ 25 ]


Although the exact cause of  Bell's palsy —a type of facial  paralysis —is unknown, it may be related to the reactivation of HSV-1. [ 26 ]  This theory has been contested, however, since HSV is detected in large numbers of individuals having never experienced facial paralysis, and higher levels of antibodies for HSV are not found in HSV-infected individuals with Bell's palsy compared to those without. [ 27 ]  Antivirals may improve the condition slightly when used together with  corticosteroids  in those with severe disease. [ 28 ]


HSV-1 has been proposed as a possible cause of  Alzheimer's disease . [ 29 ] [ 30 ]  In the presence of a certain gene variation ( APOE -epsilon4 allele carriers), HSV-1 appears to be particularly damaging to the nervous system and increases one's risk of developing Alzheimer's disease.  The virus interacts with the components and receptors of  lipoproteins , which may lead to its development. [ 31 ] [ 32 ]


Herpes is contracted through direct contact with an active lesion or body fluid of an infected person. [ 34 ]  Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person. Herpes simplex virus 2 is  typically contracted through direct skin-to-skin contact with an infected individual, but can also be contracted by exposure to infected saliva, semen, vaginal fluid, or the fluid from herpetic blisters. [ 35 ]  To infect a new individual, HSV travels through tiny breaks in the skin or mucous membranes in the mouth or genital areas. Even microscopic abrasions on mucous membranes are sufficient to allow viral entry.


HSV asymptomatic  shedding  occurs at some time in most individuals infected with herpes.  It can occur more than a week before or after a symptomatic recurrence in 50% of cases. [ 36 ]   Virus enters into susceptible cells by entry receptors [ 37 ]
such as nectin-1, HVEM and 3-O sulfated heparan sulfate. [ 38 ]  Infected people who show no visible symptoms may still shed and transmit viruses through their skin; asymptomatic shedding may represent the most common form of HSV-2 transmission. [ 36 ]  Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV. Concurrent infection with HIV increases the frequency and duration of asymptomatic shedding. [ 39 ]   Some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified; no significant differences are seen in the frequency of asymptomatic shedding when comparing persons with one to 12 annual recurrences to those with no recurrences. [ 36 ]


Antibodies that develop following an initial infection with a type of HSV can reduce the odds of reinfection with the same virus type. [ 40 ]  In a  monogamous  couple, a seronegative female runs a greater than 30% per year risk of contracting an HSV infection from a seropositive male partner. [ 41 ]  If an oral HSV-1 infection is contracted first, seroconversion will have occurred after 6 weeks to provide protective antibodies against a future genital HSV-1 infection. [ 40 ]  Herpes simplex is a double-stranded  DNA virus . [ 42 ]


Herpes simplex virus is divided into two types. [ 4 ]  However, each may cause infections in all areas. [ 4 ]


Primary orofacial herpes is readily identified by examination of persons with no previous history of lesions and contact with an individual with known HSV infection. The appearance and distribution of sores is typically presents as multiple, round, superficial oral ulcers, accompanied by acute  gingivitis . [ 43 ]  Adults with atypical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as  allergic   stomatitis . When lesions do not appear inside the mouth, primary orofacial herpes is sometimes mistaken for  impetigo , a bacterial  infection . Common mouth ulcers ( aphthous ulcer ) also resemble intraoral herpes, but do not present a  vesicular  stage. [ 43 ]


Genital herpes can be more difficult to diagnose than oral herpes, since most people have none of the classical symptoms. [ 43 ]  Further confusing diagnosis, several other conditions resemble genital herpes, including  fungal infection ,  lichen planus ,  atopic dermatitis , and  urethritis . [ 43 ]


Laboratory  testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include culture of the virus,  direct fluorescent antibody  (DFA) studies to detect virus,  skin biopsy , and  polymerase chain reaction  to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice. [ 43 ]


Until the 1980s  serological  tests for antibodies to HSV were rarely useful to diagnosis and not routinely used in clinical practice. [ 43 ]  The older IgM serologic assay could not differentiate between antibodies generated in response to HSV-1 or HSV-2 infection.  However, a glycoprotein G-specific (IgG) HSV test introduced in the 1980s is more than 98% specific at discriminating HSV-1 from HSV-2. [ 44 ]


It should not be confused with conditions caused by other viruses in the  herpesviridae  family such as  herpes zoster  (also known as shingles), which is caused by  varicella zoster virus . The  differential diagnosis  includes  hand, foot and mouth disease  due to similar lesions on the skin.  Lymphangioma circumscriptum  and  dermatitis herpetiformis  may also have a similar appearance.


As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men. [ 45 ]  On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is about 8–11%. [ 41 ] [ 46 ]  This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Transmission risk from infected female to male is around 4–5% annually. [ 46 ]  Suppressive antiviral therapy reduces these risks by 50%. [ 47 ]  Antivirals also help prevent the development of symptomatic HSV in infection scenarios, meaning the infected partner will be seropositive but symptom-free by about 50%. Condom use also reduces the transmission risk significantly. [ 48 ] [ 49 ]  Condom use is much more effective at preventing male-to-female transmission than  vice versa . [ 48 ]  Previous HSV-1 infection may reduce the risk for acquisition of HSV-2 infection among women by a factor of three, although the one study that states this has a small sample size of 14 transmissions out of 214 couples. [ 50 ]


However, asymptomatic carriers of the HSV-2 virus are still contagious.  In many infections, the first symptom people will have of their own infections 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. [ 51 ]


In October 2011,  the anti-HIV drug  tenofovir , when used topically in a microbicidal vaginal gel, was reported to reduce herpes virus sexual transmission by 51%. [ 52 ]


Condoms offer moderate protection against HSV-2 in both men and women, with consistent condom users having a 30%-lower risk of HSV-2 acquisition compared with those who never use condoms. [ 53 ]  A  female condom  can provide greater protection than the male condom, as it covers the labia. [ 54 ]  The virus cannot pass through a synthetic condom, but a male condom's effectiveness is limited [ 55 ]   because herpes ulcers may appear on areas not covered by it. Neither type of condom prevents contact with the scrotum, anus, buttocks, or upper thighs, areas that may come in contact with ulcers or genital secretions during sexual activity. Protection against herpes simplex depends on the site of the ulcer; therefore, if ulcers appear on areas not covered by condoms, abstaining from sexual activity until the ulcers are fully healed is one way to limit risk of transmission. [ 56 ]  The risk is not eliminated, however, as viral shedding capable of transmitting infection may still occur while the infected partner is asymptomatic. [ 57 ]  The use of condoms or  dental dams  also limits the transmission of herpes from the genitals of one partner to the mouth of the other (or  vice versa ) during  oral sex . When one partner has a herpes simplex infection and the other does not, the use of antiviral medication, such as  valaciclovir , in conjunction with a condom, further decreases the chances of transmission to the uninfected partner. [ 16 ]  Topical  microbicides  that contain chemicals that directly inactivate the virus and block viral entry are being investigated. [ 16 ]


Antivirals may reduce asymptomatic shedding; asymptomatic genital HSV-2 viral shedding is believed to occur on 20% of days per year in patients not undergoing antiviral treatment, versus 10% of days while on antiviral therapy. [ 36 ]


The risk of transmission from mother to baby is highest if the mother becomes infected around the time of delivery (30% to 60%), [ 58 ] [ 59 ]  since insufficient time will have occurred for the generation and transfer of protective maternal antibodies before the birth of the child. In contrast, the risk falls to 3% if the  infection is recurrent, [ 60 ]  and is 1–3% if the woman is seropositive for both HSV-1 and HSV-2, [ 60 ] [ 61 ]  and is less than 1% if no lesions are visible. [ 60 ]  Women seropositive for only one type of HSV are only half as likely to transmit HSV as infected seronegative mothers. To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1-seropositive partner and conventional sex with a partner having a genital infection during the last trimester of pregnancy. Mothers infected with HSV are advised to avoid procedures that would cause trauma to the infant during birth (e.g. fetal scalp electrodes, forceps, and vacuum extractors) and, should lesions be present, to elect  caesarean section  to reduce exposure of the child to infected secretions in the birth canal. [ 16 ]  The use of antiviral treatments, such as aciclovir, given from the 36th week of pregnancy, limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section. [ 16 ]


Aciclovir is the recommended antiviral for herpes suppressive therapy during the last months of pregnancy.  The use of valaciclovir and famciclovir, while potentially improving compliance, have less-well-determined safety in pregnancy.


No method  eradicates herpes virus from the body, but antiviral medications can reduce the frequency, duration, and severity of outbreaks.   Analgesics  such as  ibuprofen  and  paracetamol  (acetaminophen) can reduce pain and fever.  Topical anesthetic treatments such as  prilocaine ,  lidocaine ,  benzocaine , or  tetracaine  can also relieve itching and pain. [ 62 ] [ 63 ] [ 64 ]


Several  antiviral drugs  are effective for treating herpes, including  aciclovir  (acyclovir),  valaciclovir ,  famciclovir , and  penciclovir . Aciclovir was the first discovered and is now available in  generic . [ 65 ]  Valaciclovir is also available as a generic [ 66 ]  and is slightly more effective than aciclovir for reducing lesion healing time. [ 67 ]


Evidence supports the use of aciclovir and valaciclovir in the treatment of herpes labialis [ 68 ]  as well as herpes infections in people with  cancer . [ 69 ]  The evidence to support the use of aciclovir in primary herpetic gingivostomatitis is weaker. [ 70 ]


A number of  topical  antivirals are effective for herpes labialis, including aciclovir, penciclovir, and  docosanol . [ 68 ] [ 71 ]


Evidence is insufficient to support use of many of these compounds, including  echinacea ,  eleuthero ,  L-lysine ,  zinc ,  monolaurin  bee products, and  aloe vera . [ 72 ]  While a number of small studies show possible benefit from monolaurin, L-lysine,  aspirin , lemon balm, topical zinc, or licorice root cream in treatment, these preliminary studies have not been confirmed by higher-quality  randomized controlled studies . [ 73 ]


Following active infection, herpes viruses establish a  latent  infection in sensory and autonomic  ganglia  of the nervous system.  The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the  nucleus  of a nerve's  cell body .  HSV latency is static; no virus is produced; and is controlled by a number of viral genes, including  latency-associated transcript . [ 74 ]


Many HSV-infected people experience recurrence within the first year of infection. [ 16 ]   Prodrome  precedes development of lesions.  Prodromal symptoms include tingling ( paresthesia ), itching, and pain where lumbosacral nerves innervate the skin. Prodrome may occur as long as several days or as short as a few hours before lesions develop.  Beginning antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions in some individuals. During recurrence, fewer lesions are likely to develop and  are less painful and heal faster (within 5–10 days without antiviral treatment) than those occurring during the primary infection. [ 16 ]   Subsequent outbreaks tend to be periodic or episodic, occurring on average four or five times a year when not using antiviral therapy.


The causes of reactivation are uncertain, but several potential triggers have been documented. A 2009 study showed the protein  VP16  plays a key role in reactivation of the dormant virus. [ 75 ]  Changes in the immune system during  menstruation  may play a role in HSV-1 reactivation. [ 76 ] [ 77 ]  Concurrent infections, such as viral  upper respiratory tract infection  or other febrile diseases, can cause outbreaks.  Reactivation due to other infections is the likely source of the historic terms 'cold sore' and 'fever blister'.


Other identified triggers include local injury to the face, lips, eyes, or mouth; trauma; surgery;  radiotherapy ; and exposure to wind,  ultraviolet light , or sunlight. [ 78 ] [ 79 ] [ 80 ] [ 81 ] [ 82 ]


The frequency and severity of recurrent outbreaks vary greatly between people. Some individuals' outbreaks can be quite debilitating, with large, painful lesions persisting for several weeks, while others experience only minor itching or burning for a few days. Some evidence indicates genetics play a role in the frequency of cold sore outbreaks.  An area of human chromosome 21 that includes six genes has been linked to frequent oral herpes outbreaks. An immunity to the virus is built over time. Most infected individuals experience fewer outbreaks and outbreak symptoms often become less severe. After several years, some people become perpetually  asymptomatic  and no longer experience outbreaks, though they may still be contagious to others. Immunocompromised individuals may experience longer, more frequent, and more severe episodes. Antiviral medication has been proven to shorten the frequency and duration of outbreaks. [ 83 ]   Outbreaks may occur at the original site of the infection or in proximity to nerve endings that reach out from the infected ganglia. In the case of a genital infection, sores can appear at the original site of infection or near the base of the spine, the buttocks, or the back of the thighs. HSV-2-infected individuals are at higher risk for acquiring HIV when practicing unprotected sex with HIV-positive persons, in particular during an outbreak with active lesions. [ 84 ]


Worldwide rates of either HSV-1 and/or HSV-2 are between 60 and 95% in adults. [ 4 ]  HSV-1 is more common than HSV-2, with rates of both increasing as people age. [ 4 ]  HSV-1 rates are between 70% and 80% in populations of low socioeconomic status and 40% to 60% in populations of improved socioeconomic status. [ 4 ]  An estimated 536 million people or 16% of the population worldwide were infected with HSV-2 as of 2003 with greater rates among women and in those in the developing world. [ 12 ]  Rates of infection are determined by the presence of  antibodies  against either  viral species . [ 85 ]


In the  US , 58% of the population is infected with HSV-1 [ 86 ]  and 16% are infected with HSV-2. Among those HSV-2-seropositive, only 19% were aware they were infected. [ 87 ]  During 2005–2008, the prevalence of HSV-2 was 39% in black people and 21% in women. [ 88 ]


The annual incidence in Canada of genital herpes due to HSV-1 and HSV-2 infection is not known (for a review of HSV-1/HSV-2 prevalence and incidence studies worldwide, see Smith and Robinson 2002). As many as one in seven Canadians aged 14 to 59 may be infected with herpes simplex type 2 virus [ 89 ]  and more than 90 per cent of them may be unaware of their status, a new study suggests. [ 90 ]  In the United States, it is estimated that about 1,640,000 HSV-2 seroconversions occur yearly (730,000 men and 910,000 women, or 8.4 per 1,000 persons). [ 91 ]


In British Columbia in 1999, the seroprevalence of HSV-2 antibody in leftover serum submitted for antenatal testing revealed a prevalence of 17%, ranging from 7% in women 15–19 years old to 28% in those 40–44 years. [ 92 ]


In Norway, a study published in 2000 found that up to 70–90% of genital initial infections were due to HSV-1. [ 93 ]


In Nova Scotia, 58% of 1,790 HSV isolates from genital lesion cultures in women were HSV-1; in men, 37% of 468 isolates were HSV-1. [ 94 ]


Herpes originated and evolved in Africa and could be the result of a cross-species transmission event from gibbons, orangutans, or gorillas. [ 95 ]


Herpes has been known for at least 2,000 years. Emperor  Tiberius  is said to have banned kissing in Rome for a time due to so many people having cold sores. In the 16th century  Romeo and Juliet ,  blisters "o'er ladies' lips" are mentioned. In the 18th century, it was so common among prostitutes that it was called "a vocational disease of women". [ 96 ]  The term 'herpes simplex' appeared in  Richard Boulton 's  A System of Rational and Practical Chirurgery  in 1713, where the terms 'herpes miliaris' and 'herpes exedens' also appeared. Herpes was not found to be a virus until the 1940s. [ 96 ]


Herpes antiviral therapy began in the early 1960s with the experimental use of medications that interfered with viral replication called  deoxyribonucleic acid  (DNA) inhibitors. The original use was against normally fatal or debilitating illnesses such as adult encephalitis, [ 97 ]  keratitis, [ 98 ]  in immunocompromised (transplant) patients, [ 99 ]  or  disseminated herpes zoster  (also known as disseminated shingles). [ 100 ]  The original compounds used were 5-iodo-2'-deoxyuridine, AKA idoxuridine, IUdR, or(IDU) and 1-β-D-arabinofuranosylcytosine or ara-C, [ 101 ]  later marketed under the name cytosar or cytarabine. The usage expanded to include topical treatment of herpes simplex, [ 102 ]  zoster, and varicella. [ 103 ]  Some trials combined different antivirals with differing results. [ 97 ]  The introduction of 9-β-D-arabinofuranosyladenine, (ara-A or vidarabine), considerably less toxic than ara-C, in the mid-1970s, heralded the way for the beginning of regular neonatal antiviral treatment. Vidarabine was the first systemically administered antiviral medication with activity against HSV for which therapeutic efficacy outweighed toxicity for the management of life-threatening HSV disease. Intravenous vidarabine was licensed for use by the  U.S. Food and Drug Administration  in 1977. Other experimental antivirals of that period included: heparin, [ 104 ]  trifluorothymidine (TFT), [ 105 ]  Ribivarin, [ 106 ]  interferon, [ 107 ]  Virazole, [ 108 ]  and 5-methoxymethyl-2'-deoxyuridine (MMUdR). [ 109 ]  The introduction of 9-(2-hydroxyethoxymethyl)guanine, AKA aciclovir, in the late 1970s [ 110 ]  raised antiviral treatment another notch and led to vidarabine vs. aciclovir trials in the late 1980s. [ 111 ]  The lower toxicity and ease of administration over vidarabine has led to aciclovir becoming the drug of choice for herpes treatment after it was licensed by the FDA in 1998. [ 112 ]  Another advantage in the treatment of neonatal herpes included greater reductions in mortality and morbidity with increased dosages, which did not occur when compared with increased dosages of vidarabine. [ 112 ]  However, aciclovir seems to inhibit antibody response, and newborns on aciclovir antiviral treatment experienced a slower rise in antibody titer than those on vidarabine. [ 112 ]


Some people experience negative feelings related to the condition following diagnosis, in particular, if they have acquired the genital form of the disease. Feelings can include  depression , fear of rejection, feelings of  isolation , fear of being found out, and self-destructive feelings. [ 113 ]   Herpes support groups  have been formed in the United States and the United Kingdom, providing information about herpes and running message forums and dating websites for affected people. People with the herpes virus are often hesitant to divulge to other people, including friends and family, that they are infected. This is especially true of new or potential sexual partners whom they consider casual. [ 114 ]


In a 2007 study, 1,900 people (25% of which had herpes) ranked genital herpes second for social stigma, out of all sexually transmitted diseases ( HIV  took the top spot for STD stigma). [ 115 ] [ 116 ] [ 117 ]


A source of support is the  National Herpes Resource Center  which arose from the work of the American Sexual Health Association (ASHA). [ 118 ]  The ASHA  was created in 1914 in response to the increase in sexually transmitted diseases that had spread during  World War I . [ 119 ]  During the 1970s, there was an increase in sexually transmitted diseases.  One of the diseases that increased dramatically was genital herpes. In response, ASHA created the National Herpes Resource Center in 1979. The Herpes Resource Center (HRC) was designed to meet the growing need for education and awareness about the virus. One of the projects of the HRC was to create a network of local support (HELP) groups.  The goal of these HELP groups was to provide a safe, confidential environment where participants can get accurate information and share experiences, fears, and feelings with others who are concerned about herpes. [ 120 ] [ 121 ]


In the UK, the Herpes Association (now the  Herpes Viruses Association ) was started in 1982, becoming a registered charity with a Department of Health grant in 1985. The charity started as a string of local group meetings before acquiring an office and a national spread. [ 122 ]


Research has gone into vaccines for both prevention and treatment of herpes infections.


As of October 2022, the U.S.  FDA  have not approved a vaccine for herpes. [ 123 ]  However, there are herpes vaccines currently in clinical trials, such as  Moderna  mRNA-1608. [ 124 ]  Unsuccessful clinical trials have been conducted for some glycoprotein subunit vaccines. [ citation needed ]  As of 2017, the future pipeline includes several promising replication-incompetent vaccine proposals while two replication-competent (live-attenuated) HSV vaccine are undergoing human testing. [ citation needed ]


A  genomic  study of the herpes simplex type 1 virus confirmed the human migration pattern theory known as the  out-of-Africa hypothesis . [ 125 ]


All other  Simplexvirus  sp.:


Herpes simplex virus   1  (cold sores) and  2  (genital herpes) ( HSV-1  and  HSV-2 ), also known by their taxonomic names  Human alphaherpesvirus 1  and  Human alphaherpesvirus 2 , are two members of the  human  Herpesviridae  family , a set of viruses that produce  viral infections  in the majority of  humans . [ 1 ] [ 2 ]  Both HSV-1 and HSV-2 are very common and  contagious . They can be spread when an infected person begins  shedding  the  virus .


As of 2016, about 67% of the world population under the age of 50 had HSV-1. [ 3 ]  In the United States, about 47.8% and 11.9% are estimated to have HSV-1 and HSV-2, respectively, though actual  prevalence  may be much higher. [ 4 ]  Because it can be transmitted through any intimate contact, it is one of the most common  sexually transmitted infections . [ 5 ]


Many of those who are infected never develop symptoms. [ 6 ]  Symptoms, when they occur, may include watery  blisters  in the  skin  of any location of the body, or in  mucous membranes  of the mouth, lips, nose, genitals, [ 1 ]  or eyes ( herpes simplex keratitis ). [ 7 ]  Lesions heal with a  scab  characteristic of herpetic disease. Sometimes, the viruses cause mild or atypical symptoms during outbreaks. However, they can also cause more troublesome forms of  herpes  simplex. As  neurotropic and neuroinvasive viruses , HSV-1 and -2 persist in the body by hiding from the  immune system  in the  cell  bodies of  neurons , particularly in sensory ganglia. After the initial or primary infection, some infected people experience  sporadic  episodes of viral reactivation or outbreaks. In an outbreak, the virus in a nerve cell becomes active and is transported via the neuron's  axon  to the skin, where virus replication and shedding occur and may cause new sores. [ 8 ]


HSV-1 and HSV-2 are transmitted by contact with an infected person who has reactivations of the virus.
HSV 1 and HSV-2 are periodically shed, most often asymptomatically.  [ citation needed ]


In a study of people with first-episode genital HSV-1 infection from 2022, genital shedding of HSV-1 was detected on 12% of days at 2 months and declined significantly to 7% of days at 11 months. Most genital shedding was asymptomatic; genital and oral lesions and oral shedding were rare. [ 9 ]


Most sexual transmissions of HSV-2 occur during periods of  asymptomatic shedding . [ 10 ]  Asymptomatic reactivation means that the virus causes atypical, subtle, or hard-to-notice symptoms that are not identified as an active herpes infection, so acquiring the virus is possible even if no active HSV blisters or sores are present. In one study, daily genital swab samples detected HSV-2 at a median of 12–28% of days among those who had an outbreak, and 10% of days among those with asymptomatic infection (no prior outbreaks), with many of these episodes occurring  without  visible outbreak ("subclinical shedding"). [ 11 ]


In another study, 73 subjects were randomized to receive  valaciclovir  1 g daily or  placebo  for 60 days each in a two-way  crossover design . A daily swab of the genital area was self-collected for HSV-2 detection by polymerase chain reaction, to compare the effect of valaciclovir versus placebo on asymptomatic viral shedding in immunocompetent, HSV-2 seropositive subjects without a history of symptomatic genital herpes infection. The study found that valaciclovir significantly reduced shedding during subclinical days compared to placebo, showing a 71% reduction; 84% of subjects had no shedding while receiving valaciclovir versus 54% of subjects on placebo. About 88% of patients treated with valaciclovir had no recognized signs or symptoms versus 77% for placebo. [ 12 ]


For HSV-2, subclinical shedding may account for most of the transmission. [ 11 ]  Studies on discordant partners (one infected with HSV-2, one not) show that the transmission rate is approximately 5–8.9 per 10,000 sexual contacts, with condom usage greatly reducing the risk of acquisition. [ 13 ]  Atypical symptoms are often attributed to other causes, such as a  yeast infection . [ 14 ] [ 15 ]  HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as  kissing  and  oral sex . [ 16 ]  Historically HSV-2 was primarily a sexually transmitted infection, but rates of HSV-1 genital infections have been increasing for the last few decades. [ 14 ]


Both viruses may also be  transmitted vertically  during natural childbirth. [ 17 ] [ 18 ]  However, the risk of transmission is minimal if the mother has no symptoms nor exposed blisters during delivery. The risk is considerable when the mother is infected with the virus for the first time during late pregnancy, reflecting a high viral load. [ 19 ]  While most viral STDs can not be transmitted through objects as the virus dies quickly outside of the body, HSV can survive for up to 4.5 hours on surfaces and can be transmitted through use of towels, toothbrushes, cups, cutlery, etc. [ 20 ] [ 21 ] [ 22 ] [ 23 ]


Herpes simplex viruses can affect areas of skin exposed to contact with an infected person. An example of this is  herpetic whitlow , which is a herpes infection on the fingers; it was commonly found on  dental surgeon 's hands before the routine use of gloves when treating patients. Shaking hands with an infected person does not transmit this disease. [ 24 ]  Genital infection of HSV-2 increases the risk of acquiring  HIV . [ 25 ]


HSV has been a model virus for many studies in molecular biology. For instance, one of the first functional  promoters  in  eukaryotes  was discovered in HSV (of the  thymidine kinase  gene) and the virion protein  VP16  is one of the most-studied  transcriptional activators . [ 26 ]


Animal herpes viruses all share some common properties. The structure of herpes viruses consists of a relatively large, double-stranded, linear  DNA   genome  encased within an  icosahedral  protein cage called the  capsid , which is wrapped in a  lipid bilayer  called the  envelope . The envelope is joined to the capsid through a  tegument . This complete particle is known as the  virion . [ 27 ]  HSV-1 and HSV-2 each contain at least 74 genes (or  open reading frames , ORFs) within their genomes, [ 28 ]  although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs. [ 29 ]  These genes encode a variety of proteins involved in forming the capsid, tegument and envelope of the virus, as well as controlling the replication and infectivity of the virus. These genes and their functions are summarized in the table below. [ citation needed ]


The genomes of HSV-1 and HSV-2 are complex and contain two unique regions called the long unique region (U L ) and the short unique region (U S ). Of the 74 known ORFs, U L  contains 56 viral genes, whereas U S  contains only 12. [ 28 ]  Transcription of HSV genes is catalyzed by  RNA polymerase II  of the infected host. [ 28 ]   Immediate early genes , which encode proteins, for example, ICP22 [ 30 ]  that regulate the expression of early and late viral genes, are the first to be expressed following infection.  Early gene  expression follows, to allow the synthesis of  enzymes  involved in  DNA replication  and the production of certain  envelope   glycoproteins . Expression of late genes occurs last; this group of genes predominantly encodes proteins that form the virion particle. [ 28 ]


Five proteins from (U L ) form the viral capsid -  UL6 , UL18, UL35, UL38, and the major capsid protein UL19. [ 27 ]


Entry of HSV into a host cell involves several  glycoproteins  on the surface of the enveloped virus binding to their  transmembrane receptors  on the cell surface. Many of these receptors are then pulled inwards by the cell, which is thought to open a ring of three gHgL heterodimers stabilizing a compact conformation of the gB glycoprotein so that it springs out and punctures the cell membrane. [ 31 ]  The envelope covering the virus particle then fuses with the cell membrane, creating a pore through which the contents of the viral envelope enters the host cell. [ citation needed ]


The sequential stages of HSV entry are analogous to  those of other viruses . At first, complementary receptors on the virus and the cell surface bring the viral and cell membranes into proximity. Interactions of these molecules then form a stable entry pore through which the viral envelope contents are introduced to the host cell. The virus can also be  endocytosed  after binding to the receptors, and the fusion could occur at the  endosome . In electron micrographs, the outer leaflets of the viral and cellular lipid bilayers have been seen merged; [ 32 ]  this hemifusion may be on the usual path to entry or it may usually be an arrested state more likely to be captured than a transient entry mechanism. [ citation needed ]


In the case of a herpes virus, initial interactions occur when two viral envelope glycoproteins called glycoprotein C (gC) and glycoprotein B (gB)  bind to a cell surface  polysaccharide  called  heparan sulfate . Next, the major receptor binding protein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors. [ 33 ]  These cell receptors include herpesvirus entry mediator ( HVEM ),  nectin -1 and 3-O sulfated heparan sulfate. The nectin receptors usually produce cell-cell adhesion, to provide a strong point of attachment for the virus to the host cell. [ 31 ]  These interactions bring the membrane surfaces into mutual proximity and allow for other glycoproteins embedded in the viral envelope to interact with other cell surface molecules. Once bound to the HVEM, gD changes its conformation and interacts with viral glycoproteins H (gH) and L (gL), which form a complex. The interaction of these membrane proteins may result in a hemifusion state. gB interaction with the gH/gL complex creates an entry pore for the viral capsid. [ 32 ]  gB interacts with  glycosaminoglycans  on the surface of the host cell.  [ citation needed ]


After the viral capsid enters the cellular  cytoplasm , it starts to express viral protein  ICP27 . ICP27 is a regulator protein that causes disruption in host protein synthesis and utilizes it for viral replication. ICP27 binds with a cellular enzyme  Serine-Arginine Protein Kinase 1, SRPK1 . Formation of this complex causes the SRPK1 shift from the cytoplasm to the nucleus, and the viral genome gets transported to the  cell nucleus . [ 34 ]  Once attached to the nucleus at a nuclear entry pore, the capsid ejects its DNA contents via the capsid portal. The capsid portal is formed by 12 copies of the portal protein, UL6, arranged as a ring; the proteins contain a  leucine zipper  sequence of  amino acids , which allow them to adhere to each other. [ 35 ]  Each  icosahedral  capsid contains a single portal, located in one  vertex . [ 36 ] [ 37 ]
The DNA exits the capsid in a single linear segment. [ 38 ]


HSV evades the immune system through interference with  MHC class I   antigen presentation  on the cell surface, by blocking the  transporter associated with antigen processing  (TAP) induced by the secretion of  ICP-47  by HSV. In the host cell, TAP transports digested viral antigen epitope peptides from the cytosol to the endoplasmic reticulum, allowing these epitopes to be combined with MHC class I molecules and presented on the surface of the cell. Viral epitope presentation with MHC class I is a requirement for the activation of cytotoxic T-lymphocytes (CTLs), the major effectors of the cell-mediated immune response against virally infected cells. ICP-47 prevents the initiation of a CTL-response against HSV, allowing the virus to survive for a protracted period in the host. [ 39 ]  HSV usually produces cytopathic effect (CPE) within 24–72 hours post-infection in permissive cell lines which is observed by classical plaque formation. However, HSV-1 clinical isolates have also been reported that did not show any CPE in Vero and A549 cell cultures over several passages with low levels of virus protein expression. Probably these HSV-1 isolates are evolving towards a more "cryptic" form to establish chronic infection thereby unravelling yet another strategy to evade the host immune system, besides neuronal latency. [ 40 ]


Following the infection of a cell, a cascade of herpes virus proteins, called immediate-early,  early , and late, is produced. Research using  flow cytometry  on another member of the herpes virus family,  Kaposi's sarcoma-associated herpesvirus , indicates the possibility of an additional  lytic stage , delayed-late. [ 41 ]  These stages of lytic infection, particularly late lytic, are distinct from the latency stage. In the case of HSV-1, no protein products are detected during latency, whereas they are detected during the lytic cycle. [ citation needed ]


The early proteins transcribed are used in the regulation of genetic replication of the virus. On entering the cell, an α-TIF protein joins the viral particle and aids in immediate-early  transcription . The virion host shutoff protein (VHS or UL41) is very important to viral replication. [ 42 ]  This enzyme shuts off protein synthesis in the host, degrades host  mRNA , helps in viral replication, and regulates  gene expression  of viral proteins. The viral genome immediately travels to the nucleus, but the VHS protein remains in the cytoplasm. [ 43 ] [ 44 ]


The late proteins form the capsid and the receptors on the surface of the virus. Packaging of the viral particles — including the  genome , core, and capsid - occurs in the nucleus of the cell. Here,  concatemers  of the viral genome are separated by cleavage and are placed into formed capsids. HSV-1 undergoes a process of primary and secondary envelopment. The primary envelope is acquired by budding into the inner nuclear membrane of the cell. This then fuses with the outer nuclear membrane. The virus acquires its final envelope by budding into cytoplasmic  vesicles . [ 45 ]


HSVs may persist in a quiescent but persistent form known as latent infection, notably in  neural ganglia . [ 1 ]  The HSV genome circular DNA resides in the  cell nucleus  as an  episome . [ 46 ]  HSV-1 tends to reside in the  trigeminal ganglia , while HSV-2 tends to reside in the  sacral ganglia , but these are historical tendencies only. During latent infection of a cell, HSVs express  latency-associated transcript  (LAT)  RNA . LAT regulates the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows subsequent, usually symptomatic, periodic recurrences or "outbreaks" characteristic of non-latency. Whether or not recurrences are symptomatic, viral shedding occurs to infect a new host. [ citation needed ]


A protein found in neurons may bind to herpes virus DNA and regulate  latency . Herpes virus DNA contains a gene for a protein called ICP4, which is an important  transactivator  of genes associated with lytic infection in HSV-1. [ 47 ]  Elements surrounding the gene for ICP4 bind a protein known as the human neuronal protein neuronal restrictive silencing factor (NRSF) or  human repressor element silencing transcription factor (REST) . When bound to the viral DNA elements,  histone deacetylation  occurs atop the  ICP4  gene sequence to prevent initiation of transcription from this gene, thereby preventing transcription of other viral genes involved in the lytic cycle. [ 47 ] [ 48 ]  Another HSV protein reverses the inhibition of ICP4 protein synthesis.  ICP0  dissociates NRSF from the  ICP4  gene and thus prevents silencing of the viral DNA. [ 49 ]


The HSV genome spans about 150,000 bp and consists of two unique segments, named unique long (UL) and unique short (US), as well as  terminal inverted repeats  found to the two ends of them named repeat long (RL) and repeat short (RS). There are also minor "terminal redundancy" (α) elements found on the further ends of RS. The overall arrangement is RL-UL-RL-α-RS-US-RS-α with each pair of repeats inverting each other. The whole sequence is then encapsulated in a terminal direct repeat. The long and short parts each have their own  origins of replication , with OriL located between UL28 and UL30 and OriS located in a pair near the RS. [ 50 ]  As the L and S segments can be assembled in any direction, they can be inverted relative to each other freely, forming various linear isomers. [ 51 ]


HSV genes are expressed in 3 temporal classes: immediate early (IE or α), early (E or ß), and late (γ) genes. However, the progression of viral  gene expression  is rather gradual than in clearly distinct stages. Immediate early genes are transcribed right after infection and their gene products activate transcription of the early genes. Early gene products help to replicate the viral DNA. Viral  DNA replication , in turn, stimulates the expression of the late genes, encoding the structural proteins. [ 26 ]


Transcription of the immediate early (IE) genes begins right after virus DNA enters the nucleus. All virus genes are transcribed by the host  RNA polymerase II . Although host proteins are sufficient for virus transcription, viral proteins are necessary for the transcription of certain genes. [ 26 ]  For instance, VP16 plays an important role in IE transcription and the virus particle brings it into the host cell, so that it does not need to be produced first. Similarly, the IE proteins RS1 (ICP4), UL54 (ICP27), and ICP0 promote the transcription of the early (E) genes. Like IE genes, early gene promoters contain binding sites for cellular transcription factors. One early protein, ICP8, is necessary for both transcription of late genes and DNA replication. [ 26 ]


Later in the life cycle of HSV, the expression of immediate early and early genes is shut down. This is mediated by specific virus proteins, e.g. ICP4, which represses itself by binding to elements in its promoter. As a consequence, the down-regulation of ICP4 levels leads to a reduction of early and late gene expression, as ICP4 is important for both. [ 26 ]


Importantly, HSV shuts down host cell RNA, DNA, and protein synthesis to direct cellular resources to virus production. First, the virus protein vhs induces the degradation of existing  mRNAs  early in infection. Other viral genes impede cellular transcription and translation. For instance, ICP27 inhibits  RNA splicing , so that virus mRNAs (which are usually not spliced) gain an advantage over host mRNAs. Finally,  virus proteins destabilize certain cellular proteins involved in the host  cell cycle , so that both cell division and host cell DNA replication are disturbed in favor of virus replication. [ 26 ]


The herpes simplex 1 genomes can be classified into six  clades . [ 57 ]  Four of these occur in  East Africa , one in  East Asia  and one in  Europe  and  North America . This suggests that the virus may have originated in East Africa. The  most recent common ancestor  of the Eurasian strains appears to have evolved ~60,000 years ago. [ 58 ]  The East Asian HSV-1 isolates have an unusual pattern that is currently best explained by the two waves of migration responsible for the peopling of  Japan . [ 58 ]


Herpes simplex 2 genomes can be divided into two groups: one is globally distributed and the other is mostly limited to  sub Saharan Africa . [ 59 ]  The globally distributed  genotype  has undergone four ancient recombinations with herpes simplex 1. It has also been reported that HSV-1 and HSV-2 can have contemporary and stable recombination events in hosts simultaneously infected with both pathogens. All of the cases are HSV-2 acquiring parts of the HSV-1 genome, sometimes changing parts of its antigen epitope in the process. [ 60 ]


The mutation rate has been estimated to be ~1.38×10 −7  substitutions/site/year. [ 57 ]  In the clinical setting, mutations in either the thymidine kinase gene or DNA polymerase gene have caused resistance to  aciclovir . However, most of the mutations occur in the thymidine kinase gene rather than the DNA polymerase gene. [ 61 ]


Another analysis has estimated the mutation rate in the herpes simplex 1 genome to be 1.82×10 −8  nucleotide substitution per site per year. This analysis placed the most recent common ancestor of this virus ~710,000 years ago. [ 62 ]


Herpes simplex 1 and 2 diverged about  6  million years ago . [ 60 ]


Similar to other  herpesviridae , the herpes simplex viruses establish latent lifelong infection, and thus cannot be eradicated from the body with current treatments. [ 63 ]


Treatment usually involves general-purpose  antiviral drugs  that interfere with viral replication, reduce the physical severity of outbreak-associated lesions, and lower the chance of transmission to others. Studies of vulnerable patient populations have indicated that daily use of antivirals such as  aciclovir [ 64 ]  and valaciclovir can reduce reactivation rates. [ 15 ]  The extensive use of antiherpetic drugs has led to the development of some  drug resistance , [ citation needed ]  which in turn may lead to treatment failure. Therefore, new sources of drugs are broadly investigated to address the problem. In January 2020, a comprehensive review article was published that demonstrated the effectiveness of natural products as promising anti-HSV drugs. [ 65 ]   Pyrithione , a zinc  ionophore , has shown antiviral activity against herpes simplex. [ 66 ]


In 1979, it was reported that there is a possible link between HSV-1 and  Alzheimer's disease , in people with the epsilon4  allele  of the gene  APOE . [ 67 ]  HSV-1 appears to be particularly damaging to the nervous system and increases one's risk of developing Alzheimer's disease. The virus interacts with the components and receptors of  lipoproteins , which may lead to the development of Alzheimer's disease. [ 68 ]  This research identifies HSVs as the  pathogen  most clearly linked to the establishment of Alzheimer's. [ 69 ]  According to a study done in 1997, without the presence of the gene  allele , HSV-1 does not appear to cause any neurological damage or increase the risk of Alzheimer's. [ 70 ]  However, a more recent prospective study published in 2008 with a cohort of 591 people showed a statistically significant difference between patients with antibodies indicating recent reactivation of HSV and those without these antibodies in the incidence of Alzheimer's disease, without direct correlation to the APOE-epsilon4 allele. [ 71 ]


The trial had a small sample of patients who did not have the antibody at baseline, so the results should be viewed as highly  uncertain . In 2011, Manchester University scientists showed that treating HSV1-infected cells with antiviral agents decreased the accumulation of  β-amyloid  and  tau protein  and also decreased HSV-1 replication. [ 72 ]


A 2018 retrospective study from  Taiwan  on 33,000 patients found that being infected with herpes simplex virus increased the risk of dementia 2.56 times (95% CI: 2.3-2.8) in patients not receiving anti-herpetic medications (2.6 times for HSV-1 infections  and 2.0 times for HSV-2 infections).  However, HSV-infected patients who were receiving anti-herpetic medications (e.g.,  acyclovir ,  famciclovir ,  ganciclovir ,  idoxuridine ,  penciclovir ,  tromantadine ,  valaciclovir , or  valganciclovir ) showed no elevated risk of dementia compared to patients uninfected with HSV. [ 73 ]


Multiplicity reactivation (MR) is the process by which viral genomes containing inactivating damage interact within an infected cell to form a viable viral genome. MR was originally discovered with the bacterial virus bacteriophage T4 but was subsequently also found with pathogenic viruses including influenza virus, HIV-1, adenovirus simian virus 40, vaccinia virus, reovirus, poliovirus, and herpes simplex virus. [ 74 ]


When HSV particles are exposed to doses of a DNA-damaging agent that would be lethal in single infections but are then allowed to undergo multiple infections (i.e. two or more viruses per host cell), MR is observed. Enhanced survival of HSV-1 due to MR occurs upon exposure to different DNA damaging agents, including  methyl methanesulfonate , [ 75 ]  trimethylpsoralen (which causes inter-strand DNA cross-links), [ 76 ] [ 77 ]  and UV light. [ 78 ]  After treatment of genetically marked HSV with trimethylpsoralen, recombination between the marked viruses increases, suggesting that trimethylpsoralen damage stimulates recombination. [ 76 ]  MR of HSV appears to partially depend on the host cell recombinational repair machinery since skin fibroblast cells defective in a component of this machinery (i.e. cells from Bloom's syndrome patients) are deficient in MR. [ 78 ]


These observations suggest that MR in HSV infections involves genetic recombination between damaged viral genomes resulting in the production of viable progeny viruses. HSV-1, upon infecting host cells, induces inflammation and oxidative stress. [ 79 ]  Thus it appears that the HSV genome may be subjected to oxidative DNA damage during infection, and that MR may enhance viral survival and virulence under these conditions. [ citation needed ]


Modified Herpes simplex virus is considered as a potential therapy for  cancer  and has been extensively clinically tested to assess its  oncolytic  (cancer-killing) ability. [ 80 ]   Interim overall survival data from  Amgen 's phase 3 trial of a  genetically attenuated herpes virus  suggests efficacy against  melanoma . [ 81 ]


Herpes simplex virus is also used as a transneuronal tracer defining connections among neurons by traversing synapses. [ 82 ]


HSV-2 is the most common cause of  Mollaret's meningitis . [ 83 ]  HSV-1 can lead to potentially fatal cases of  herpes simplex encephalitis . [ 84 ]  Herpes simplex viruses have also been studied in the central nervous system disorders such as  multiple sclerosis , but research has been conflicting and inconclusive. [ 85 ]


Following a diagnosis of genital herpes simplex infection, patients may develop an episode of profound  depression . In addition to offering antiviral medication to alleviate symptoms and shorten their duration, physicians must also address the mental health impact of a new diagnosis. Providing information on the very high  prevalence  of these infections, their effective treatments, and future therapies in development may provide hope to patients who are otherwise demoralized. [ citation needed ]


HSV infection was found to increase all-cause mortality in Denmark: 19.3% excess one-year mortality for HSV-1 and 5.3% for HSV-2 in the first year of infection. Additionally, lower employment rates and higher disability pension rates were observed. [ 86 ]


There exist commonly used vaccines to some herpesviruses, such as the veterinary vaccine  HVT/LT  (Turkey herpesvirus vector laryngotracheitis vaccine). However, it prevents  atherosclerosis  (which  histologically  mirrors atherosclerosis in humans) in target animals vaccinated. [ 87 ] [ 88 ]
The only human vaccines available for herpesviruses are for  Varicella zoster virus , given to children around their first birthday to prevent  chickenpox  (varicella), or to adults to prevent an outbreak of  shingles  (herpes zoster). There is, however, no human vaccine for herpes simplex viruses. As of 2022, there are active pre-clinical and clinical studies underway on herpes simplex in humans; vaccines are being developed for both treatment and prevention. [ citation needed ]


The  human immunodeficiency viruses  ( HIV ) are two species of  Lentivirus  (a subgroup of  retrovirus ) that infect humans. Over time, they cause  acquired immunodeficiency syndrome  (AIDS), [ 1 ] [ 2 ]  a condition in which progressive failure of the  immune system  allows life-threatening  opportunistic infections  and  cancers  to thrive. [ 3 ]  Without treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the  HIV subtype . [ 4 ]


In most cases, HIV is a  sexually transmitted infection  and  occurs  by contact with or transfer of  blood ,  pre-ejaculate ,  semen , and  vaginal fluids . [ 5 ] [ 6 ]  Non-sexual transmission can occur from an infected mother to her infant during  pregnancy , during  childbirth  by exposure to her blood or vaginal fluid, and through  breast milk . [ 7 ] [ 8 ] [ 9 ] [ 10 ]  Within these bodily fluids, HIV is present as both free  virus  particles and virus within infected  immune cells .
Research has shown (for both same-sex and opposite-sex couples) that HIV is not contagious during sexual intercourse without a condom if the HIV-positive partner has a consistently undetectable  viral load . [ 5 ] [ 6 ]


HIV infects vital cells in the human immune system, such as  helper T cells  (specifically  CD4 +  T cells),  macrophages , and  dendritic cells . [ 11 ]  HIV infection leads to low levels of CD4 +  T cells through a number of mechanisms, including  pyroptosis  of abortively infected T cells, [ 12 ]   apoptosis  of uninfected bystander cells, [ 13 ]  direct viral killing of infected cells, and killing of infected CD4 +  T cells by  CD8 +  cytotoxic lymphocytes  that recognize infected cells. [ 14 ]  When CD4 +  T cell numbers decline below a critical level,  cell-mediated immunity  is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS.


HIV is a member of the  genus   Lentivirus , [ 15 ]  part of the family  Retroviridae . [ 16 ]  Lentiviruses have many  morphologies  and  biological  properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long  incubation period . [ 17 ]  Lentiviruses are transmitted as  single-stranded , positive- sense ,  enveloped   RNA viruses . Upon entry into the target cell, the viral  RNA   genome  is converted (reverse transcribed) into double-stranded  DNA  by a virally encoded enzyme,  reverse transcriptase , that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the  cell nucleus  and integrated into the cellular DNA by a virally encoded enzyme,  integrase , and host  co-factors . [ 18 ]  Once integrated, the virus may become  latent , allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time. [ 19 ]  The virus can remain dormant in the human body for up to ten years after primary infection; during this period the virus does not cause symptoms. Alternatively, the integrated viral DNA may be  transcribed , producing new RNA genomes and viral proteins, using host cell resources, that are packaged and released from the cell as new virus particles that will begin the replication cycle anew.


Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus (LAV) and human T-lymphotropic virus 3 (HTLV-III). HIV-1 is more  virulent  and more  infective  than HIV-2, [ 20 ]  and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2, compared to HIV-1, implies that fewer of those exposed to HIV-2 will be infected per exposure. Due to its relatively poor capacity for transmission, HIV-2 is largely confined to  West Africa . [ 21 ]