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{{Short description|Species of virus}} |
{{Short description|Species of virus}} |
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{{cs1 config|name-list-style=vanc|display-authors=6}} |
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{{About|the virus|information about the disease caused by the virus|Herpes simplex|the genus of viruses|Simplexvirus}} |
{{About|the virus|information about the disease caused by the virus|Herpes simplex|the genus of viruses|Simplexvirus}} |
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{{Paraphyletic group |
{{Paraphyletic group |
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| name |
| name = Herpes simplex viruses |
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| image |
| image = Herpes simplex virus TEM B82-0474 lores.jpg |
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| image_alt |
| image_alt = TEM micrograph of virions of a herpes simplex virus species |
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| image_caption = [[Transmission electron microscopy|TEM]] [[micrograph]] of virions of a herpes simplex virus species |
| image_caption = [[Transmission electron microscopy|TEM]] [[micrograph]] of virions of a herpes simplex virus species |
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| auto |
| auto = yes |
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| parent |
| parent = Simplexvirus |
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| includes |
| includes = * ''[[Human alphaherpesvirus 1]]'' |
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* ''[[Human alphaherpesvirus 2]]'' |
* ''[[Human alphaherpesvirus 2]]'' |
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| excludes |
| excludes = All other ''Simplexvirus'' sp.: |
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* ''[[Ateline alphaherpesvirus 1]]'' |
* ''[[Ateline alphaherpesvirus 1]]'' |
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* ''[[Bovine alphaherpesvirus 2]]'' |
* ''[[Bovine alphaherpesvirus 2]]'' |
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* ''[[Leporid alphaherpesvirus 4]]'' |
* ''[[Leporid alphaherpesvirus 4]]'' |
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* ''[[Macacine alphaherpesvirus 1]]'' |
* ''[[Macacine alphaherpesvirus 1]]'' |
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* ''[[Macacine alphaherpesvirus 3]]'' |
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* ''[[Macropodid alphaherpesvirus 1]]'' |
* ''[[Macropodid alphaherpesvirus 1]]'' |
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* ''[[Macropodid alphaherpesvirus 2]]'' |
* ''[[Macropodid alphaherpesvirus 2]]'' |
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* ''[[Simplexvirus macropodidalpha4|Macropodid alphaherpesvirus 4]]'' |
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* ''[[Panine alphaherpesvirus 3]]'' |
* ''[[Panine alphaherpesvirus 3]]'' |
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* ''[[Papiine alphaherpesvirus 2]]'' |
* ''[[Papiine alphaherpesvirus 2]]'' |
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* ''[[Pteropodid alphaherpesvirus 1]]'' |
* ''[[Pteropodid alphaherpesvirus 1]]'' |
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* ''[[Simplexvirus pteropodidalpha2|Pteropodid alphaherpesvirus 2]]'' |
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* ''[[Saimiriine |
* ''[[Saimiriine alphaherpesvirus1]]'' |
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}} |
}} |
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'''Herpes simplex virus''' '''1''' and '''2''' ('''HSV-1''' and '''HSV-2'''), also known by their |
'''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 [[Herpesviridae#Human herpesvirus types|human ''Herpesviridae'' family]], a set of viruses that produce [[Viral disease|viral infections]] in the majority of [[human]]s.<ref name=Sherris>{{cite book| veditors = Ryan KJ, Ray CG | title = Sherris Medical Microbiology| edition = 4th| pages = 555–62| publisher = McGraw Hill| year = 2004| isbn = 978-0-8385-8529-0 }}</ref><ref name="Peds09">{{cite journal|vauthors=Chayavichitsilp P, Buckwalter JV, Krakowski AC, Friedlander SF|date=April 2009|title=Herpes simplex|journal=Pediatr Rev|volume=30|issue=4|pages=119–29; quiz 130|doi=10.1542/pir.30-4-119|pmid=19339385|s2cid=34735917 }}</ref> Both HSV-1 and HSV-2 are very common and [[Infectious disease|contagious]]. They can be spread when an infected person begins [[viral shedding|shedding]] the [[virus]]. |
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As of 2016, about 67% of the world population under the age of 50 had HSV-1.<ref>{{cite web |title=Herpes simplex virus |website=World Health Organization |date=31 January 2017 |url=https://www.who.int/mediacentre/factsheets/fs400/en/}}</ref> 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.<ref>{{cite web|url=https://www.cdc.gov/nchs/data/databriefs/db304.pdf|title=Prevalence of Herpes Simplex Virus Type 1 and 2|date=16 February 2020|website=CDC NCHS Data Brief}}</ref> Because it can be transmitted through any intimate contact, it is one of the most common [[sexually transmitted infection]]s.<ref name="StrafaceSelmin2012">{{cite journal | vauthors = Straface G, Selmin A, Zanardo V, De Santis M, Ercoli A, Scambia G | title = Herpes simplex virus infection in pregnancy | journal = Infectious Diseases in Obstetrics and Gynecology | volume = 2012 | pages = 385697 | year = 2012 | pmid = 22566740 | pmc = 3332182 | doi = 10.1155/2012/385697 | doi-access = free }}</ref> |
As of 2016, about 67% of the world population under the age of 50 had HSV-1.<ref>{{cite web |title=Herpes simplex virus |website=World Health Organization |date=31 January 2017 |url=https://www.who.int/mediacentre/factsheets/fs400/en/}}</ref> 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.<ref>{{cite web|url=https://www.cdc.gov/nchs/data/databriefs/db304.pdf|title=Prevalence of Herpes Simplex Virus Type 1 and 2|date=16 February 2020|website=CDC NCHS Data Brief}}</ref> Because it can be transmitted through any intimate contact, it is one of the most common [[sexually transmitted infection]]s.<ref name="StrafaceSelmin2012">{{cite journal | vauthors = Straface G, Selmin A, Zanardo V, De Santis M, Ercoli A, Scambia G | title = Herpes simplex virus infection in pregnancy | journal = Infectious Diseases in Obstetrics and Gynecology | volume = 2012 | pages = 385697 | year = 2012 | pmid = 22566740 | pmc = 3332182 | doi = 10.1155/2012/385697 | doi-access = free }}</ref> |
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== Symptoms == |
== Symptoms == |
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Many of those who are infected |
Many of those who are infected never develop symptoms.<ref name=":0">{{cite web|url=https://www.who.int/mediacentre/factsheets/fs400/en/|title=Herpes simplex virus|date=31 January 2017|website=World Health Organization|access-date=September 22, 2018}}</ref> Symptoms, when they occur, may include watery [[blister]]s in the [[Human skin|skin]] of any location of the body,orin [[mucous membranes]] of the mouth, lips, nose, genitals,<ref name=Sherris /> or eyes ([[herpes simplex keratitis]]).<ref>{{Cite web | vauthors = Stephenson M |date=2020-09-09 |title=How to Manage Ocular Herpes |url=https://www.reviewofophthalmology.com/article/how-to-manage-ocular-herpes |access-date=2021-06-07 |website=Review of Ophthalmology}}</ref> Lesions heal with a [[Coagulation|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 virus|neurotropic and neuroinvasive viruses]], HSV-1 and -2 persist in the body by hiding from the [[immune system]] in the [[cell (biology)|cell]] bodies of [[neurons]], particularly in sensory ganglia. After the initial or primary infection, some infected people experience [[wikt:sporadic|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.<ref>{{cite web | title=Herpes simplex | url=http://www.dermnetnz.org/viral/herpes-simplex.html | date=2006-09-16 | publisher=DermNet NZ — New Zealand Dermatological Society | access-date=2006-10-15}}</ref> |
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==Transmission== |
==Transmission== |
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{{Main|Herpes simplex}} |
{{Main|Herpes simplex}} |
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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 transmitted by contact with an infected person who has reactivations of the virus. |
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HSV 1 and HSV-2 are periodically shed, most often asymptomatically. {{ |
HSV 1 and HSV-2 are periodically shed, most often asymptomatically. {{citation needed|date=January 2023}} |
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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.<ref>{{ |
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.<ref>{{cite journal | vauthors = Johnston C, Magaret A, Son H, Stern M, Rathbun M, Renner D, Szpara M, Gunby S, Ott M, Jing L, Campbell VL, Huang ML, Selke S, Jerome KR, Koelle DM, Wald A | title = Viral Shedding 1 Year Following First-Episode Genital HSV-1 Infection | journal = JAMA | volume = 328 | issue = 17 | pages = 1730–1739 | date = November 2022 | pmid = 36272098 | pmc = 9588168 | doi = 10.1001/jama.2022.19061 }}</ref> |
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Most sexual transmissions of HSV-2 occur during periods of ''asymptomatic shedding''.<ref name="pmid24671939">{{cite journal |vauthors=Schiffer JT, Mayer BT, Fong Y, Swan DA, Wald A | title = Herpes simplex virus-2 transmission probability estimates based on quantity of viral shedding | journal = J R Soc Interface | volume = 11 | issue = 95 | pages = 20140160 | year = 2014 | pmid = 24671939 | doi = 10.1098/rsif.2014.0160 | pmc = 4006256 }}</ref> 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").<ref name=Johnstonetal_2011>{{Cite journal |vauthors=Johnston C, Koelle DM, Wald A | title = HSV-2: in pursuit of a vaccine. | journal = J Clin Invest | volume = 121 | issue = 12 | pages = 4600–9 |date=Dec 2011 | doi = 10.1172/JCI57148 | pmid = 22133885 | pmc=3223069}}</ref> |
Most sexual transmissions of HSV-2 occur during periods of ''asymptomatic shedding''.<ref name="pmid24671939">{{cite journal |vauthors=Schiffer JT, Mayer BT, Fong Y, Swan DA, Wald A | title = Herpes simplex virus-2 transmission probability estimates based on quantity of viral shedding | journal = J R Soc Interface | volume = 11 | issue = 95 | pages = 20140160 | year = 2014 | pmid = 24671939 | doi = 10.1098/rsif.2014.0160 | pmc = 4006256 }}</ref> 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").<ref name=Johnstonetal_2011>{{Cite journal |vauthors=Johnston C, Koelle DM, Wald A | title = HSV-2: in pursuit of a vaccine. | journal = J Clin Invest | volume = 121 | issue = 12 | pages = 4600–9 |date=Dec 2011 | doi = 10.1172/JCI57148 | pmid = 22133885 | pmc=3223069}}</ref> |
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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.<ref name="pmid18157071">{{cite journal |vauthors=Sperling RS, Fife KH, Warren TJ, Dix LP, Brennan CA | title = The effect of daily valacyclovir suppression on herpes simplex virus type 2 viral shedding in HSV-2 seropositive subjects without a history of genital herpes | journal = Sex Transm Dis | volume = 35 | issue = 3 | pages = 286–90 |date=March 2008 | pmid = 18157071 | doi = 10.1097/OLQ.0b013e31815b0132 | s2cid = 20687438 }}</ref> |
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.<ref name="pmid18157071">{{cite journal |vauthors=Sperling RS, Fife KH, Warren TJ, Dix LP, Brennan CA | title = The effect of daily valacyclovir suppression on herpes simplex virus type 2 viral shedding in HSV-2 seropositive subjects without a history of genital herpes | journal = Sex Transm Dis | volume = 35 | issue = 3 | pages = 286–90 |date=March 2008 | pmid = 18157071 | doi = 10.1097/OLQ.0b013e31815b0132 | s2cid = 20687438 | doi-access = free }}</ref> |
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For HSV-2, subclinical shedding may account for most of the transmission.<ref name=Johnstonetal_2011/> Studies on discordant partners (one infected with HSV-2, one not) show that the transmission rate is approximately |
For HSV-2, subclinical shedding may account for most of the transmission.<ref name=Johnstonetal_2011/> 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.<ref>{{cite journal | vauthors = Wald A, Langenberg AG, Link K, Izu AE, Ashley R, Warren T, Tyring S, Douglas JM, Corey L | title = Effect of condomsonreducing the transmissionofherpes simplex virus type2from mentowomen | journal = JAMA | volume = 285 | issue = 24 | pages = 3100–3106 | date = June 2001 | pmid = 11427138 | doi = 10.1001/jama.285.24.3100 | doi-access = free }}</ref> Atypical symptoms are often attributed to other causes, such as a [[yeast infection]].<ref name="pmid18156035">{{cite journal | vauthors = Gupta R, Warren T, Wald A | title = Genital herpes | journal = Lancet | volume = 370 | issue = 9605 | pages = 2127–2137 | date = December 2007 | pmid = 18156035 | doi = 10.1016/S0140-6736(07)61908-4 | s2cid = 40916450 }}</ref><ref name="PMID_18186706"/> HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as [[kissing]] and [[oral sex]].<ref>{{cite web|title=EVERYTHING YOU NEED TO KNOW ABOUT HERPES|url=http://medweb.mit.edu/wellness/programs/herpes.html|date=2017-12-11}}</ref> Historically HSV-2 was primarily a sexually transmitted infection, but rates of HSV-1 genital infections have been increasing for the last few decades.<ref name="pmid18156035"/> |
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Both viruses may also be [[Vertically transmitted infection|transmitted vertically]] during childbirth.<ref name="pmid19797284">{{cite journal |vauthors=Corey L, Wald A | title = Maternal and |
Both viruses may also be [[Vertically transmitted infection|transmitted vertically]] during childbirth.<ref name="pmid19797284">{{cite journal | vauthors = Corey L, Wald A | title = Maternal and neonatal herpes simplex virus infections | journal = The New England Journal of Medicine | volume = 361 | issue = 14 | pages = 1376–1385 | date = October 2009 | pmid = 19797284 | pmc = 2780322 | doi = 10.1056/NEJMra0807633 }}</ref><ref>{{cite journal | vauthors = Usatine RP, TinitiganR| title = Nongenital herpes simplex virus | journal = American Family Physician | volume = 82 | issue = 9 | pages = 1075–1082 | date = November 2010 | pmid = 21121552 | url = https://pubmed.ncbi.nlm.nih.gov/21121552/ }}</ref> 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.<ref name="pmid17317423">{{cite journal | vauthors = Kimberlin DW | title = Herpes simplex virus infections of the newborn | journal = Seminars in Perinatology | volume = 31 | issue = 1 | pages = 19–25 | date = February 2007 | pmid = 17317423 | doi = 10.1053/j.semperi.2007.01.003 }}</ref> 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.<ref>{{Cite web |title=Mijn kind heeft blaasjes in de mond door herpes {{!}} Thuisarts.nl |url=https://www.thuisarts.nl/mondproblemen/mijn-kind-heeft-blaasjes-in-mond-door-herpes |access-date=2022-12-18 |website=www.thuisarts.nl |date=21 September 2022 |language=nl}}</ref><ref>{{cite web |title=Can You Catch STDs From A Toilet Seat? |url=https://www.mylabbox.com/can-you-catch-std-toilet-seat/ |website=mylabbox.com |access-date=16 July 2019|date=2019-02-12 }}</ref><ref>{{cite journal | vauthors = García-García B, Galache-Osuna C, Coto-Segura P, Suárez-Casado H, Mallo-García S, JiménezJS | title = Unusual presentation of herpes simplex virus infection in a boxer: 'Boxing glove herpes' | journal = The Australasian Journal of Dermatology | volume = 54 | issue = 1 | pages = e22–e24 | date = February 2013 | pmid = 23373892 | doi = 10.1111/j.1440-0960.2011.00815.x | s2cid = 11353611 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Suissa CA, Upadhyay R, Dabney MD, Mack RJ, Masica D, MarguliesBJ | title = Investigating the survival of herpes simplex virus on toothbrushes and surrogate phallic devices | journal = International Journal of STD & AIDS | volume = 34 | issue = 3 | pages = 152–158 | date = March 2023 | pmid = 36448203 | doi = 10.1177/09564624221142380 | s2cid = 254095088 }}</ref> |
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Herpes simplex viruses can affect areas of skin exposed to contact with an infected person |
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 prior to the routine use of gloves when treating patients. Shaking hands with an infected person does not transmit this disease.<ref>{{cite book | chapter = Chapter 1 - Vesiculobullous Diseases|date=2012-01-01 | title = Oral Pathology | edition = Sixth |pages=1–21| veditors = Regezi JA, Sciubba JJ, Jordan RC |place=St. Louis|publisher=W.B. Saunders |doi=10.1016/B978-1-4557-0262-6.00001-X |hdl=20.500.12613/9321 |language=en |isbn=978-1-4557-0262-6 }}</ref> Genital infection of HSV-2 increases the risk of acquiring [[HIV]].<ref>{{cite journal | vauthors = Looker KJ, Elmes JA, Gottlieb SL, Schiffer JT, Vickerman P, Turner KM, Boily MC | title = Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis | journal = The Lancet. Infectious Diseases | volume = 17 | issue = 12 | pages = 1303–1316 | date = December 2017 | pmid = 28843576 | pmc = 5700807 | doi = 10.1016/S1473-3099(17)30405-X }}</ref> |
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==Virology== |
==Virology== |
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HSV has been a model virus for many studies in molecular biology. For instance, one of the first functional [[Promoter (genetics)|promoters]] in [[eukaryote]]s was discovered in HSV (of the [[thymidine kinase]] gene) and the virion protein [[Herpes simplex virus protein vmw65|VP16]] is one of the most-studied [[Activator (genetics)|transcriptional activators]].<ref name=":1">{{ |
HSV has been a model virus for many studies in molecular biology. For instance, one of the first functional [[Promoter (genetics)|promoters]] in [[eukaryote]]s was discovered in HSV (of the [[thymidine kinase]] gene) and the virion protein [[Herpes simplex virus protein vmw65|VP16]] is one of the most-studied [[Activator (genetics)|transcriptional activators]].<ref name=":1">{{cite journal | vauthors = Taylor TJ, Brockman MA, McNamee EE, KnipeDM | title = Herpes simplex virus | journal = Frontiers in Bioscience | volume = 7 | issue = 1–3 | pages = d752–d764 | date = March 2002 | pmid = 11861220 | doi = 10.2741/taylor | doi-access = free }}</ref> |
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===Viral |
===Viral structure=== |
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[[File:A-Tail-like-Assembly-at-the-Portal-Vertex-in-Intact-Herpes-Simplex-Type-1-Virions-ppat.1002961.s003.ogv|thumb|A three-dimensional reconstruction and animation of a tail-like assembly on HSV-1 capsid]] |
[[File:A-Tail-like-Assembly-at-the-Portal-Vertex-in-Intact-Herpes-Simplex-Type-1-Virions-ppat.1002961.s003.ogv|thumb|A three-dimensional reconstruction and animation of a tail-like assembly on HSV-1 capsid]] |
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[[File:HSV-1-EM.png|thumb|3D reconstruction of the HSV-1 capsid]] |
[[File:HSV-1-EM.png|thumb|3D reconstruction of the HSV-1 capsid]] |
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[[File:HSV 2.jpg|thumb|Herpes |
[[File:HSV 2.jpg|thumb|Herpes simplex virus2 capsid]] |
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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 [[icosahedron|icosahedral]] protein cage called the [[capsid]], which is wrapped in a [[lipid bilayer]] called the [[Envelope (biology)|envelope]]. The envelope is joined to the capsid by means of a [[Viral tegument|tegument]]. This complete particle is known as the [[virion]].<ref name="pmid16814597">{{cite journal |vauthors=Mettenleiter TC, Klupp BG, Granzow H | title = Herpesvirus assembly: a tale of two membranes | journal = Curr. Opin. Microbiol. | volume = 9 | issue = 4 | pages = 423–9 | year = 2006 | pmid = 16814597 | doi = 10.1016/j.mib.2006.06.013 }}</ref> HSV-1 and HSV-2 each contain at least 74 genes (or [[open reading frames]], ORFs) within their genomes,<ref name="pmid16490275">{{cite journal |vauthors=McGeoch DJ, Rixon FJ, Davison AJ | title = Topics in herpesvirus genomics and evolution | journal = Virus Res. | volume = 117 | issue = 1 | pages = 90–104 | year = 2006 | pmid = 16490275 | doi = 10.1016/j.virusres.2006.01.002 }}</ref> although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.<ref name="pmid15266111">{{cite journal |vauthors=Rajcáni J, Andrea V, Ingeborg R | title = Peculiarities of herpes simplex virus (HSV) transcription: an overview | journal = Virus Genes | volume = 28 | issue = 3 | pages = 293–310 | year = 2004 | pmid = 15266111 | doi = 10.1023/B:VIRU.0000025777.62826.92 | s2cid = 19737920 }}</ref> 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|date=September 2020}} |
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 [[icosahedron|icosahedral]] protein cage called the [[capsid]], which is wrapped in a [[lipid bilayer]] called the [[Envelope (biology)|envelope]]. The envelope is joined to the capsid by means of a [[Viral tegument|tegument]]. This complete particle is known as the [[virion]].<ref name="pmid16814597">{{cite journal |vauthors=Mettenleiter TC, Klupp BG, Granzow H | title = Herpesvirus assembly: a tale of two membranes | journal = Curr. Opin. Microbiol. | volume = 9 | issue = 4 | pages = 423–9 | year = 2006 | pmid = 16814597 | doi = 10.1016/j.mib.2006.06.013 }}</ref> HSV-1 and HSV-2 each contain at least 74 genes (or [[open reading frames]], ORFs) within their genomes,<ref name="pmid16490275">{{cite journal |vauthors=McGeoch DJ, Rixon FJ, Davison AJ | title = Topics in herpesvirus genomics and evolution | journal = Virus Res. | volume = 117 | issue = 1 | pages = 90–104 | year = 2006 | pmid = 16490275 | doi = 10.1016/j.virusres.2006.01.002 }}</ref> although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.<ref name="pmid15266111">{{cite journal |vauthors=Rajcáni J, Andrea V, Ingeborg R | title = Peculiarities of herpes simplex virus (HSV) transcription: an overview | journal = Virus Genes | volume = 28 | issue = 3 | pages = 293–310 | year = 2004 | pmid = 15266111 | doi = 10.1023/B:VIRU.0000025777.62826.92 | s2cid = 19737920 }}</ref> 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|date=September 2020}} |
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The genomes of HSV-1 and HSV-2 are complex and contain two unique regions called the long unique region (U<sub>L</sub>) and the short unique region (U<sub>S</sub>). Of the 74 known ORFs, U<sub>L</sub> contains 56 viral genes, whereas U<sub>S</sub> contains only 12.<ref name="pmid16490275"/> Transcription of HSV genes is catalyzed by [[RNA polymerase II]] of the infected host.<ref name="pmid16490275"/> [[Immediate early gene]]s, which encode proteins for example ICP22<ref>{{ |
The genomes of HSV-1 and HSV-2 are complex and contain two unique regions called the long unique region (U<sub>L</sub>) and the short unique region (U<sub>S</sub>). Of the 74 known ORFs, U<sub>L</sub> contains 56 viral genes, whereas U<sub>S</sub> contains only 12.<ref name="pmid16490275"/> Transcription of HSV genes is catalyzed by [[RNA polymerase II]] of the infected host.<ref name="pmid16490275"/> [[Immediate early gene]]s, which encode proteins for example ICP22<ref>{{cite journal | vauthors = Isa NF, Bensaude O, Aziz NC, Murphy S | title = HSV-1 ICP22 Is a Selective Viral Repressor of Cellular RNA Polymerase II-Mediated Transcription Elongation | journal = Vaccines | volume = 9 | issue = 10 | pages = 1054 | date = September 2021 | pmid = 34696162 | pmc = 8539892 | doi = 10.3390/vaccines9101054 | doi-access = free }}</ref> that regulate the expression of early and late viral genes, are the first to be expressed following infection. [[early protein|Early gene]] expression follows, to allow the synthesis of [[enzyme]]s involved in [[DNA replication]] and the production of certain [[Viral envelope|envelope]] [[glycoprotein]]s. Expression of late genes occurs last; this group of genes predominantly encode proteins that form the virion particle.<ref name="pmid16490275"/> |
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Five proteins from (U<sub>L</sub>) form the viral capsid - [[HHV capsid portal protein|UL6]], UL18, UL35, UL38, and the major capsid protein UL19.<ref name="pmid16814597"/> |
Five proteins from (U<sub>L</sub>) form the viral capsid - [[HHV capsid portal protein|UL6]], UL18, UL35, UL38, and the major capsid protein UL19.<ref name="pmid16814597"/> |
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===Cellular |
===Cellular entry=== |
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[[File:HSV replication.png|thumb|right|350px|A simplified diagram of HSV replication]] |
[[File:HSV replication.png|thumb|right|350px|A simplified diagram of HSV replication]] |
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Entry of HSV into a host cell involves several [[glycoprotein]]s on the surface of the enveloped virus binding to their [[transmembrane receptor]]s 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.<ref name="ACSID-P">{{cite journal |vauthors=Clarke RW| title = Forces and Structures of the Herpes Simplex Virus (HSV) Entry Mechanism | journal = ACS Infectious Diseases | volume = 1 | issue = 9 | pages = 403–415 | year = 2015 | doi = 10.1021/acsinfecdis.5b00059 | pmid = 27617923 | url = https://www.repository.cam.ac.uk/handle/1810/257391 }}</ref> 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|date=September 2020}} |
Entry of HSV into a host cell involves several [[glycoprotein]]s on the surface of the enveloped virus binding to their [[transmembrane receptor]]s 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.<ref name="ACSID-P">{{cite journal |vauthors=Clarke RW| title = Forces and Structures of the Herpes Simplex Virus (HSV) Entry Mechanism | journal = ACS Infectious Diseases | volume = 1 | issue = 9 | pages = 403–415 | year = 2015 | doi = 10.1021/acsinfecdis.5b00059 | pmid = 27617923 | url = https://www.repository.cam.ac.uk/handle/1810/257391 }}</ref> 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|date=September 2020}} |
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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 [[polysaccharide]] called [[heparan sulfate]]. Next, the major receptor binding protein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors.<ref>{{cite journal |vauthors=Akhtar J, Shukla D | title = Viral entry mechanisms: Cellular and viral mediators of herpes simplex virus entry | journal = FEBS Journal | volume = 276 | issue = 24 | pages = 7228–7236 | year = 2009 | pmid = 19878306 | pmc = 2801626 | doi = 10.1111/j.1742-4658.2009.07402.x }}</ref> These cell receptors include herpesvirus entry mediator ([[TNFRSF14|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.<ref name="ACSID-P"/> 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.<ref name="Subramanian_17299053"/> gB interacts with [[glycosaminoglycan]]s on the surface of the host cell. {{Citation needed|date=February 2015}} |
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 [[polysaccharide]] called [[heparan sulfate]]. Next, the major receptor binding protein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors.<ref>{{cite journal |vauthors=Akhtar J, Shukla D | title = Viral entry mechanisms: Cellular and viral mediators of herpes simplex virus entry | journal = FEBS Journal | volume = 276 | issue = 24 | pages = 7228–7236 | year = 2009 | pmid = 19878306 | pmc = 2801626 | doi = 10.1111/j.1742-4658.2009.07402.x }}</ref> These cell receptors include herpesvirus entry mediator ([[TNFRSF14|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.<ref name="ACSID-P"/> 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.<ref name="Subramanian_17299053"/> gB interacts with [[glycosaminoglycan]]s on the surface of the host cell. {{Citation needed|date=February 2015}} |
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===Genetic |
===Genetic inoculation=== |
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After the viral capsid enters the cellular [[cytoplasm]], it is transported to the [[cell nucleus]]. 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 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.<ref name="pmid17188319"> |
After the viral capsid enters the cellular [[cytoplasm]], it starts to express viral protein [https://www.uniprot.org/uniprotkb/P10238/entry ICP27]. ICP27is a regulator protein that causes disruption in host protein synthesis and utilizes it for viral replication. ICP27 binds with a cellular enzyme [[SRPK1|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]].<ref>{{cite journal | vauthors = Tunnicliffe RB, Hu WK, Wu MY, Levy C, Mould AP, McKenzie EA, Sandri-Goldin RM, Golovanov AP | title = Molecular Mechanism of SR Protein Kinase 1 Inhibition by the Herpes Virus Protein ICP27 | journal = mBio | volume = 10 | issue = 5 | pages = e02551–19 | date = October 2019 | pmid = 31641093 | pmc = 6805999 | doi = 10.1128/mBio.02551-19 | veditors = Damania B }}</ref> 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 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.<ref name="pmid17188319"> |
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{{cite journal |vauthors=Cardone G, Winkler DC, Trus BL, Cheng N, Heuser JE, Newcomb WW, Brown JC, Steven AC | title = Visualization of the Herpes Simplex Virus Portal in situ by Cryo-electron Tomography | journal = Virology | volume = 361 | issue = 2 | pages = 426–34 | date = May 2007 | pmid = 17188319 | pmc = 1930166 | doi = 10.1016/j.virol.2006.10.047 }} |
{{cite journal |vauthors=Cardone G, Winkler DC, Trus BL, Cheng N, Heuser JE, Newcomb WW, Brown JC, Steven AC | title = Visualization of the Herpes Simplex Virus Portal in situ by Cryo-electron Tomography | journal = Virology | volume = 361 | issue = 2 | pages = 426–34 | date = May 2007 | pmid = 17188319 | pmc = 1930166 | doi = 10.1016/j.virol.2006.10.047 }} |
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</ref> Each [[icosahedral]] capsid contains a single portal, located in one [[Vertex (geometry)|vertex]].<ref name="pmid15507654">{{cite journal |vauthors=Trus BL, Cheng N, Newcomb WW, Homa FL, Brown JC, Steven AC | title = Structure and Polymorphism of the UL6 Portal Protein of Herpes Simplex Virus Type 1 | journal = Journal of Virology | volume = 78 | issue = 22 | pages = 12668–71 | date = November 2004 | pmid = 15507654 | pmc = 525097 | doi = 10.1128/JVI.78.22.12668-12671.2004 }} |
</ref> Each [[icosahedral]] capsid contains a single portal, located in one [[Vertex (geometry)|vertex]].<ref name="pmid15507654">{{cite journal |vauthors=Trus BL, Cheng N, Newcomb WW, Homa FL, Brown JC, Steven AC | title = Structure and Polymorphism of the UL6 Portal Protein of Herpes Simplex Virus Type 1 | journal = Journal of Virology | volume = 78 | issue = 22 | pages = 12668–71 | date = November 2004 | pmid = 15507654 | pmc = 525097 | doi = 10.1128/JVI.78.22.12668-12671.2004 }} |
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The DNA exits the capsid in a single linear segment.<ref name="pmid17540405">{{cite journal |vauthors=Newcomb WW, Booy FP, Brown JC | title = Uncoating the Herpes Simplex Virus Genome | journal = J. Mol. Biol. | volume = 370 | issue = 4 | pages = 633–42 | year = 2007 | pmid = 17540405 | pmc = 1975772 | doi = 10.1016/j.jmb.2007.05.023 }}</ref> |
The DNA exits the capsid in a single linear segment.<ref name="pmid17540405">{{cite journal |vauthors=Newcomb WW, Booy FP, Brown JC | title = Uncoating the Herpes Simplex Virus Genome | journal = J. Mol. Biol. | volume = 370 | issue = 4 | pages = 633–42 | year = 2007 | pmid = 17540405 | pmc = 1975772 | doi = 10.1016/j.jmb.2007.05.023 }}</ref> |
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===Immune |
===Immune evasion=== |
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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 activation of cytotoxic T-lymphocytes (CTLs), the major effectors of the cell-mediated immune response against virally-infected cells. ICP-47 prevents initiation of a CTL-response against HSV, allowing the virus to survive for a protracted period in the host.<ref name=pmid10775582>{{cite journal | vauthors = Berger C, Xuereb S, Johnson DC, Watanabe KS, Kiem HP, Greenberg PD, Riddell SR | title = Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes | journal = Journal of Virology | volume = 74 | issue = 10 | pages = 4465–73 | date = May 2000 | pmid = 10775582 | pmc = 111967 | doi = 10.1128/jvi.74.10.4465-4473.2000 }}</ref> 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 level 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.<ref name=pmid35079057>{{cite journal | vauthors = Roy S, Sukla S, De A, Biswas S | title = Non-cytopathic herpes simplex virus type-1 isolated from acyclovir-treated patients with recurrent infections | journal = Scientific Reports | volume = 12 | date = January 2022 | issue = 1 | page = 1345 | pmid = 35079057 | pmc = 8789845 | doi = 10.1038/s41598-022-05188-w | bibcode = 2022NatSR..12.1345R }}</ref> |
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 activation of cytotoxic T-lymphocytes (CTLs), the major effectors of the cell-mediated immune response against virally-infected cells. ICP-47 prevents initiation of a CTL-response against HSV, allowing the virus to survive for a protracted period in the host.<ref name=pmid10775582>{{cite journal | vauthors = Berger C, Xuereb S, Johnson DC, Watanabe KS, Kiem HP, Greenberg PD, Riddell SR | title = Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes | journal = Journal of Virology | volume = 74 | issue = 10 | pages = 4465–73 | date = May 2000 | pmid = 10775582 | pmc = 111967 | doi = 10.1128/jvi.74.10.4465-4473.2000 }}</ref> 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 level 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.<ref name=pmid35079057>{{cite journal | vauthors = Roy S, Sukla S, De A, Biswas S | title = Non-cytopathic herpes simplex virus type-1 isolated from acyclovir-treated patients with recurrent infections | journal = Scientific Reports | volume = 12 | date = January 2022 | issue = 1 | page = 1345 | pmid = 35079057 | pmc = 8789845 | doi = 10.1038/s41598-022-05188-w | bibcode = 2022NatSR..12.1345R }}</ref> |
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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 the capsid - occurs in the nucleus of the cell. Here, [[concatemer]]s 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 [[Vesicle (biology)|vesicles]].<ref>{{cite journal |vauthors=Granzow H, Klupp BG, Fuchs W, Veits J, Osterrieder N, Mettenleiter TC | title = Egress of Alphaherpesviruses: Comparative Ultrastructural Study | journal = J. Virol. | volume = 75 | issue = 8 | pages = 3675–84 | date = April 2001 | pmid = 11264357 | pmc = 114859 | doi = 10.1128/JVI.75.8.3675-3684.2001 }}</ref> |
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 the capsid - occurs in the nucleus of the cell. Here, [[concatemer]]s 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 [[Vesicle (biology)|vesicles]].<ref>{{cite journal |vauthors=Granzow H, Klupp BG, Fuchs W, Veits J, Osterrieder N, Mettenleiter TC | title = Egress of Alphaherpesviruses: Comparative Ultrastructural Study | journal = J. Virol. | volume = 75 | issue = 8 | pages = 3675–84 | date = April 2001 | pmid = 11264357 | pmc = 114859 | doi = 10.1128/JVI.75.8.3675-3684.2001 }}</ref> |
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===Latent |
===Latent infection=== |
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HSVs may persist in a quiescent but persistent form known as latent infection, notably in [[Ganglion|neural ganglia]].<ref name=Sherris /> HSV-1 tends to reside in the [[trigeminal ganglion|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 [[HHV Latency Associated Transcript|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|date=September 2020}} |
HSVs may persist in a quiescent but persistent form known as latent infection, notably in [[Ganglion|neural ganglia]].<ref name=Sherris /> The HSV genome circular DNA resides in the [[cell nucleus]] as an [[episome]].<ref>{{cite Q |1=Q94509178}}</ref> HSV-1 tends to reside in the [[trigeminal ganglion|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 [[HHV Latency Associated Transcript|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|date=September 2020}} |
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A protein found in neurons may bind to herpes virus DNA and regulate [[Virus latency|latency]]. Herpes virus DNA contains a gene for a protein called ICP4, which is an important [[Transactivation|transactivator]] of genes associated with lytic infection in HSV-1.<ref name="PMID17555596">{{cite journal |vauthors=Pinnoji RC, Bedadala GR, George B, Holland TC, Hill JM, Hsia SC | title = Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification | journal = Virol. J. | volume = 4 | pages = 56 | year = 2007 | pmid = 17555596 | pmc = 1906746 | doi = 10.1186/1743-422X-4-56 }}</ref> Elements surrounding the gene for ICP4 bind a protein known as the human neuronal protein neuronal restrictive silencing factor (NRSF) or [[REST (gene)|human repressor element silencing transcription factor (REST)]]. When bound to the viral DNA elements, [[histone|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.<ref name="PMID17555596"/><ref name="pmid17502875">{{cite journal |vauthors=Bedadala GR, Pinnoji RC, Hsia SC | title = Early growth response gene 1 (Egr-1) regulates HSV-1 ICP4 and ICP22 gene expression | journal = Cell Res. | volume = 17 | issue = 6 | pages = 546–55 | year = 2007 | pmid = 17502875 | doi = 10.1038/cr.2007.44 | pmc = 7092374 | doi-access = free }}</ref> Another HSV protein reverses the inhibition of ICP4 protein synthesis. [[HHV Infected Cell Polypeptide 0 (ICP0)|ICP0]] dissociates NRSF from the ''ICP4'' gene and thus prevents silencing of the viral DNA.<ref name="pmid16082207">{{cite journal |vauthors=Roizman B, Gu H, Mandel G | title = The first 30 minutes in the life of a virus: unREST in the nucleus | journal = Cell Cycle | volume = 4 | issue = 8 | pages = 1019–21 | year = 2005 | pmid = 16082207 | doi = 10.4161/cc.4.8.1902 | doi-access = free }}</ref> |
{{anchor|ICP4}} A protein found in neurons may bind to herpes virus DNA and regulate [[Virus latency|latency]]. Herpes virus DNA contains a gene for a protein called ICP4, which is an important [[Transactivation|transactivator]] of genes associated with lytic infection in HSV-1.<ref name="PMID17555596">{{cite journal |vauthors=Pinnoji RC, Bedadala GR, George B, Holland TC, Hill JM, Hsia SC | title = Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification | journal = Virol. J. | volume = 4 | pages = 56 | year = 2007 | pmid = 17555596 | pmc = 1906746 | doi = 10.1186/1743-422X-4-56 | doi-access = free }}</ref> Elements surrounding the gene for ICP4 bind a protein known as the human neuronal protein neuronal restrictive silencing factor (NRSF) or [[REST (gene)|human repressor element silencing transcription factor (REST)]]. When bound to the viral DNA elements, [[histone|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.<ref name="PMID17555596"/><ref name="pmid17502875">{{cite journal |vauthors=Bedadala GR, Pinnoji RC, Hsia SC | title = Early growth response gene 1 (Egr-1) regulates HSV-1 ICP4 and ICP22 gene expression | journal = Cell Res. | volume = 17 | issue = 6 | pages = 546–55 | year = 2007 | pmid = 17502875 | doi = 10.1038/cr.2007.44 | pmc = 7092374 | doi-access = free }}</ref> Another HSV protein reverses the inhibition of ICP4 protein synthesis. [[HHV Infected Cell Polypeptide 0 (ICP0)|ICP0]] dissociates NRSF from the ''ICP4'' gene and thus prevents silencing of the viral DNA.<ref name="pmid16082207">{{cite journal |vauthors=Roizman B, Gu H, Mandel G | title = The first 30 minutes in the life of a virus: unREST in the nucleus | journal = Cell Cycle | volume = 4 | issue = 8 | pages = 1019–21 | year = 2005 | pmid = 16082207 | doi = 10.4161/cc.4.8.1902 | doi-access = free }}</ref> |
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=== Genome === |
=== Genome === |
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|E3 [[ubiquitin]] ligase that activates viral gene transcription by opposing chromatinization of the viral genome and counteracts intrinsic- and [[interferon]]-based antiviral responses.<ref name="pmid 21765858">{{cite journal|vauthors=Smith MC, Boutell C, Davido DJ|year=2011|title=HSV-1 ICP0: paving the way for viral replication|journal=Future Virology|volume=6|issue=4|pages=421–429|doi=10.2217/fvl.11.24|pmc=3133933|pmid=21765858}}</ref> |
|E3 [[ubiquitin]] ligase that activates viral gene transcription by opposing chromatinization of the viral genome and counteracts intrinsic- and [[interferon]]-based antiviral responses.<ref name="pmid 21765858">{{cite journal|vauthors=Smith MC, Boutell C, Davido DJ|year=2011|title=HSV-1 ICP0: paving the way for viral replication|journal=Future Virology|volume=6|issue=4|pages=421–429|doi=10.2217/fvl.11.24|pmc=3133933|pmid=21765858}}</ref> |
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|[[RL1]]||RL1; [[ICP34.5]] || {{UniProt|O12396}} || ||Neurovirulence factor. Antagonizes [[Protein kinase R|PKR]] by de-phosphorylating eIF4a. Binds to [[beclin|BECN1]] and inactivates [[autophagy]]. |
|[[RL1]]||RL1; [[ICP34.5]] || {{UniProt|O12396}} || {{uniprot|P28283}}||Neurovirulence factor. Antagonizes [[Protein kinase R|PKR]] by de-phosphorylating eIF4a. Binds to [[beclin|BECN1]] and inactivates [[autophagy]]. |
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|[[HHV Latency Associated Transcript|LAT]] ||LRP1, LRP2 || {{UniProt|P17588}}<br />{{UniProt|P17589}} || ||Latency-associated transcript abd protein products (latency-related protein) |
|[[HHV Latency Associated Transcript|LAT]] ||LRP1, LRP2 || {{UniProt|P17588}}<br />{{UniProt|P17589}} || ||Latency-associated transcript abd protein products (latency-related protein) |
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| UL1 || [[Glycoprotein]] L || {{UniProt|P10185}} |
| UL1 || [[Glycoprotein]] L || {{UniProt|P10185}} |
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|[https://www.uniprot.org/uniprotkb/P28278/ P28278] |
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|Surface and membrane |
|Surface and membrane |
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| UL2 || |
| UL2 ||Uracil-DNA glycosylase || {{UniProt|P10186}} |
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|{{uniprot|P13158}} {{uniprot|P28275}} |
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|[[Uracil-DNA glycosylase]] |
|[[Uracil-DNA glycosylase]] |
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| UL3 ||UL3 || {{UniProt|P10187}} |
| UL3 ||UL3 || {{UniProt|P10187}} {{uniprot|Q1XBW5}} |
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|{{uniprot|P0C012}} {{uniprot|P28279}} |
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|unknown |
|unknown |
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|- |
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| UL4 ||UL4 || {{UniProt|P10188}} |
| UL4 ||UL4 || {{UniProt|P10188}} |
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|{{uniprot|P28280}} |
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|unknown |
|unknown |
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|UL5 || |
|UL5 ||HELI || {{uniprot|P10189}} |
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|{{uniprot|P28277}} |
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| [[DNA |
| [[DNA helicase]] |
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|- |
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| UL6 ||[[HHV capsid portal protein|Portal protein U<sub>L</sub>-6]] || {{UniProt|P10190}} |
| UL6 ||[[HHV capsid portal protein|Portal protein U<sub>L</sub>-6]] || {{UniProt|P10190}} |
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Line 145: | Line 149: | ||
|Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid.<ref name="pmid17188319" /><ref name="pmid15507654" /><ref name="Nellissery_2007" /> |
|Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid.<ref name="pmid17188319" /><ref name="pmid15507654" /><ref name="Nellissery_2007" /> |
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| UL7 || |
| UL7 ||Cytoplasmic envelopment protein 1 || {{UniProt|P10191}} |
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|{{uniprot|P89430}} |
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|Virion maturation |
|Virion maturation |
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|UL8 || |
|UL8 ||DNA helicase/primase complex-associated protein || {{UniProt|P10192}} |
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|{{uniprot|P89431}} |
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|[[DNA virus]] [[helicase-primase complex]]-associated protein |
|[[DNA virus]] [[helicase-primase complex]]-associated protein |
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|UL9 || |
|UL9 ||Replication origin-binding protein || {{UniProt|P10193}} |
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|{{uniprot|P89432}} |
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|[[origin of replication|Replication origin]]-binding protein |
|[[origin of replication|Replication origin]]-binding protein |
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| UL10 ||Glycoprotein M || {{UniProt|P04288}} |
| UL10 ||Glycoprotein M || {{UniProt|P04288}} |
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|{{uniprot|P89433}} |
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|Surface and membrane |
|Surface and membrane |
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|- |
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| UL11 || |
| UL11 ||Cytoplasmic envelopment protein 3 || {{UniProt|P04289}} {{uniprot|Q68980}} |
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|{{uniprot|P13294}} |
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|virion exit and secondary envelopment |
|virion exit and secondary envelopment |
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|- |
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| UL12 || |
| UL12 ||Alkaline nuclease || {{uniprot|P04294}} |
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|{{uniprot|P06489}} |
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|[[Alkaline]] [[exonuclease]] |
|[[Alkaline]] [[exonuclease]] |
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| UL13 ||UL13 || {{ |
| UL13 ||UL13 || {{uniprot|P04290}} |
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|{{uniprot|P89436}} |
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|[[Serine]]-[[threonine]] [[protein kinase]] |
|[[Serine]]-[[threonine]] [[protein kinase]] |
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|- |
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| UL14 ||UL14 || {{UniProt|P04291}} |
| UL14 ||UL14 || {{UniProt|P04291}} |
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|{{uniprot|P89437}} |
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|[[Viral tegument|Tegument]] protein |
|[[Viral tegument|Tegument]] protein |
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| UL15 || |
| UL15 ||TRM3|| {{UniProt|P04295}} |
||
|{{uniprot|P89438}} |
|||
| |
|||
|Processing and packaging of DNA |
|Processing and packaging of DNA |
||
|- |
|- |
||
| UL16 ||UL16 || {{UniProt|P10200}} |
| UL16 ||UL16 || {{UniProt|P10200}} |
||
|{{uniprot|P89439}} |
|||
| |
|||
|Tegument protein |
|Tegument protein |
||
|- |
|- |
||
| UL17 || |
| UL17 ||CVC1 || {{UniProt|P10201}} |
||
| |
| |
||
|Processing and packaging DNA |
|Processing and packaging DNA |
||
|- |
|- |
||
| UL18 || |
| UL18 ||TRX2 || {{UniProt|P10202}} |
||
|{{uniprot|P89441}} |
|||
| |
|||
|[[Capsid]] protein |
|[[Capsid]] protein |
||
|- |
|- |
||
| UL19 ||VP5; ICP5 || {{UniProt|P06491}} |
| UL19 ||VP5; ICP5 || {{UniProt|P06491}} |
||
|[https://www.uniprot.org/uniprotkb/P89442 P89442] |
|||
| |
|||
|Major capsid protein |
|Major capsid protein |
||
|- |
|- |
||
| UL20 ||UL20 || {{UniProt|P10204}} |
| UL20 ||UL20 || {{UniProt|P10204}} |
||
|{{uniprot|P89443}} |
|||
| |
|||
|Membrane protein |
|Membrane protein |
||
|- |
|- |
||
| UL21 ||UL21 || {{UniProt|P10205}} |
| UL21 ||UL21 || {{UniProt|P10205}} {{uniprot|P09855}} |
||
|{{uniprot|P89444}} |
|||
| |
|||
|Tegument protein<ref name="pmid16014918">{{cite journal |vauthors=Vittone V, Diefenbach E, Triffett D, Douglas MW, Cunningham AL, Diefenbach RJ | title = Determination of Interactions between Tegument Proteins of Herpes Simplex Virus Type 1 | journal = J. Virol. | volume = 79 | issue = 15 | pages = 9566–71 | year = 2005 | pmid = 16014918 | pmc = 1181608 | doi = 10.1128/JVI.79.15.9566-9571.2005 }}</ref> |
|Tegument protein<ref name="pmid16014918">{{cite journal |vauthors=Vittone V, Diefenbach E, Triffett D, Douglas MW, Cunningham AL, Diefenbach RJ | title = Determination of Interactions between Tegument Proteins of Herpes Simplex Virus Type 1 | journal = J. Virol. | volume = 79 | issue = 15 | pages = 9566–71 | year = 2005 | pmid = 16014918 | pmc = 1181608 | doi = 10.1128/JVI.79.15.9566-9571.2005 }}</ref> |
||
|- |
|- |
||
| UL22 ||Glycoprotein H || {{UniProt|P06477}} |
| UL22 ||Glycoprotein H || {{UniProt|P06477}} |
||
|[https://www.uniprot.org/uniprotkb/P89445 P89445] |
|||
| |
|||
|Surface and membrane |
|Surface and membrane |
||
|- |
|- |
||
Line 225: | Line 229: | ||
|- |
|- |
||
| UL27 ||[[Herpesvirus glycoprotein B|Glycoprotein B]] || {{UniProt|A1Z0P5}} |
| UL27 ||[[Herpesvirus glycoprotein B|Glycoprotein B]] || {{UniProt|A1Z0P5}} |
||
|[https://www.uniprot.org/uniprotkb/P08666 P08666] |
|||
| |
|||
|Surface and membrane |
|Surface and membrane |
||
|- |
|- |
||
Line 280: | Line 284: | ||
| UL43 ||UL43 || {{UniProt|P10227}} || ||Membrane protein |
| UL43 ||UL43 || {{UniProt|P10227}} || ||Membrane protein |
||
|- |
|- |
||
| UL44 ||Glycoprotein C || {{UniProt|P10228}} || ||Surface and membrane |
| UL44 ||Glycoprotein C || {{UniProt|P10228}} || [https://www.uniprot.org/uniprot/Q89730 Q89730]||Surface and membrane |
||
|- |
|- |
||
| UL45 ||UL45 || {{UniProt|P10229}} || ||Membrane protein; C-type lectin<ref name="pmid18256535">{{cite journal|vauthors=Wyrwicz LS, Ginalski K, Rychlewski L|year=2007|title=HSV-1 UL45 encodes a carbohydrate binding C-type lectin protein|journal=Cell Cycle|volume=7|issue=2|pages=269–71|doi=10.4161/cc.7.2.5324|pmid=18256535|doi-access=free}}</ref> |
| UL45 ||UL45 || {{UniProt|P10229}} || ||Membrane protein; C-type lectin<ref name="pmid18256535">{{cite journal|vauthors=Wyrwicz LS, Ginalski K, Rychlewski L|year=2007|title=HSV-1 UL45 encodes a carbohydrate binding C-type lectin protein|journal=Cell Cycle|volume=7|issue=2|pages=269–71|doi=10.4161/cc.7.2.5324|pmid=18256535|doi-access=free}}</ref> |
||
Line 288: | Line 292: | ||
| UL47 ||UL47; VP13/14 || {{UniProt|P10231}} || ||Tegument protein |
| UL47 ||UL47; VP13/14 || {{UniProt|P10231}} || ||Tegument protein |
||
|- |
|- |
||
| UL48 ||VP16 (Alpha-TIF) || {{UniProt|P04486}} || ||Virion maturation; activate [[Immediate early gene|IE genes]] by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence <sup>5'</sup>TAATGARAT<sup>3'</sup>. |
| UL48 ||VP16 (Alpha-TIF) || {{UniProt|P04486}} || [https://www.uniprot.org/uniprot/Q89730 P68336]||Virion maturation; activate [[Immediate early gene|IE genes]] by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence <sup>5'</sup>TAATGARAT<sup>3'</sup>. |
||
|- |
|- |
||
| UL49 ||UL49A || {{UniProt|O09800}} || ||Envelope protein |
| UL49 ||UL49A || {{UniProt|O09800}} || ||Envelope protein |
||
Line 300: | Line 304: | ||
|UL53 ||Glycoprotein K || {{UniProt|P68333}} || ||Surface and membrane |
|UL53 ||Glycoprotein K || {{UniProt|P68333}} || ||Surface and membrane |
||
|- |
|- |
||
|UL54 ||IE63; ICP27 || {{UniProt|P10238}} || ||Transcriptional regulation and inhibition of the [[Stimulator of interferon genes|STING]] signalsome<ref name="ChristensenJensen2016">{{cite journal | vauthors = Christensen MH, Jensen SB, Miettinen JJ, Luecke S, Prabakaran T, Reinert LS, Mettenleiter T, Chen ZJ, Knipe DM, Sandri-Goldin RM, Enquist LW, Hartmann R, Mogensen TH, Rice SA, Nyman TA, Matikainen S, Paludan SR |
|UL54 ||IE63; ICP27 || {{UniProt|P10238}} || ||Transcriptional regulation and inhibition of the [[Stimulator of interferon genes|STING]] signalsome<ref name="ChristensenJensen2016">{{cite journal | vauthors = Christensen MH, Jensen SB, Miettinen JJ, Luecke S, Prabakaran T, Reinert LS, Mettenleiter T, Chen ZJ, Knipe DM, Sandri-Goldin RM, Enquist LW, Hartmann R, Mogensen TH, Rice SA, Nyman TA, Matikainen S, Paludan SR | title = HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression | journal = The EMBO Journal | volume = 35 | issue = 13 | pages = 1385–99 | date = July 2016 | pmid = 27234299 | pmc = 4931188 | doi = 10.15252/embj.201593458 }}</ref> |
||
|- |
|- |
||
|UL55 ||UL55 || {{UniProt|P10239}} || ||Unknown |
|UL55 ||UL55 || {{UniProt|P10239}} || ||Unknown |
||
Line 318: | Line 322: | ||
|[[HHV US3|US3]]||US3 || {{UniProt|P04413}} || ||Serine/threonine-protein kinase |
|[[HHV US3|US3]]||US3 || {{UniProt|P04413}} || ||Serine/threonine-protein kinase |
||
|- |
|- |
||
|US4 ||Glycoprotein G || {{UniProt|P06484}} || ||Surface and membrane |
|US4 ||Glycoprotein G || {{UniProt|P06484}} || [https://www.uniprot.org/uniprot/P13290 P13290]||Surface and membrane |
||
|- |
|- |
||
|[[HHV US5|US5]]||Glycoprotein J || {{UniProt|P06480}} || ||Surface and membrane |
|[[HHV US5|US5]]||Glycoprotein J || {{UniProt|P06480}} || ||Surface and membrane |
||
|- |
|- |
||
|[[HHV US6|US6]]||Glycoprotein D || {{UniProt|A1Z0Q5}} || ||Surface and membrane |
|[[HHV US6|US6]]||Glycoprotein D || {{UniProt|A1Z0Q5}} || [https://www.uniprot.org/uniprot/Q69467 Q69467]||Surface and membrane |
||
|- |
|- |
||
|US7 ||Glycoprotein I || {{UniProt|P06487}} || ||Surface and membrane |
|US7 ||Glycoprotein I || {{UniProt|P06487}} || ||Surface and membrane |
||
|- |
|- |
||
|US8 ||Glycoprotein E || {{UniProt|Q703F0}} || ||Surface and membrane |
|US8 ||Glycoprotein E || {{UniProt|Q703F0}} || [https://www.uniprot.org/uniprotkb/P89475 P89475]||Surface and membrane |
||
|- |
|- |
||
|US9 ||US9 || {{UniProt|P06481}} || ||Tegument protein |
|US9 ||US9 || {{UniProt|P06481}} || ||Tegument protein |
||
Line 348: | Line 352: | ||
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.<ref name=":1" /> |
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.<ref name=":1" /> |
||
Importantly, HSV shuts down host cell RNA, DNA and protein synthesis to direct cellular resources to virus production. First, the virus |
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 [[Messenger RNA|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.<ref name=":1" /> |
||
==Evolution== |
==Evolution== |
||
The herpes simplex 1 genomes can be classified into six [[clade]]s.<ref name=Kolb2013>{{cite journal |vauthors=Kolb AW, Ané C, Brandt CR | year = 2013 | title = Using HSV-1 genome phylogenetics to track past human migrations | journal = PLOS ONE | volume = 8 | issue = 10| page = e76267 | doi = 10.1371/journal.pone.0076267 | pmid=24146849 | pmc=3797750| bibcode = 2013PLoSO...876267K | doi-access = free }}</ref> 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.<ref name=Bowden2006>{{cite journal |vauthors=Bowden R, Sakaoka H, Ward R, Donnelly P | year = 2006 | title = Patterns of Eurasian HSV-1 molecular diversity and inferences of human migrations | journal = Infect Genet Evol | volume = 6 | issue = 1| pages = 63–74 | doi=10.1016/j.meegid.2005.01.004| pmid = 16376841 }}</ref> 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]].<ref name="Bowden2006" /> |
The herpes simplex 1 genomes can be classified into six [[clade]]s.<ref name=Kolb2013>{{cite journal |vauthors=Kolb AW, [[Cécile Ané|Ané C]], Brandt CR | year = 2013 | title = Using HSV-1 genome phylogenetics to track past human migrations | journal = PLOS ONE | volume = 8 | issue = 10| page = e76267 | doi = 10.1371/journal.pone.0076267 | pmid=24146849 | pmc=3797750| bibcode = 2013PLoSO...876267K | doi-access = free }}</ref> 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.<ref name=Bowden2006>{{cite journal |vauthors=Bowden R, Sakaoka H, Ward R, Donnelly P | year = 2006 | title = Patterns of Eurasian HSV-1 molecular diversity and inferences of human migrations | journal = Infect Genet Evol | volume = 6 | issue = 1| pages = 63–74 | doi=10.1016/j.meegid.2005.01.004| pmid = 16376841 }}</ref> 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]].<ref name="Bowden2006" /> |
||
Herpes simplex 2 genomes can be divided into two groups: one is globally distributed and the other is mostly limited to [[sub Saharan Africa]].<ref name=Burrel2017>{{cite journal | |
Herpes simplex 2 genomes can be divided into two groups: one is globally distributed and the other is mostly limited to [[sub Saharan Africa]].<ref name=Burrel2017>{{cite journal | vauthors = Burrel S, Boutolleau D, Ryu D, Agut H, Merkel K, Leendertz FH, Calvignac-Spencer S | title = Ancient Recombination Events between Human Herpes Simplex Viruses | journal = Molecular Biology and Evolution | volume = 34 | issue = 7 | pages = 1713–1721 | date = July 2017 | pmid = 28369565 | pmc = 5455963 | doi = 10.1093/molbev/msx113 | doi-access = free }}</ref> 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.<ref name=Casto2019>{{cite journal | vauthors = Casto AM, Roychoudhury P, Xie H, Selke S, Perchetti GA, Wofford H, Huang ML, Verjans GM, Gottlieb GS, Wald A, Jerome KR, Koelle DM, Johnston C, Greninger AL | title = Large, Stable, Contemporary Interspecies Recombination EventsinCirculating Human Herpes Simplex Viruses | journal = The Journal of Infectious Diseases | volume = 221 | issue = 8 | pages = 1271–1279 | date = March 2020 | pmid = 31016321 | pmc = 7325804 | doi = 10.1093/infdis/jiz199 | author14-link = Alexander L. Greninger | doi-access = free | biorxiv = 10.1101/472639 }}</ref> |
||
The mutation rate has been estimated to be ~1.38×10<sup>−7</sup> substitutions/site/year.<ref name="Kolb2013"/> In clinical setting, |
The mutation rate has been estimated to be ~1.38×10<sup>−7</sup> substitutions/site/year.<ref name="Kolb2013"/> 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.<ref name=Hussin2013>{{cite journal | vauthors = Hussin A, Md Nor NS, Ibrahim N | title = Phenotypic and genotypic characterization of induced acyclovir-resistant clinical isolates of herpes simplex virus type 1 | journal = Antiviral Research | volume = 100 | issue = 2 | pages = 306–13 | date = November 2013 | pmid = 24055837 | doi = 10.1016/j.antiviral.2013.09.008 }}</ref> |
||
Another analysis has estimated the mutation rate in the herpes simplex 1 genome to be 1.82×10<sup>−8</sup> nucleotide substitution per site per year. This analysis placed the most recent common ancestor of this virus ~710,000 years ago.<ref name=Norberg2011>{{cite journal | vauthors = Norberg P, Tyler S, Severini A, Whitley R, Liljeqvist JÅ, Bergström T | title = A genome-wide comparative evolutionary analysis of herpes simplex virus type 1 and varicella zoster virus | journal = PLOS ONE | volume = 6 | issue = 7 | pages = e22527 | date = 2011 | pmid = 21799886 | pmc = 3143153 | doi = 10.1371/journal.pone.0022527 | bibcode = 2011PLoSO...622527N | doi-access = free }}</ref> |
Another analysis has estimated the mutation rate in the herpes simplex 1 genome to be 1.82×10<sup>−8</sup> nucleotide substitution per site per year. This analysis placed the most recent common ancestor of this virus ~710,000 years ago.<ref name=Norberg2011>{{cite journal | vauthors = Norberg P, Tyler S, Severini A, Whitley R, Liljeqvist JÅ, Bergström T | title = A genome-wide comparative evolutionary analysis of herpes simplex virus type 1 and varicella zoster virus | journal = PLOS ONE | volume = 6 | issue = 7 | pages = e22527 | date = 2011 | pmid = 21799886 | pmc = 3143153 | doi = 10.1371/journal.pone.0022527 | bibcode = 2011PLoSO...622527N | doi-access = free }}</ref> |
||
Line 367: | Line 371: | ||
Similar to other [[herpesviridae]], the herpes simplex viruses establish latent lifelong infection, and thus cannot be eradicated from the body with current treatments.<ref name="CDC2017Bas2">{{cite web|url=https://www.cdc.gov/std/Herpes/STDFact-Herpes.htm|title=STD Facts – Genital Herpes|date=2017-12-11|access-date=30 October 2018}}</ref> |
Similar to other [[herpesviridae]], the herpes simplex viruses establish latent lifelong infection, and thus cannot be eradicated from the body with current treatments.<ref name="CDC2017Bas2">{{cite web|url=https://www.cdc.gov/std/Herpes/STDFact-Herpes.htm|title=STD Facts – Genital Herpes|date=2017-12-11|access-date=30 October 2018}}</ref> |
||
Treatment usually involves general-purpose [[antiviral drug]]s 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]]<ref name="pmid21991950">{{cite journal |vauthors=Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, Palmer A, Sánchez PJ, Jacobs RF, Bradley JS, Robinson JL, Shelton M, Dennehy PH, Leach C, Rathore M, Abughali N, Wright P, Frenkel LM, Brady RC, Van Dyke R, Weiner LB, Guzman-Cottrill J, McCarthy CA, Griffin J, Jester P, Parker M, Lakeman FD, Kuo H, Lee CH, Cloud GA | title = Oral acyclovir suppression and neurodevelopment after neonatal herpes | journal = N. Engl. J. Med. | volume = 365 | issue = 14 | pages = 1284–92 | year = 2011 | pmid = 21991950 | pmc = 3250992 | doi = 10.1056/NEJMoa1003509 }}</ref> and valaciclovir can reduce reactivation rates.<ref name="PMID_18186706">{{cite journal |vauthors=Koelle DM, Corey L | title = Herpes simplex: insights on pathogenesis and possible vaccines | journal = Annual Review of Medicine | volume = 59 | pages = 381–95 | year = 2008 | pmid = 18186706 | doi = 10.1146/annurev.med.59.061606.095540 }}</ref> The extensive use of antiherpetic drugs has led to the development of some [[drug resistance]],{{Citation needed|date=March 2022}} 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.<ref>{{ |
Treatment usually involves general-purpose [[antiviral drug]]s 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]]<ref name="pmid21991950">{{cite journal |vauthors=Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, Palmer A, Sánchez PJ, Jacobs RF, Bradley JS, Robinson JL, Shelton M, Dennehy PH, Leach C, Rathore M, Abughali N, Wright P, Frenkel LM, Brady RC, Van Dyke R, Weiner LB, Guzman-Cottrill J, McCarthy CA, Griffin J, Jester P, Parker M, Lakeman FD, Kuo H, Lee CH, Cloud GA | title = Oral acyclovir suppression and neurodevelopment after neonatal herpes | journal = N. Engl. J. Med. | volume = 365 | issue = 14 | pages = 1284–92 | year = 2011 | pmid = 21991950 | pmc = 3250992 | doi = 10.1056/NEJMoa1003509 }}</ref> and valaciclovir can reduce reactivation rates.<ref name="PMID_18186706">{{cite journal |vauthors=Koelle DM, Corey L | title = Herpes simplex: insights on pathogenesis and possible vaccines | journal = Annual Review of Medicine | volume = 59 | pages = 381–95 | year = 2008 | pmid = 18186706 | doi = 10.1146/annurev.med.59.061606.095540 }}</ref> The extensive use of antiherpetic drugs has led to the development of some [[drug resistance]],{{Citation needed|date=March 2022}} 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.<ref>{{cite journal | vauthors = Treml J, Gazdová M, Šmejkal K, Šudomová M, Kubatka P, Hassan ST | title = Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development | journal = Viruses | volume = 12 | issue = 2 | page = 154 | date = January 2020 | pmid = 32013134 | pmc = 7077281 | doi = 10.3390/v12020154 | doi-access = free }}</ref> [[Pyrithione]], a zinc [[ionophore]], has shown antiviral activity against herpes simplex.<ref>{{cite journal | vauthors = Qiu M, Chen Y, Chu Y, Song S, Yang N, Gao J,WuZ | title = Zinc ionophores pyrithione inhibits herpes simplex virus replication through interfering with proteasome function and NF-κB activation | journal = Antiviral Research | volume = 100 | issue = 1 | pages = 44–53 | date = October 2013 | pmid = 23867132 | doi = 10.1016/j.antiviral.2013.07.001 }}</ref> |
||
==Alzheimer's disease== |
==Alzheimer's disease== |
||
Line 374: | Line 378: | ||
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 [[Amyloid beta|β-amyloid]] and [[tau protein]] and also decreased HSV-1 replication.<ref>{{cite journal |vauthors=Wozniak MA, Frost AL, Preston CM, Itzhaki RF | year = 2011 | title = Antivirals Reduce the Formation of Key Alzheimer's Disease Molecules in Cell Cultures Acutely Infected with Herpes Simplex Virus Type 1 | journal = PLOS ONE | volume = 6 | issue = 10| page = e25152 | doi = 10.1371/journal.pone.0025152 | pmid=22003387 | pmc=3189195| bibcode = 2011PLoSO...625152W | doi-access = free }}</ref> |
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 [[Amyloid beta|β-amyloid]] and [[tau protein]] and also decreased HSV-1 replication.<ref>{{cite journal |vauthors=Wozniak MA, Frost AL, Preston CM, Itzhaki RF | year = 2011 | title = Antivirals Reduce the Formation of Key Alzheimer's Disease Molecules in Cell Cultures Acutely Infected with Herpes Simplex Virus Type 1 | journal = PLOS ONE | volume = 6 | issue = 10| page = e25152 | doi = 10.1371/journal.pone.0025152 | pmid=22003387 | pmc=3189195| bibcode = 2011PLoSO...625152W | doi-access = free }}</ref> |
||
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 ([[acyclovir]], [[famciclovir]], [[ganciclovir]], [[idoxuridine]], [[penciclovir]], [[tromantadine]], [[valaciclovir]], or [[valganciclovir]]) showed no elevated risk of dementia compared to patients uninfected with HSV.<ref>{{cite journal | vauthors = Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Yeh HW, Chiang WS, Chou YC, Tsao CH, Wu YF, Chien WC | title = Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan | journal = Neurotherapeutics | volume = 15 | issue = 2 | pages = 417–429 | date = April 2018 | pmid = 29488144 | pmc = 5935641 | doi = 10.1007/s13311-018-0611-x }}</ref> |
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.<ref>{{cite journal | vauthors = Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Yeh HW, Chiang WS, Chou YC, Tsao CH, Wu YF, Chien WC | title = Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan | journal = Neurotherapeutics | volume = 15 | issue = 2 | pages = 417–429 | date = April 2018 | pmid = 29488144 | pmc = 5935641 | doi = 10.1007/s13311-018-0611-x }}</ref> |
||
==Multiplicity reactivation== |
==Multiplicity reactivation== |
||
Line 394: | Line 398: | ||
==Other related outcomes== |
==Other related outcomes== |
||
HSV-2 the most common cause of [[Mollaret's meningitis]].<ref>Harrisons Principles of Internal Medicine, 19th edition. p. 1179. {{ISBN|9780071802154}}.</ref> HSV-1 can lead to potentially fatal cases of [[herpes simplex encephalitis]].<ref>{{Cite web|url=http://www.antimicrobe.org/e7.asp|title=Meningitis - Infectious Disease and Antimicrobial Agents|website=www.antimicrobe.org|access-date=2016-03-14}}</ref> Herpes simplex viruses have also been studied in the central nervous system disorders such as [[multiple sclerosis]], but research has been conflicting and inconclusive.<ref>{{cite journal |vauthors=Boukhvalova MS, Mortensen E, Mbaye A, Lopez D, Kastrukoff L, Blanco JC |date=12 December 2019 |title=Herpes Simplex Virus 1 Induces Brain Inflammation and Multifocal Demyelination in the Cotton Rat Sigmodon hispidus |journal=J Virol |volume=94 |issue=1 |pages=e01161-19 |doi=10.1128/JVI.01161-19 |pmc=6912097 |pmid=31597775}}</ref> |
HSV-2is the most common cause of [[Mollaret's meningitis]].<ref>Harrisons Principles of Internal Medicine, 19th edition. p. 1179. {{ISBN|9780071802154}}.</ref> HSV-1 can lead to potentially fatal cases of [[herpes simplex encephalitis]].<ref>{{Cite web|url=http://www.antimicrobe.org/e7.asp|title=Meningitis - Infectious Disease and Antimicrobial Agents|website=www.antimicrobe.org|access-date=2016-03-14}}</ref> Herpes simplex viruses have also been studied in the central nervous system disorders such as [[multiple sclerosis]], but research has been conflicting and inconclusive.<ref>{{cite journal |vauthors=Boukhvalova MS, Mortensen E, Mbaye A, Lopez D, Kastrukoff L, Blanco JC |date=12 December 2019 |title=Herpes Simplex Virus 1 Induces Brain Inflammation and Multifocal Demyelination in the Cotton Rat Sigmodon hispidus |journal=J Virol |volume=94 |issue=1 |pages=e01161-19 |doi=10.1128/JVI.01161-19 |pmc=6912097 |pmid=31597775}}</ref> |
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Following a diagnosis of genital herpes simplex infection, patients may develop an episode of profound [[major depressive disorder|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.{{ |
Following a diagnosis of genital herpes simplex infection, patients may develop an episode of profound [[major depressive disorder|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|date=January 2023}} |
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==Research== |
==Research== |
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{{main|Herpes simplex research}} |
{{main|Herpes simplex research}} |
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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 [[histology|histologically]] mirrors atherosclerosis in humans) in target animals vaccinated.<ref>{{cite journal | vauthors = Esaki M, Noland L, Eddins T, Godoy A, Saeki S, Saitoh S, Yasuda A, Dorsey KM | title = Safety and efficacy of a turkey herpesvirus vector laryngotracheitis vaccine for chickens | journal = Avian Diseases | volume = 57 | issue = 2 | pages = 192–8 | date = June 2013 | pmid = 24689173 | doi = 10.1637/10383-092412-reg.1 | s2cid = 23804575 }}</ref><ref>{{cite book | |
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 [[histology|histologically]] mirrors atherosclerosis in humans) in target animals vaccinated.<ref>{{cite journal | vauthors = Esaki M, Noland L, Eddins T, Godoy A, Saeki S, Saitoh S, Yasuda A, Dorsey KM | title = Safety and efficacy of a turkey herpesvirus vector laryngotracheitis vaccine for chickens | journal = Avian Diseases | volume = 57 | issue = 2 | pages = 192–8 | date = June 2013 | pmid = 24689173 | doi = 10.1637/10383-092412-reg.1 | s2cid = 23804575 }}</ref><ref>{{cite book | vauthors = Shih JC |title=Role of Herpesvirus in Artherogenesis |page=25 |chapter-url=https://books.google.com/books?id=0ToGnkORSAMC&pg=PA25 |chapter=Animal studies of virus-induced atherosclerosis|date=22 February 1999 |publisher=CRC Press |isbn=978-90-5702-321-7 }}</ref> |
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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) |
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|date=January 2023}} |
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==References== |
==References== |
Herpes simplex viruses | |
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![]() | |
TEM micrograph of virions of a herpes simplex virus species | |
Scientific classification![]() | |
(unranked): | Virus |
Realm: | Duplodnaviria |
Kingdom: | Heunggongvirae |
Phylum: | Peploviricota |
Class: | Herviviricetes |
Order: | Herpesvirales |
Family: | Orthoherpesviridae |
Subfamily: | Alphaherpesvirinae |
Genus: | Simplexvirus |
Groups included | |
Cladistically included but traditionally excluded taxa | |
All other Simplexvirus sp.:
|
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.
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 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 herpetic whitlow, which is a herpes infection on the fingers; it was commonly found on dental surgeon's hands prior to 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 promotersineukaryotes 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 by means of a tegument. This complete particle is known as the virion.[27] HSV-1 and HSV-2 each contain at least 74 genes (oropen 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 (UL) and the short unique region (US). Of the 74 known ORFs, UL contains 56 viral genes, whereas US 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 (UL) 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 glycoprotein 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 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 activation of cytotoxic T-lymphocytes (CTLs), the major effectors of the cell-mediated immune response against virally-infected cells. ICP-47 prevents 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 level 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 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 the 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 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 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 encapsuled 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]
ORF | Protein alias | HSV-1 | HSV-2 | Function/description |
---|---|---|---|---|
Repeat long (RL) | ||||
ICP0/RL2 | ICP0; IE110; α0 | P08393 | P28284 | E3 ubiquitin ligase that activates viral gene transcription by opposing chromatinization of the viral genome and counteracts intrinsic- and interferon-based antiviral responses.[53] |
RL1 | RL1; ICP34.5 | O12396 | P28283 | Neurovirulence factor. Antagonizes PKR by de-phosphorylating eIF4a. Binds to BECN1 and inactivates autophagy. |
LAT | LRP1, LRP2 | P17588 P17589 |
Latency-associated transcript abd protein products (latency-related protein) | |
Unique long (UL) | ||||
UL1 | GlycoproteinL | P10185 | P28278 | Surface and membrane |
UL2 | Uracil-DNA glycosylase | P10186 | P13158 P28275 | Uracil-DNA glycosylase |
UL3 | UL3 | P10187 Q1XBW5 | P0C012 P28279 | unknown |
UL4 | UL4 | P10188 | P28280 | unknown |
UL5 | HELI | P10189 | P28277 | DNA helicase |
UL6 | Portal protein UL-6 | P10190 | Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid.[35][36][37] | |
UL7 | Cytoplasmic envelopment protein 1 | P10191 | P89430 | Virion maturation |
UL8 | DNA helicase/primase complex-associated protein | P10192 | P89431 | DNA virus helicase-primase complex-associated protein |
UL9 | Replication origin-binding protein | P10193 | P89432 | Replication origin-binding protein |
UL10 | Glycoprotein M | P04288 | P89433 | Surface and membrane |
UL11 | Cytoplasmic envelopment protein 3 | P04289 Q68980 | P13294 | virion exit and secondary envelopment |
UL12 | Alkaline nuclease | P04294 | P06489 | Alkaline exonuclease |
UL13 | UL13 | P04290 | P89436 | Serine-threonine protein kinase |
UL14 | UL14 | P04291 | P89437 | Tegument protein |
UL15 | TRM3 | P04295 | P89438 | Processing and packaging of DNA |
UL16 | UL16 | P10200 | P89439 | Tegument protein |
UL17 | CVC1 | P10201 | Processing and packaging DNA | |
UL18 | TRX2 | P10202 | P89441 | Capsid protein |
UL19 | VP5; ICP5 | P06491 | P89442 | Major capsid protein |
UL20 | UL20 | P10204 | P89443 | Membrane protein |
UL21 | UL21 | P10205 P09855 | P89444 | Tegument protein[54] |
UL22 | Glycoprotein H | P06477 | P89445 | Surface and membrane |
UL23 | Thymidine kinase | O55259 | Peripheral to DNA replication | |
UL24 | UL24 | P10208 | unknown | |
UL25 | UL25 | P10209 | Processing and packaging DNA | |
UL26 | P40; VP24; VP22A; UL26.5 (HHV2 short isoform) | P10210 | P89449 | Capsid protein |
UL27 | Glycoprotein B | A1Z0P5 | P08666 | Surface and membrane |
UL28 | ICP18.5 | P10212 | Processing and packaging DNA | |
UL29 | UL29; ICP8 | Q2MGU6 | Major DNA-binding protein | |
UL30 | DNA polymerase | Q4ACM2 | DNA replication | |
UL31 | UL31 | Q25BX0 | Nuclear matrix protein | |
UL32 | UL32 | P10216 | Envelope glycoprotein | |
UL33 | UL33 | P10217 | Processing and packaging DNA | |
UL34 | UL34 | P10218 | Inner nuclear membrane protein | |
UL35 | VP26 | P10219 | Capsid protein | |
UL36 | UL36 | P10220 | Large tegument protein | |
UL37 | UL37 | P10216 | Capsid assembly | |
UL38 | UL38; VP19C | P32888 | Capsid assembly and DNA maturation | |
UL39 | UL39; RR-1; ICP6 | P08543 | Ribonucleotide reductase (large subunit) | |
UL40 | UL40; RR-2 | P06474 | Ribonucleotide reductase (small subunit) | |
UL41 | UL41; VHS | P10225 | Tegument protein; virion host shutoff[42] | |
UL42 | UL42 | Q4H1G9 | DNA polymerase processivity factor | |
UL43 | UL43 | P10227 | Membrane protein | |
UL44 | Glycoprotein C | P10228 | Q89730 | Surface and membrane |
UL45 | UL45 | P10229 | Membrane protein; C-type lectin[55] | |
UL46 | VP11/12 | P08314 | Tegument proteins | |
UL47 | UL47; VP13/14 | P10231 | Tegument protein | |
UL48 | VP16 (Alpha-TIF) | P04486 | P68336 | Virion maturation; activate IE genes by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'. |
UL49 | UL49A | O09800 | Envelope protein | |
UL50 | UL50 | P10234 | dUTP diphosphatase | |
UL51 | UL51 | P10234 | Tegument protein | |
UL52 | UL52 | P10236 | DNA helicase/primase complex protein | |
UL53 | Glycoprotein K | P68333 | Surface and membrane | |
UL54 | IE63; ICP27 | P10238 | Transcriptional regulation and inhibition of the STING signalsome[56] | |
UL55 | UL55 | P10239 | Unknown | |
UL56 | UL56 | P10240 | Unknown | |
Inverted repeat long (IRL) | ||||
Inverted repeat short (IRS) | ||||
Unique short (US) | ||||
US1 | ICP22; IE68 | P04485 | Viral replication | |
US2 | US2 | P06485 | Unknown | |
US3 | US3 | P04413 | Serine/threonine-protein kinase | |
US4 | Glycoprotein G | P06484 | P13290 | Surface and membrane |
US5 | Glycoprotein J | P06480 | Surface and membrane | |
US6 | Glycoprotein D | A1Z0Q5 | Q69467 | Surface and membrane |
US7 | Glycoprotein I | P06487 | Surface and membrane | |
US8 | Glycoprotein E | Q703F0 | P89475 | Surface and membrane |
US9 | US9 | P06481 | Tegument protein | |
US10 | US10 | P06486 | Capsid/Tegument protein | |
US11 | US11; Vmw21 | P56958 | Binds DNA and RNA | |
US12 | ICP47; IE12 | P03170 | Inhibits MHC class I pathway by preventing binding of antigen to TAP | |
Terminal repeat short (TRS) | ||||
RS1 | ICP4; IE175 | P08392 | Major transcriptional activator. Essential for progression beyond the immediate-early phase of infection. IEG transcription repressor. |
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]
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]
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 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]
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 virtue of 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]
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]
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Bacterial |
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Protozoal |
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Parasitic |
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Viral |
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General inflammation |
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Skin infections, symptoms and signs related to viruses
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Ungrouped |
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Taxonomy of the Herpesvirales
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Higher taxonomy: Duplodnaviria > Heunggongvirae > Peploviricota > Herviviricetes > Herpesvirales | |||||||||||||||||||||||||||||||||||||||||
Malacoherpesviridae |
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Herpesviridae IgHV-2 |
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Unassigned species listed below parent taxon –– Source: ICTV –– |
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DNA |
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RNA |
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