Herpes simplex virus
Herpes simplex virus 1 and 2 (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.
This article is about the virus. For information about the disease caused by the virus, see Herpes simplex. For the genus of viruses, see Simplexvirus.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]
Symptoms[edit]
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]
Evolution[edit]
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 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]
Alzheimer's disease[edit]
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[edit]
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 infection (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 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.
[edit]
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.