Herpes simplex virus 4774419 225928663 2008-07-16T01:45:12Z 68.198.219.91 {{Taxobox | color=violet | name = ''Herpes simplex virus'' | image = Herpes simpex virus.jpg | image_caption = [[Transmission electron microscopy|TEM]] [[micrograph]] of a herpes simplex virus. | image_width = 240px | virus_group = i | familia = ''[[Herpesviridae]]'' | subfamilia = [[Alphaherpesvirinae]] | genus = ''[[Simplexvirus]]'' | subdivision_ranks = Species | subdivision = '''''Herpes simplex virus 1''''' (HWJ-1)<br /> '''''Herpes simplex virus 2''''' (HWJ-2)<br /> }} :''This article is about the virus. For information about the disease, see [[Herpes simplex]].'' '''Herpes simplex virus''' '''1''' and '''2''' ('''HSV-1''' and '''HSV-2''') are two species of the herpes virus family, [[Herpesviridae]], which cause infections in [[human]]s.<ref name=Sherris>{{cite book| author = Ryan KJ, Ray CG (editors)| title = Sherris Medical Microbiology| edition = 4th ed.| pages = 555&ndash;62| publisher = McGraw Hill| year = 2004| isbn = 0838585299 }}</ref> Eight members of herpesviridae infect [[human]]s to cause a variety of illnesses including [[cold sores]], [[chickenpox]] or varicella, [[shingles]] or herpes zoster (VZV), [[cytomegalovirus]] (CMV), and various [[cancer]]s, and can cause brain [[inflammation]] (encephalitis). All viruses in the herpes family produce life-long infections. They are also called ''Human Herpes Virus'' ''1'' and ''2'' (''HHV-1'' and ''HHV-2'') and are [[neurotropic virus|neurotropic and neuroinvasive viruses]]; they enter and hide in the human [[nervous system]], accounting for their durability in the human body. HSV-1 is commonly associated with herpes outbreaks of the face known as [[cold sore]]s or fever blisters, whereas HSV-2 is more often associated with [[Sex organ|genital]] herpes. An [[infection]] by a herpes simplex virus is marked by 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. However, the infection is persistent and symptoms may recur periodically as ''outbreaks'' of sores near the site of original infection. After the initial, or ''primary'', infection, HSV becomes ''latent'' in the [[cell (biology)|cell]] bodies of [[nerve]]s in the area. Some infected people experience sporadic episodes of viral ''reactivation'', followed by transportation of the virus via the nerve's [[axon]] to the skin, where virus replication and shedding occurs.<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 | accessdate=2006-10-15}}</ref> Herpes is [[Infectious disease|contagious]] if the carrier is producing and [[viral shedding|shedding]] the virus. This is especially likely during an outbreak but possible at other times. There is no cure yet, but there are treatments which reduce the likelihood of viral shedding. == Transmission == {{main|Herpes simplex}} HSV is transmitted during close contact with an infected person who is shedding virus from the skin, in [[saliva]] or in [[secretion]]s from the genitals. This [[horizontal transmission]] of the virus is more likely to occur when sores are present, although viral shedding, and therefore transmission, does occur in the absence of visible sores.<ref name="pmid18156035">{{cite journal |author=Gupta R, Warren T, Wald A |title=Genital herpes |journal=Lancet |volume=370 |issue=9605 |pages=2127–37 |year=2007 |pmid=18156035 |doi=10.1016/S0140-6736(07)61908-4}}</ref> In addition, [[vertical transmission]] of HSV may occur between mother and child during childbirth, which can be fatal to the infant.<ref name="pmid17317423">{{cite journal |author=Kimberlin DW |title=Herpes simplex virus infections of the newborn |journal=Semin. Perinatol. |volume=31 |issue=1 |pages=19–25 |year=2007 |pmid=17317423 |doi=10.1053/j.semperi.2007.01.003}}</ref> The immature [[immune system]] of the child is unable to defend against the virus and even if treated, the infection can result in inflammation of the brain ([[encephalitis]]) that may cause brain damage. Transmission occurs when the infant passes through the [[birth canal]], but the risk of infection is reduced if there are no symptoms or exposed blisters during delivery. The first outbreak after exposure to HSV is commonly more severe than future outbreaks, as the body has not had a chance to produce [[antibodies]]; this first outbreak carries a low (~1%) risk of developing [[aseptic meningitis]].<ref name=Sherris /> == 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 [[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 |author=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 |author=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 |author=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=}}</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. 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 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"/> 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"/> {| class = "prettytable" style = "width:90%; float:centre; font-size:90%; margin-left:40px" |- | colspan="6" align="center" style="color: black; background: #ccccff" | '''The open reading frames (ORFs) of HSV-1'''<ref>[http://www.expasy.org/cgi-bin/sprot-search-de?HHV1 Search in UniProt Knowledgebase (Swiss-Prot and TrEMBL) for: HHV1<!-- Bot generated title -->]</ref><ref name="pmid16490275"/> |- align="left" style="color: black; background: #ccccff" | | width="25px" | <small>'''Gene''' || width="130px" |<small> '''Protein''' || width="240px"|<small>'''Function/description'''</small> || width="25px"|<small>'''Gene''' || width="130px" |<small> '''Protein''' || width="220px"|<small>'''Function/description'''</small> |- | <small> [[UL1]] || <small> [[Glycoprotein]] L [http://www.expasy.org/uniprot/P10185] || <small>Surface and membrane | |<small> [[UL38]] || <small> UL38; VP19C [http://www.expasy.org/uniprot/P32888] || <small>Capsid assembly and DNA maturation |- | <small> [[UL2]] || <small>UL2 [http://www.expasy.org/uniprot/P10186] || <small>[[Uracil-DNA glycosylase]] | |<small> [[UL39]] || <small>UL39 [http://www.expasy.org/uniprot/P08543] || <small>[[Ribonucleotide reductase]] (Large subunit) |- | <small> [[UL3]] || <small>UL3 [http://www.expasy.org/uniprot/P10187] || <small>unknown | |<small> [[UL40]] || <small>UL40 [http://www.expasy.org/uniprot/P06474] || <small>Ribonucleotide reductase (Small subunit) |- | <small> [[UL4]] || <small>UL4 [http://www.expasy.org/uniprot/P10188] || <small>unknown | |<small> [[UL41]] || <small>UL41; VHS [http://www.expasy.org/uniprot/P10225] || <small>Tegument protein; Virion host shutoff<ref name="pmid12083325">{{cite journal |author=Matis J, Kúdelová M |title=Early shutoff of host protein synthesis in cells infected with herpes simplex viruses |journal=Acta Virol. |volume=45 |issue=5-6 |pages=269–77 |year=2001 |pmid=12083325 |doi=}}</ref> |- | <small>[[UL5]] || <small>UL5 [http://www.expasy.org/uniprot/Q2MGV2] || <small> [[DNA replication]] | |<small> [[UL42]] || <small>UL42 [http://www.expasy.org/uniprot/Q4H1G9] || <small>[[DNA polymerase]] processivity factor |- | <small> [[HHV capsid portal protein|UL6]] || <small>UL6 [http://www.expasy.org/uniprot/P10190] || <small>Processing and packaging DNA | |<small> [[UL43]] || <small>UL43 [http://www.expasy.org/uniprot/P10227] || <small>Membrane protein |- | <small> [[UL7]] || <small>UL7 [http://www.expasy.org/uniprot/P10190] || <small>Virion maturation | |<small> [[UL44]] || <small>Glycoprotein C [http://www.expasy.org/uniprot/P10228] || <small>Surface and membrane |- | <small>[[UL8]] || <small>UL8 [http://www.expasy.org/uniprot/P10192] || <small>[[DNA helicase]]/[[DNA primase|primase]] complex-associated protein | |<small> [[UL45]] || <small>UL45 [http://www.expasy.org/uniprot/P10229] || <small>Membrane protein; C-type lectin<ref name="pmid18256535">{{cite journal |author=Wyrwicz LS, Ginalski K, Rychlewski L |title=HSV-1 UL45 encodes a carbohydrate binding C-type lectin protein |journal=Cell Cycle |volume=7 |issue=2 |pages= |year=2007 |pmid=18256535 |doi=}}</ref> |- | <small>[[UL9]] || <small>UL9 [http://www.expasy.org/uniprot/P10193] || <small>[[origin of replication|Replication origin]]-binding protein | |<small> [[UL46]] ||VP11/12 <small> [http://www.expasy.org/uniprot/P08314] || <small>Tegument proteins |- | <small> [[UL10]] || <small>Glycoprotein M [http://www.expasy.org/uniprot/P04288] || <small>Surface and membrane | |<small> [[UL47]] || <small>UL47; VP13/14 [http://www.expasy.org/uniprot/P10231] || <small>Tegument protein |- | <small> [[UL11]] || <small>UL11 [http://www.expasy.org/uniprot/P04289] || <small>virion exit and secondary envelopment | <small> [[UL48]] || <small>VP16 (Alpha-TIF) [http://www.expasy.org/uniprot/P04486] || <small>Virion maturation; activate [[Immediate early gene|IEGs]] by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence <sup>5'</sup>TAATGARAT<sup>3'</sup>. |- | <small> [[UL12]] || <small>UL12 [http://www.expasy.org/uniprot/Q68978] || <small>[[Alkaline]] [[exonuclease]] | |<small> [[UL49]] || <small>UL49A [http://www.expasy.org/uniprot/O09800] || <small>Envelope protein |- | <small> [[UL13]] || <small>UL13 [http://www.expasy.org/uniprot/Q9QNF2] || <small>[[Serine]]-[[threonine]] [[protein kinase]] | |<small>[[UL50]] || <small>UL50 [http://www.expasy.org/uniprot/P10234] || <small>[[dUTP diphosphatase]] |- | <small> [[UL14]] || <small>UL14 [http://www.expasy.org/uniprot/P04291] || <small>[[Viral tegument|Tegument]] protein | |<small> [[UL51]] || <small>UL51 [http://www.expasy.org/uniprot/P10234] || <small>Tegument protein |- | <small> [[UL15]] || <small>[[Terminase]] [http://www.expasy.org/uniprot/P04295] || <small>Processing and packaging of DNA | |<small>[[UL52]] || <small>UL52 [http://www.expasy.org/uniprot/P10236] || <small>DNA helicase/primase complex protein |- | <small> [[UL16]] || <small>UL16 [http://www.expasy.org/uniprot/P10200] || <small>Tegument protein | |<small>[[UL53]] || <small>Glycoprotein K [http://www.expasy.org/uniprot/P68333] || <small>Surface and membrane |- | <small> [[UL17]] || <small>UL17 [http://www.expasy.org/uniprot/P10201] || <small>Processing and packaging DNA | |<small>[[UL54]] || <small>IE63; ICP27 [http://www.expasy.org/uniprot/P10238] || <small>Transcriptional regulation |- | <small> [[UL18]] || <small>VP23 [http://www.expasy.org/uniprot/P10202] || <small>[[Capsid]] protein | |<small>[[UL55]] || <small>UL55 [http://www.expasy.org/uniprot/P10239] || <small>Unknown |- | <small> [[UL19]] || <small>VP5 [http://www.expasy.org/uniprot/P06491] || <small>Major capsid protein | |<small>[[UL56]] || <small>UL56 [http://www.expasy.org/uniprot/P10240] || <small>Unknown |- | <small> [[UL20]] || <small>UL20 [http://www.expasy.org/uniprot/P10204] || <small>Membrane protein | |<small>[[US1]] || <small>ICP22; IE68 [http://www.expasy.org/uniprot/P04485] || <small>Viral replication |- | <small> [[UL21]] || <small>UL21 [http://www.expasy.org/uniprot/P10205] || <small>Tegument protein<ref name="pmid16014918">{{cite journal |author=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 |doi=10.1128/JVI.79.15.9566-9571.2005}}</ref> | |<small>[[US2]] || <small>US2 [http://www.expasy.org/uniprot/P06485] || <small>Unknown |- | <small> [[UL22]] || <small>Glycoprotein H [http://www.expasy.org/uniprot/P06477] || <small>Surface and membrane | |<small>[[US3]] || <small>US3 [http://www.expasy.org/uniprot/P04413] || <small>Serine/threonine-protein kinase |- | <small>[[UL23]] || <small>[[Thymidine kinase]] [http://www.expasy.org/uniprot/O55259] || <small>Peripheral to DNA replication | |<small>[[US4]] || <small>Glycoprotein G [http://www.expasy.org/uniprot/P06484] || <small>Surface and membrane |- | <small>[[UL24]] || <small>UL24 [http://www.expasy.org/uniprot/P10208] || <small>unknown | |<small>[[US5]] || <small>Glycoprotein J [http://www.expasy.org/uniprot/P06480] || <small>Surface and membrane |- | <small> [[UL25]] || <small>UL25 [http://www.expasy.org/uniprot/P10209] || <small>Processing and packaging DNA | |<small>[[US6]] || <small>Glycoprotein D [http://www.expasy.org/uniprot/A1Z0Q5] || <small>Surface and membrane |- | <small> [[UL26]] || <small>P40; VP24; VP22A [http://www.expasy.org/uniprot/P10210] || <small>Capsid protein | |<small>[[US7]] || <small>Glycoprotein I [http://www.expasy.org/uniprot/P06487] || <small>Surface and membrane |- | <small> [[UL27]] || <small>Glycoprotein B [http://www.expasy.org/uniprot/A1Z0P5] || <small>Surface and membrane | |<small>[[US8]] || <small>Glycoprotein E [http://www.expasy.org/uniprot/Q703F0] || <small>Surface and membrane |- | <small> [[UL28]] || <small>ICP18.5 [http://www.expasy.org/uniprot/P10212] || <small>Processing and packaging DNA | |<small>[[US9]] || <small>US9 [http://www.expasy.org/uniprot/P06481] || <small>Tegument protein |- | <small> [[UL29]] || <small>UL29 [http://www.expasy.org/uniprot/Q2MGU6] || <small>Major DNA-binding protein | |<small>[[US10]] || <small>US10 [http://www.expasy.org/uniprot/P06486] || <small>Capsid/Tegument protein |- | <small> [[UL30]] || <small>[[DNA polymerase]] [http://www.expasy.org/uniprot/Q4ACM2] || <small>DNA replication | |<small>[[US11]] || <small>US11; Vmw21 [http://www.expasy.org/uniprot/P56958] || <small>Binds DNA and RNA |- | <small> [[UL31]] || <small>UL31 [http://www.expasy.org/uniprot/Q25BX0] || <small>Nuclear matrix protein | |<small>[[US12]] || <small>ICP47; IE12 [http://www.expasy.org/uniprot/P03170] || <small>Inhibits [[MHC class I]] pathway by preventing binding of antigen to [[Transporter_associated_with_antigen_processing|TAP]] |- | <small> [[UL32]] || <small>UL32 [http://www.expasy.org/uniprot/P10216] || <small>[[Viral envelope|Envelope]] [[glycoprotein]] | |<small>[[RS1]] || <small>ICP4; IE175 [http://www.expasy.org/uniprot/P08392] || <small>Activates gene transcription |- | <small> [[UL33]] || <small>UL33 [http://www.expasy.org/uniprot/P10217] || <small>Processing and packaging DNA | |<small>[[HHV Infected Cell Polypeptide 0 (ICP0)|ICP0]] || <small>ICP0; IE110; α0 [http://www.expasy.org/uniprot/P08393] || <small>E3 [[ubiquitin]] ligase that activates viral gene transcription and counteracts the [[interferon]] response |- | <small> [[UL34]] || <small>UL34 [http://www.expasy.org/uniprot/P10218] || <small>Inner nuclear membrane protein | |<small>[[HHV1 Latency-related protein 1|LRP1]] || <small>LRP1 [http://www.expasy.org/uniprot/P17588] || <small>Latency-related protein |- | <small> [[UL35]] || <small>VP26 [http://www.expasy.org/uniprot/P10219] || <small>Capsid protein | |<small>[[HHV1 Latency-related protein 2|LRP2]] || <small>LRP2 [http://www.expasy.org/uniprot/P17589] || <small>Latency-related protein |- | <small> [[UL36]] || <small>UL36 [http://www.expasy.org/uniprot/P10220] || <small>Large tegument protein | |<small>[[RL1]] || <small>RL1; ICP34.5 [http://www.expasy.org/uniprot/O12396] || <small>Neurovirulence factor. Antagonizes [[Protein_kinase_R|PKR]] by de-phosphorylating eIF4a. |- | |<small>[[UL37]] || <small>UL37 [http://www.expasy.org/uniprot/P10216] || <small>Capsid assembly | | <small>[[HHV Latency Associated Transcript|LAT]] || <small>none [http://www.expasy.org/uniprot/Q69079] || <small>Latency-associated transcript |} === Cellular entry === [[Image:HSV replication.png|thumb|right|450px|A simplified diagram of HSV replication]] Entry of HSV into the host cell involves interactions of several [[glycoprotein]]s on the surface of the enveloped virus, with [[Transmembrane receptor|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 [[Viral entry|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.<ref name="Subramanian_17299053">{{cite journal |author=Subramanian RP, Geraghty RJ |title=Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=8 |pages=2903–8 |year=2007 |pmid=17299053 |doi=10.1073/pnas.0608374104}}</ref> 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 a receptor called the herpesvirus entry mediator receptor ([[TNFRSF14|HVEM]]) and 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.<ref name="Subramanian_17299053"/> Glycoprotein B interacts with [[glycosaminoglycan]]s 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.<ref name="pmid17188319"> {{cite journal|title=Visualization of the herpes simplex virus portal in situ by cryo-electron tomography|author=Cardone G, Winkler DC, Trus BL, Cheng N, Heuser JE, Newcomb WW, Brown JC, Steven AC|journal=Virology|date=May 2007|volume=361|issue=2|pmid=17188319|pages=426–34|doi=10.1016/j.virol.2006.10.047}} </ref> Each [[icosahedral]] capsid contains a single portal, located in one [[Vertex (geometry)|vertex]].<ref name="pmid15507654">{{cite journal|pmid=15507654|title=Structure and polymorphism of the UL6 portal protein of herpes simplex virus type 1|author=Trus BL, Cheng N, Newcomb WW, Homa FL, Brown JC, Steven AC|journal=Journal of Virology|date=2004 Nov|volume=78|issue=22|pages=12668–71|doi=10.1128/JVI.78.22.12668-12671.2004}}(Article: [http://jvi.asm.org/cgi/content/full/78/22/12668?view=long&pmid=15507654]) </ref><ref name="Nellissery_2007"> {{cite journal|journal=Journal Virology|date=2007 Jun 20|title=A putative leucine zipper within the HSV-1 UL6 protein is required for portal ring formation|author=Nellissery JK, Szczepaniak R, Lamberti C, Weller SK|pmid=17581990}} </ref> The DNA exits the capsid in a single linear segment.<ref name="pmid17540405">{{cite journal |author=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 |doi=10.1016/j.jmb.2007.05.023}}</ref> === Replication === Consequent to a cell being infected, groups of Herpes virus proteins, termed ''immediate-early'', ''[[Early protein|early]]'', and ''late'' proteins, are produced following specific time periods. Research using a new [[flow cytometry]] methodology in another member of the herpes virus family, [[Kaposi's sarcoma-associated herpesvirus|KSHV]], indicates the possibility of an additional [[Lytic cycle|lytic stage]], ''delayed-late''.<ref name="PMID_17005685">{{cite journal |author=Adang LA, Parsons CH, Kedes DH |title=Asynchronous progression through the lytic cascade and variations in intracellular viral loads revealed by high-throughput single-cell analysis of Kaposi's sarcoma-associated herpesvirus infection |journal=J. Virol. |volume=80 |issue=20 |pages=10073–82 |year=2006 |pmid=17005685 |doi=10.1128/JVI.01156-06}}</ref> These stages of lytic infection, particularly ''late lytic'', are distinct from the latency stage. For example, 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 protein|early]] [[Transcription (genetics)|transcription]]. The virion host shutoff protein (VHS or UL41) is very important to viral replication.<ref name="pmid12083325"/> This enzyme shuts off protein synthesis in the host, degrades host [[Messenger RNA|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.<ref name="pmid16940547">{{cite journal |author=Taddeo B, Roizman B |title=The virion host shutoff protein (UL41) of herpes simplex virus 1 is an endoribonuclease with a substrate specificity similar to that of RNase A |journal=J. Virol. |volume=80 |issue=18 |pages=9341–5 |year=2006 |pmid=16940547 |doi=10.1128/JVI.01008-06}}</ref><ref>{{cite journal |author=Skepper JN, Whiteley A, Browne H, Minson A |title=Herpes simplex virus nucleocapsids mature to progeny virions by an envelopment --> deenvelopment --> reenvelopment pathway |journal=J. Virol. |volume=75 |issue=12 |pages=5697–702 |year=2001 |month=June |pmid=11356979 |pmc=114284 |doi=10.1128/JVI.75.12.5697-5702.2001 |url=}}</ref> The late proteins are used in forming 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 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 [[Vesicle (biology)|vesicles]].<ref>{{cite journal |author=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 |year=2001 |month=April |pmid=11264357 |pmc=114859 |doi=10.1128/JVI.75.8.3675-3684.2001 |url=}}</ref> === Latent infection === HSV may persist in a quiescent but persistent form known as ''latent infection'', notably in [[Ganglion|neural ganglia]].<ref name=Sherris /> During latent infection of a cell, HSV express [[HHV LAT|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 later recurrences to produce further infections. A protein found in [[neuron]]s may bind to herpes virus DNA and regulate [[Virus latency|latency]]. Herpes virus DNA contains a gene for a protein called ICP4, which an important [[Transactivation|transactivator]] of genes associated with lytic infection in HSV-1.<ref name="pmid17555596">{{cite journal |author=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 |issue= |pages=56 |year=2007 |pmid=17555596 |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 deacytalization]] occurs atop the ICP4 gene sequence to prevent initiation of transription from this gene, thereby preventing transcription of other viral genes involved in the lytic cycle.<ref name="PMID17555596">{{cite journal |author=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 |issue= |pages=56 |year=2007 |pmid=17555596 |doi=10.1186/1743-422X-4-56}}</ref><ref name="pmid17502875">{{cite journal |author=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}}</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 |author=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=}}</ref> === Reactivation === Ther virus can be reactivated due to the effects of other illnesses such as cold and influenza, eczema, emotional and physical stress, exposure to bright sunlight, gastric upset, fatigue or injury, as well as menstruation resulting in the reappearance of surface sores. == Anti-viral medication == === Nucleoside analogs === {| class = "prettytable" style = "width:55%; float:right; font-size:90%; margin-left:15px" !Oral Prodrug<br> !Drug !Analog of [[Nucleoside]] !Nucleoside Family |- |[[Famciclovir]]<ref name=ASHA>{{cite web | title = Learn About Herpes: Treatment | work = | url = http://www.ashastd.org/herpes/herpes_learn_treatment.cfm | publisher = American Social Health Association | accessdate = 2007-07-09}}</ref><br>(bioavailability: 75% oral)<br>(trade names: ''Famvir'') |[[Penciclovir]]<br>(1.5% oral, IV, locally topical)<br>(''Denavir'', ''Fenistil'') |rowspan="3"|<math>\Bigg\}</math>[[guanosine]] |rowspan="3"|[[purine]] |- | [[Valaciclovir]]<br>(55% oral)<br>(''Valtrex'') | [[Aciclovir]]<br>(10-20% oral)<br>(''Zovirax'', ''Zovir'') |- | [[Valganciclovir]]<br>(60% oral)<br>(''Valcyte'') | [[Ganciclovir]]<br>(5% oral, IV, locally intraocular)<br>(''Cytovene'', ''Cymevene'') |- | [[Brivudine]]<ref>{{cite journal | author = Ciucci A, Lafrate EM, Manzini S, Giachetti A | title = Mechanism of antiviral action of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) : direct evidence with 14-C-BVDU in herpes simplex virus-infected cells | journal = Antiviral Chemistry & Chemotherapy | year = 1997 | volume = 8 | pages = 565&ndash;71 | url=http://cat.inist.fr/?aModele=afficheN&cpsidt=2064708 }}</ref> (BVDU) | &nbsp; | [[thymidine]] | [[pyrimidine]] |} Treatment is available in the form of antiviral medications such as [[Nucleoside analogues|nucleoside analogs]], which reduce the duration of symptoms of a herpes simplex virus outbreak and accelerate healing. [[Nucleoside]] analogs are molecules which possess a similarity to natural [[nucleotide]]s - the building-blocks of [[DNA]] and [[RNA]]. Active herpes simplex virus will [[viral replication|replicate]]; a virus replicating in the presence of these analogs will incorporate them into its DNA, so that its genetic material will contain defects and [[mutations]]. As a result, the next generation of virus will be damaged and reduced in number. Nucleoside analogs are typically used at the first symptoms of an viral outbreak to reduce the duration of the outbreak and improve healing of the lesion. Treatment taken prior to the appearance of lesions may avert or reduce the symptoms of the outbreak. Occasionally nucleoside analogs are used as a daily suppressive therapy, and taken daily for several years. Suppressive therapy reduces frequency of symptoms and recurrence of outbreaks. In addition, suppressive therapy reduces [[Subclinical infection|subclinical]] [[viral shedding]], lowering the risk of transmission through sexual contact or kissing. Common nucleoside analogs are listed in the table above. Of these, Ganciclovir is known to have [[cytotoxic]] effects on infected cells but Acyclovir is not known to have this effect.<ref>{{cite journal |author=Rubsam LZ, Davidson BL, Shewach DS |title=Superior cytotoxicity with ganciclovir compared with acyclovir and 1-beta-D-arabinofuranosylthymine in herpes simplex virus-thymidine kinase-expressing cells: a novel paradigm for cell killing |journal=Cancer Res. |volume=58 |issue=17 |pages=3873–82 |year=1998 |pmid=9731497 |doi=}}</ref> === Fusion inhibitors === Fusion inhibitors prevent "fusion" of the viral envelope with the cell membrane. This prevents [[viral entry]] to the cell. One example of a fusion inhibitor is [[Docosanol]], which is supplied in a cream formulation for topical application.<ref name="pmid15571473">{{cite journal |author=Leung DT, Sacks SL |title=Docosanol: a topical antiviral for herpes labialis |journal=Expert Opin Pharmacother |volume=5 |issue=12 |pages=2567–71 |year=2004 |pmid=15571473 |doi=10.1517/14656566.5.12.2567}}</ref> === Helicase-primase inhibitors === One of three key protein structures involved in HSV DNA replication is the [[Helicase]]-[[Primase]] structure. New research compounds which bind to this megamolecule show remarkable effectiveness against HSV. In particular, BAY 57-1293 has shown positive results in animal models of HSV infection.<ref>{{cite journal |author=Kleymann et al |title=New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease |journal=Nat. Med. |volume=8 |issue=4 |pages=392–8 |year=2002 |pmid=11927946 |doi=10.1038/nm0402-392 |url=http://www.nature.com/nm/journal/v8/n4/full/nm0402-392.html}}</ref> === Dietary supplements === The [[amino acid]] [[lysine]] has demonstrated the ability to reduce the duration of infection through inhibiting the replication of the HSV. When foods high in lysine (such as lentils) are consumed in preference to foods high in [[arginine]], HSV replication may be inhibited; conversely, consuming foods high in arginine (such as nuts or peanuts) may interfere with the therapeutic use of lysine.<ref>{{cite web | title = Cold Sores | work = | url = http://www.puritan.com/vf/healthnotes/HN_live/Concern/Cold_Sores.htm | publisher = Healthnotes | accessdate = 2007-07-09}}</ref> However, according to the American Social Health Association: "While some studies have suggested that lysine supplements can reduce the frequency of recurrences or healing time, other trials have been unable to replicate those results. Therefore, there is not sufficient information to discern how effective it may be, in addition to what the effective dosages or frequency of L-lysine may be."<ref name=ASHA /> === Other anti-viral medication === [[Undecylenic acid]] (Castor oil derivative) is proven to have anti-bacterial and anti-viral properties that are effective on viral skin infections such as the herpes simplex virus (HSV). Used as a cream formulation, this treatment reduces viral shedding and severity of itching associated with an HSV outbreak, but does not prevent episodes, speed up healing, or reduce lesion size.<ref name="pmid9207352">{{cite journal |author=Shafran SD, Sacks SL, Aoki FY, ''et al'' |title=Topical undecylenic acid for herpes simplex labialis: a multicenter, placebo-controlled trial |journal=J. Infect. Dis. |volume=176 |issue=1 |pages=78–83 |year=1997 |pmid=9207352 |doi=}}</ref> [[Butylated hydroxytoluene]] (BHT), commonly available as a food preservative, has been shown ''in vitro'' to inactivate enveloped viruses including herpes.<ref>{{cite journal |author=Snipes W, Person S, Keith A, Cupp J |title=Butylated hydroxytoluene inactivated lipid-containing viruses |journal=Science |volume=188 |issue=4183 |pages=64–6 |year=1975 |pmid=163494 |doi=}}</ref><ref>{{cite journal |author=Coohill TP, Babich M, Taylor WD, Snipes W |title=A comparison of herpes simplex virus plaque development after viral treatment with anti-DNA or antilipid agents |journal=Biophys. J. |volume=30 |issue=3 |pages=517–21 |year=1980 |pmid=6266532 |doi=}}</ref> ''In-vivo'' studies of topical application to animals confirmed the anti-viral activity of BHT during outbreaks.<ref>{{cite journal |author=Richards JT, Katz ME, Kern ER |title=Topical butylated hydroxytoluene treatment of genital herpes simplex virus infections of guinea pigs |journal=Antiviral Res. |volume=5 |issue=5 |pages=281–90 |year=1985 |pmid=2998276 |doi=}}</ref> BHT has not been clinically tested and approved to treat herpes in humans. Researchers at the [[University of Florida]] have made a hammerhead [[ribozyme]] that targets and cleaves the mRNA of essential genes in HSV-1. The hammerhead which targets the mRNA of the UL20 gene greatly reduced the level of HSV-1 ocular infection in rabbits and reduced the viral yield in vivo.<ref>[http://www.nature.com/mt/journal/v13/n1s/abs/mt2006942a.html Molecular Therapy - Abstract of article: 801. RNA Gene Therapy Targeting Herpes Simplex Virus<!-- Bot generated title -->]</ref> === Drug resistance === Resistance of HSVes in cell culture has been reported for nucleosides in the range of 10<sup>-2</sup> to 10<sup>-4</sup> and for [[Helicase]]-[[Primase]] inhibitors in the range of 10<sup>-4</sup> to 10<sup>-6</sup>. However, in the clinic roughly 1-2% of the patients are infected by nucleoside-resistant HSVes. In the immunocompromised patient population such as transplant, AIDS or cancer patients the resistance rate can reach up to 10%. == Vaccine research == {{main|Herpes simplex}} Herpevac, a vaccine for HSV-2 is currently (as of February 2007) undergoing clinical testing in women in the United States and Canada.<ref>{{cite news | author = Baker T | title = First herpes vaccine under study| url = https://my.mcg.edu/portal/page/portal/News/archive/2006/First%20herpes%20vaccine%20under%20study | work = Press release | publisher = Medical College of Georgia | date = 2006-06-13 | accessdate = 2007-06-17 }}</ref><ref>{{cite web | title = Herpevac Trial for Women | publisher = NIH | url =http://www.niaid.nih.gov/dmid/stds/herpevac/default.htm | accessdate = 2007-07-09}}</ref> Previous studies have determined that this vaccine is approximately 70% effective in women, but does not prevent the disease in men.<ref>{{cite web | title = Major Herpes Vaccine Trial Launched in Women | work = | url = http://www.nih.gov/news/pr/nov2002/niaid-20.htm | date = 2002-11-20 | accessdate = 2007-07-09}}</ref> Currently the [[University of Florida]] is seeking a company interested in commercializing a novel method for preventing the spread and recurrence of herpes simplex virus. Researchers at the University of Florida have developed a gene therapy that employs hammerhead ribozymes to inhibit herpes viral replication. When administered by a single injection after the initial infection, the therapy provides life-long inhibition of recurring outbreaks.<ref>{{cite web | title = Major Herpes Vaccine Breakthrough | work = | url = http://apps.rgp.ufl.edu/otl/viewTechInfo.cfm?case=10994 | date = 2008 | accessdate = 2008-05-17}}</ref> == References == <!-- --------------------------------------------------------------- See http://en.wikipedia.org/wiki/Wikipedia:Footnotes for a discussion of different citation methods and how to generate footnotes using the<ref> & </ref> tags and the {{Reflist}} template -------------------------------------------------------------------- --> {{Reflist|2}} == External links == * [http://www.ihmf.org International Herpes Management Forum] * [http://www.mayoclinic.com/health/cold-sore/DS00358 Mayo Clinic on Cold Sores] * [http://www.phac-aspc.gc.ca/publicat/std-mts/sti_k.html Genital Herpes - Public Health Agency of Canada] * [http://www.herpes.org.uk UK Genital Herpes Resource Site] * [http://www.nhsdirect.nhs.uk/articles/article.aspx?articleId=194 NHS Health Encyclopaedia - Information on Cold Sores] * [http://news.bbc.co.uk/1/hi/health/7483832.stm Cold sore virus secret revealed] [[BBC News]] {{DEFAULTSORT:Herpes simplex virus}} [[Category:Herpesviruses]] [[de:Herpes-simplex-Virus]] [[dv:ޖެނިޓަލް ހާރޕީޒް]] [[hr:Herpes simpleks]] [[id:Virus herpes simpleks]] [[it:Herpes simplex]] [[lt:Herpesas]] [[nl:Herpes simplexvirus]] [[ja:単純ヘルペスウイルス]] [[no:Herpes simplex]] [[pl:Wirus opryszczki pospolitej]] [[ro:Virusul herpes simplex]] [[simple:Herpes simplex]] [[sl:Virus herpesa simpleksa]] [[fi:Herpes simplex]] [[sv:Herpes simplex]] [[ta:பாலுறுப்பு ஹேர்பீஸ்]] [[tr:Herpes simpleks]] [[zh:单纯疱疹病毒]]