Herpes simplex 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]

Symptoms

Many of those who are infected never develop symptoms.

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

Both viruses may also be transmitted vertically during 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 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

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]

Viral structure

Animal herpes viruses all share some common properties. The structure of herpes viruses consists of a relatively large, double-stranded, linear

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 encode 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]

Cellular entry

Entry of HSV into a host cell involves several

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 glycoprotein called glycoprotein C (gC) and glycoprotein B (gB) bind to a cell surface

Immune evasion

HSV evades the immune system through interference with MHC class I

Following 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

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 nonlatency. 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

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 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 apparently 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, 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 own 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 disturbed in favor of virus replication.^[26]

Evolution

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

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]

Treatment

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]

Alzheimer's disease

In 1979, it was reported that there is a possible link between HSV-1 and

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

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.^{[citation needed]}

Use as an anti-cancer agent

Modified Herpes simplex virus is considered as a potential therapy for

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

Other related outcomes

HSV-2 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]}

Research

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.^[86][87] 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]}

References