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'''Herpes simplex virus''' '''1''' and '''2''' ('''HSV-1''' and '''HSV-2'''), also known as '''Human herpes virus 1''' and '''2''' ('''HHV-1''' and '''-2'''), are two members of the herpes [[virus]] family, [[Herpesviridae]], that infect [[human]]s.<ref name=Sherris>{{cite book| author = Ryan KJ, Ray CG (editors)| title = Sherris Medical Microbiology| edition = 4th| pages = 555–62| publisher = McGraw Hill| year = 2004| isbn = 0-8385-8529-9 }}</ref> Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are [[wikt:ubiquitous|ubiquitous]] and [[Infectious disease|contagious]]. They can be spread when an infected person is producing and [[viral shedding|shedding]] the virus.
'''Herpes simplex virus''' '''1''' and '''2''' ('''HSV-1''' and '''HSV-2'''), also known as '''Human herpes virus 1''' and '''2''' ('''HHV-1''' and '''-2'''), are two members of the herpes [[virus]] family, every person in the US has the virus, except Sarah from Arlington TX. [[Herpesviridae]], that infect [[human]]s.<ref name=Sherris>{{cite book| author = Ryan KJ, Ray CG (editors)| title = Sherris Medical Microbiology| edition = 4th| pages = 555–62| publisher = McGraw Hill| year = 2004| isbn = 0-8385-8529-9 }}</ref> Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are [[wikt:ubiquitous|ubiquitous]] and [[Infectious disease|contagious]]. They can be spread when an infected person is producing and [[viral shedding|shedding]] the virus.


Symptoms of herpes simplex virus [[infection]] include watery [[blister]]s in the [[skin]] or [[mucous membranes]] of the mouth, lips or genitals.<ref name=Sherris /> Lesions heal with a [[Coagulation|scab]] characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, as [[neurotropic virus|neurotropic and neuroinvasive viruses]], HSV-1 and -2 persist in the body by becoming ''latent'' and hiding from the [[immune system]] in the [[cell (biology)|cell]] bodies of [[neurons]]. 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 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&nbsp;— New Zealand Dermatological Society | accessdate=2006-10-15}}</ref>
Symptoms of herpes simplex virus [[infection]] include watery [[blister]]s in the [[skin]] or [[mucous membranes]] of the mouth, lips or genitals.<ref name=Sherris /> Lesions heal with a [[Coagulation|scab]] characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, as [[neurotropic virus|neurotropic and neuroinvasive viruses]], HSV-1 and -2 persist in the body by becoming ''latent'' and hiding from the [[immune system]] in the [[cell (biology)|cell]] bodies of [[neurons]]. 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 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&nbsp;— New Zealand Dermatological Society | accessdate=2006-10-15}}</ref>

Revision as of 19:44, 11 February 2013

This article is about the virus. For information about the disease caused by the virus, see Herpes simplex.

Herpes simplex virus
TEM micrograph of a herpes simplex virus.
Virus classification
Group:
Group I (dsDNA)
Family:
Herpesviridae
Subfamily:
Alphaherpesvirinae
Genus:
Simplexvirus
Species

Herpes simplex virus 1 (HSV-1)
Herpes simplex virus 2 (HSV-2)

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as Human herpes virus 1 and 2 (HHV-1 and -2), are two members of the herpes virus family, every person in the US has the virus, except Sarah from Arlington TX. Herpesviridae, that infect humans.[1] Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious. They can be spread when an infected person is producing and shedding the virus.

Symptoms of herpes simplex virus infection include watery blisters in the skin or mucous membranes of the mouth, lips or genitals.[1] Lesions heal with a scab characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, as neurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the body by becoming latent and hiding from the immune system in the cell bodies of neurons. 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 cause new sores.[2]

Transmission

Main article: Herpes simplex

HSV-1 and -2 are transmitted by contact with an infectious area of the skin during re-activations of the virus. Although less likely, the herpes viruses can be transmitted during latency. Transmission is likely to occur during symptomatic re-activation of the virus that causes visible and typical skin sores. Asymptomatic reactivation means that the virus causes atypical, subtle or hard to notice symptoms that are not identified as an active herpes infection. Atypical symptoms are often attributed to other causes such as a yeast infection.[3][4] HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as kissing and mouth-to-genital contact (oral sex).[5] HSV-2 is primarily a sexually transmitted infection but rates of HSV-1 genital infections are increasing.[3]

Both viruses may also be transmitted vertically during childbirth, although the real risk is very low.[6] The risk of infection is minimal if the mother has no symptoms or exposed blisters during delivery. The risk is considerable when the mother gets the virus for the first time during late pregnancy.[7]

Microbiology

Viral structure

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.[8] HSV-1 and HSV-2 each contain at least 74 genes (or open reading frames, ORFs) within their genomes,[9] although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.[10] 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.

The genomes of HSV1 and HSV2 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.[9] Transcription of HSV genes is catalyzed by RNA polymerase II of the infected host.[9] Immediate early genes, which encode proteins 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.[9]

Five proteins from (UL) form the viral capsid; UL6, UL18, UL35, UL38 and the major capsid protein UL19.[8]

Cellular entry

A simplified diagram of HSV replication

Entry of HSV into the host cell involves interactions of several glycoproteins on the surface of the enveloped virus, with receptors on the surface of the host cell. The envelope covering the virus particle, when bound to specific receptors on the cell surface, will fuse with the host cell membrane and create an opening, or pore, through which the virus enters the host cell.

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. In an intermediate state, the two membranes begin to merge, forming a hemifusion state. Finally, a stable entry pore is formed through which the viral envelope contents are introduced to the host cell.[11] In the case of a herpes virus, initial interactions occur when a viral envelope glycoprotein called glycoprotein C (gC) binds to a cell surface particle called heparan sulfate. A second glycoprotein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors. These include herpesvirus entry mediator(HVEM), nectin-1 and 3-O sulfated heparan sulfate. The receptor provides a strong, fixed attachment to the host cell. 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 results in the hemifusion state. Afterward, gB interaction with the gH/gL complex creates an entry pore for the viral capsid.[11] Glycoprotein B interacts with glycosaminoglycans on the surface of the host cell.

Genetic inoculation

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 twelve 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.[12] Each icosahedral capsid contains a single portal, located in one vertex.[13][14] The DNA exits the capsid in a single linear segment.[15]

Immune evasion

HSV evades the immune system through interference with MHC class I presentation of antigen on the cell surface. It achieves this through blockade of the transporter associated with atigen processing (TAP) induced by the secretion of ICP-47 by HSV.[16] In the host cell, TAP transports digested viral antigen epitopes 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.

Replication

Micrograph showing the viral cytopathic effect of HSV (multi-nucleation, ground glass chromatin).

Following infection of a cell, a cascade of herpes virus proteins, called immediate-early, early, and late, are 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.[17] 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.

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.[18] 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.[19][20]

The late proteins are used in to 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 pre-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 releasing a naked capsid into the cytoplasm. The virus acquires its final envelope by budding into cytoplasmic vesicles.[21]

Latent infection

HSVs may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia.[1] HSV-1 tends to reside in the trigeminal ganglia, while HSV-2 tends to reside in the sacral ganglia, but note that these are tendencies only, not fixed behavior. During such latent infection of a cell, HSVs express Latency Associated Transcript (LAT) RNA. LAT is known to regulate the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows subsequent, usually symptomatic, periodic recurrences or "outbreaks" characteristic of non-latency. Whether or not recurrences are noticeable (symptomatic), viral shedding occurs to produce further infections (usually in a new host, if any). 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.[22] 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.[22][23] 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.[24]

The virus can be reactivated by illnesses such as colds and influenza, eczema, emotional and physical stress, gastric upset, fatigue or injury, by menstruation and possibly exposure to bright sunlight.

Viral genome

Template:Genome header | UL1 || Glycoprotein L [1] || Surface and membrane | | UL38 || UL38; VP19C [2] || Capsid assembly and DNA maturation |- | UL2 || UL2 [3] || Uracil-DNA glycosylase | | UL39 || UL39 [4] || Ribonucleotide reductase (Large subunit) |- | UL3 || UL3 [5] || unknown | | UL40 || UL40 [6] || Ribonucleotide reductase (Small subunit) |- | UL4 || UL4 [7] || unknown | | UL41 || UL41; VHS [8] || Tegument protein; Virion host shutoff[18] |- | UL5 || UL5 [9] || DNA replication | | UL42 || UL42 [10] || DNA polymerase processivity factor |- | UL6 || Portal protein UL-6 || Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid.[12][13][14] | | UL43 || UL43 [11] || Membrane protein |- | UL7 || UL7 [12] || Virion maturation | | UL44 || Glycoprotein C [13] || Surface and membrane |- | UL8 || UL8 [14] || DNA helicase/primase complex-associated protein | | UL45 || UL45 [15] || Membrane protein; C-type lectin[25] |- | UL9 || UL9 [16] || Replication origin-binding protein | | UL46 ||VP11/12 [17] || Tegument proteins |- | UL10 || Glycoprotein M [18] || Surface and membrane | | UL47 || UL47; VP13/14 [19] || Tegument protein |- | UL11 || UL11 [20] || virion exit and secondary envelopment | UL48 || VP16 (Alpha-TIF) [21] || Virion maturation; activate IEGs by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'. |- | UL12 || UL12 [22] || Alkaline exonuclease | | UL49 || UL49A [23] || Envelope protein |- | UL13 || UL13 [24] || Serine-threonine protein kinase | |UL50 || UL50 [25] || dUTP diphosphatase |- | UL14 || UL14 [26] || Tegument protein | | UL51 || UL51 [27] || Tegument protein |- | UL15 || Terminase [28] || Processing and packaging of DNA | |UL52 || UL52 [29] || DNA helicase/primase complex protein |- | UL16 || UL16 [30] || Tegument protein | |UL53 || Glycoprotein K [31] || Surface and membrane |- | UL17 || UL17 [32] || Processing and packaging DNA | |UL54 || IE63; ICP27 [33] || Transcriptional regulation |- | UL18 || VP23 [34] || Capsid protein | |UL55 || UL55 [35] || Unknown |- | UL19 || VP5 [36] || Major capsid protein | |UL56 || UL56 [37] || Unknown |- | UL20 || UL20 [38] || Membrane protein | |US1 || ICP22; IE68 [39] || Viral replication |- | UL21 || UL21 [40] || Tegument protein[26] | |US2 || US2 [41] || Unknown |- | UL22 || Glycoprotein H [42] || Surface and membrane | |US3 || US3 [43] || Serine/threonine-protein kinase |- | UL23 || Thymidine kinase [44] || Peripheral to DNA replication | |US4 || Glycoprotein G [45] || Surface and membrane |- | UL24 || UL24 [46] || unknown | |US5 || Glycoprotein J [47] || Surface and membrane |- | UL25 || UL25 [48] || Processing and packaging DNA | |US6 || Glycoprotein D [49] || Surface and membrane |- | UL26 || P40; VP24; VP22A [50] || Capsid protein | |US7 || Glycoprotein I [51] || Surface and membrane |- | UL27 || Glycoprotein B [52] || Surface and membrane | |US8 || Glycoprotein E [53] || Surface and membrane |- | UL28 || ICP18.5 [54] || Processing and packaging DNA | |US9 || US9 [55] || Tegument protein |- | UL29 || UL29; ICP8 [56] || Major DNA-binding protein | |US10 || US10 [57] || Capsid/Tegument protein |- | UL30 || DNA polymerase [58] || DNA replication | |US11 || US11; Vmw21 [59] || Binds DNA and RNA |- | UL31 || UL31 [60] || Nuclear matrix protein | |US12 || ICP47; IE12 [61] || Inhibits MHC class I pathway by preventing binding of antigen to TAP |- | UL32 || UL32 [62] || Envelope glycoprotein | |RS1 || ICP4; IE175 [63] || Major transcriptional activator. Essential for progression beyond the immediate-early phase of infection. IEG transcription repressor. |- | UL33 || UL33 [64] || Processing and packaging DNA | |ICP0 || ICP0; IE110; α0 [65] || E3 ubiquitin ligase that activates viral gene transcription and counteracts the interferon response |- | UL34 || UL34 [66] || Inner nuclear membrane protein | |LRP1 || LRP1 [67] || Latency-related protein |- | UL35 || VP26 [68] || Capsid protein | |LRP2 || LRP2 [69] || Latency-related protein |- | UL36 || UL36 [70] || Large tegument protein | |RL1 || RL1; ICP34.5 [71] || Neurovirulence factor. Antagonizes PKR by de-phosphorylating eIF4a. |- | |UL37 || UL37 [72] || Capsid assembly | | LAT || none [73] || Latency-associated transcript |}

Treatment and vaccine development

For more details on treatment of herpes simplex virus, see Herpes simplex.

Herpes viruses establish lifelong infections, and the virus cannot yet be eradicated from the body. 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 acyclovir and valacyclovir can reduce reactivation rates.[4]

Connection between facial sores and Alzheimer's disease

In the presence of a certain gene variation (APOE-epsilon4 allele carriers), a possible link between HSV-1 (i.e., the virus that causes cold sores or oral herpes) and Alzheimer's disease was reported in 1979.[27] 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.[28] This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer’s.[29] 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.[30] However, a more recent prospective study from 2008 with a cohort of several thousand people showed a high correlation between seropositivity for HSV and Alzheimer's disease, without direct correlation to the APOE-epsilon4 allele.[31] There is also strong evidence throughout current literature that herpes simplex carriers have an increased relative risk of developing sever's disease and pars defects.

References

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  19. ^ Taddeo B, Roizman B (2006). "The Virion Host Shutoff Protein (UL41) of Herpes Simplex Virus 1 Is an Endoribonuclease with a Substrate Specificity Similar to That of RNase A". J. Virol. 80 (18): 9341–5. doi:10.1128/JVI.01008-06. PMC 1563938. PMID 16940547.
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  21. ^ Granzow H, Klupp BG, Fuchs W, Veits J, Osterrieder N, Mettenleiter TC (2001). "Egress of Alphaherpesviruses: Comparative Ultrastructural Study". J. Virol. 75 (8): 3675–84. doi:10.1128/JVI.75.8.3675-3684.2001. PMC 114859. PMID 11264357. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ a b Pinnoji RC, Bedadala GR, George B, Holland TC, Hill JM, Hsia SC (2007). "Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification". Virol. J. 4: 56. doi:10.1186/1743-422X-4-56. PMC 1906746. PMID 17555596.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  23. ^ Bedadala GR, Pinnoji RC, Hsia SC (2007). "Early growth response gene 1 (Egr-1) regulates HSV-1 ICP4 and ICP22 gene expression". Cell Res. 17 (6): 546–55. doi:10.1038/cr.2007.44. PMID 17502875.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  26. ^ Vittone V, Diefenbach E, Triffett D, Douglas MW, Cunningham AL, Diefenbach RJ (2005). "Determination of Interactions between Tegument Proteins of Herpes Simplex Virus Type 1". J. Virol. 79 (15): 9566–71. doi:10.1128/JVI.79.15.9566-9571.2005. PMC 1181608. PMID 16014918.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  29. ^ Pyles RB (2001). "The association of herpes simplex virus and Alzheimer's disease: a potential synthesis of genetic and environmental factors" (PDF). Herpes. 8 (3): 64–8. PMID 11867022. {{cite journal}}: Unknown parameter |month= ignored (help)
  30. ^ Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997). "Herpes simplex virus type 1 in brain and risk of Alzheimer's disease". Lancet. 349 (9047): 241–4. doi:10.1016/S0140-6736(96)10149-5. PMID 9014911. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  31. ^ Letenneur, L (2008). "Seropositivity to herpes simplex virus antibodies and risk of Alzheimer's disease: a population-based cohort study". PLoS ONE. 3 (11): e3637. doi:10.1371/journal.pone.0003637. PMC 2572852. PMID 18982063. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: unflagged free DOI (link)
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