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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);

VisualWikitext

Latest revision as of 17:58, 18 September 2017

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are two strains of the herpes virus family, Herpesviridae, which cause extremely painful infections in humans.^[1] They are also called Human Herpes Virus 1 and 2 (HHV-1 and HHV-2).

An infection is marked by watery blisters in the skin or mucous membranes (such as the mouth or lips) or on the genitals.^[1] Lesions heal with a 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 present in the cell bodies of nerves in the area. When it becomes reactivated, it is produced in the nerve cell and transported to the skin via the nerve's axon.^[2]

Herpes is contagious if the carrier is producing and shedding 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. An HSV infection on the lips is commonly known as a "cold sore" or "fever blister". The blisters resemble those of chickenpox, an infection caused by another member of the alpha-Herpesviridae subfamily, Varicella Zoster Virus (VZV), also known as Human Herpes Virus 3 (HHV-3).

Transmission

HSV is transmitted by contact with lips or genitals when the sores are present, or possibly when sores are not visible (known as viral shedding). HSV can be present in semen, vaginal fluids, shedded skin in the pelvic region from eczema, and saliva. In addition, herpes may be transmitted during childbirth, which can be fatal to the infant. The immature immune system of the child is unable to defend against the virus and even if treated, infection can result in brain damage. Transmission occurs when passing through the birth canal. But, risk of infection is minimal 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.^[1]

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.^[3] HSV-1 and HSV-2 each contain at least 74 genes (or open-reading frames, ORFs) within their genomes,^[4] although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.^[5] 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_L) and the short unique region (U_S). Of the 74 known ORFs, U_L contains 56 viral genes, whereas U_S contains only 12.^[4] Transcription of HSV genes is catalyzed by RNA polymerase II of the infected host.^[4] 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.^[4]

Five proteins from (U_L) form the viral capsid; UL6, UL18, UL35, UL38 and the major capsid protein UL19.^[3]

The open reading frames (ORFs) of HSV-1^[6]^[4]
Gene	Protein	Function/description	Gene	Protein	Function/description
UL1	Glycoprotein L [3]	Surface and membrane	UL38	UL38; VP19C [4]	Capsid assembly and DNA maturation
UL2	UL2 [5]	Uracil-DNA glycosylase	UL39	UL39 [6]	Ribonucleotide reductase (Large subunit)
UL3	UL3 [7]	unknown	UL40	UL40 [8]	Ribonucleotide reductase (Small subunit)
UL4	UL4 [9]	unknown	UL41	UL41; VHS [10]	Tegument protein; Virion host shutoff^[7]
UL5	UL5 [11]	DNA replication	UL42	UL42 [12]	DNA polymerase processivity factor
UL6	UL6 [13]	Processing and packaging DNA	UL43	UL43 [14]	Membrane protein
UL7	UL7 [15]	Virion maturation	UL44	Glycoprotein C [16]	Surface and membrane
UL8	UL8 [17]	DNA helicase/primase complex-associated protein	UL45	UL45 [18]	Membrane protein; C-type lectin^[8]
UL9	UL9 [19]	Replication origin-binding protein	UL46	Alpha-TIF [20]	Tegument protein
UL10	Glycoprotein M [21]	Surface and membrane	UL47	UL47; VP13/14 [22]	Tegument protein
UL11	UL11 [23]	virion exit and secondary envelopment	UL48	ICP25; VP16 [24]	Virion maturation; activation of IEGs
UL12	UL12 [25]	Alkaline exonuclease	UL49	UL49A [26]	Envelope protein
UL13	UL13 [27]	Serine-threonine protein kinase	UL50	UL50 [28]	dUTP diphosphatase
UL14	UL14 [29]	Tegument protein	UL51	UL51 [30]	Tegument protein
UL15	Terminase [31]	Processing and packaging of DNA	UL52	UL52 [32]	DNA helicase/primase complex protein
UL16	UL16 [33]	Tegument protein	UL53	Glycoprotein K [34]	Surface and membrane
UL17	UL17 [35]	Processing and packaging DNA	UL54	IE63; ICP27 [36]	Transcriptional regulation
UL18	VP23 [37]	Capsid protein	UL55	UL55 [38]	Unknown
UL19	VP5 [39]	Major capsid protein	UL56	UL56 [40]	Unknown
UL20	UL20 [41]	Membrane protein	US1	ICP22; IE68 [42]	Viral replication
UL21	UL21 [43]	Tegument protein^[9]	US2	US2 [44]	Unknown
UL22	Glycoprotein H [45]	Surface and membrane	US3	US3 [46]	Serine/threonine-protein kinase
UL23	Thymidine kinase [47]	Peripheral to DNA replication	US4	Glycoprotein G [48]	Surface and membrane
UL24	UL24 [49]	unknown	US5	Glycoprotein J [50]	Surface and membrane
UL25	UL25 [51]	Processing and packaging DNA	US6	Glycoprotein D [52]	Surface and membrane
UL26	P40; VP24; VP22A [53]	Capsid protein	US7	Glycoprotein I [54]	Surface and membrane
UL27	Glycoprotein B [55]	Surface and membrane	US8	Glycoprotein E [56]	Surface and membrane
UL28	ICP18.5 [57]	Processing and packaging DNA	US9	US9 [58]	Tegument protein
UL29	UL29 [59]	Major DNA-binding protein	US10	US10 [60]	Capsid/Tegument protein
UL30	DNA polymerase [61]	DNA replication	US11	US11; Vmw21 [62]	Binds DNA and RNA
UL31	UL31 [63]	Nuclear matrix protein	US12	ICP47; IE12 [64]	Inhibits MHC class I pathway
UL32	UL32 [65]	Envelope glycoprotein	RS1	ICP4; IE175 [66]	Activates gene transcription
UL33	UL33 [67]	Processing and packaging DNA	ICP0	ICP0; IE110; α0 [68]	Regulates gene transcription
UL34	UL34 [69]	Inner nuclear membrane protein	LRP1	LRP1 [70]	Latency-related protein
UL35	VP26 [71]	Capsid protein	LRP2	LRP2 [72]	Latency-related protein
UL36	UL36 [73]	Large tegument protein	RL1	RL1; ICP34.5 [74]	Neurovirulence factor
UL37	UL37 [75]	Capsid assembly	LAT	none [76]	Latency-associated transcript

Cellular entry

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.^[10] 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 (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.^[10] 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 arranged as a ring; the proteins contain a leucine zipper sequence of amino acids which allow them to adhere to each other.^[11] Each icosahedral capsid contains a single portal, located in one vertex.^[12]^[13] The DNA exits the capsid in a single linear segment.^[14]

Replication

Consequent to a cell being infected, groups of Herpes virus proteins, termed immediate-early, early, and late proteins, are produced following specific time periods. Research using a new flow cytometry methodology in KSHV indicates the possibility of an additional lytic stage, delayed-late.^[15] 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.

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 (VHF-UL41) is very important to viral replication. 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 VHF protein remains in the cytoplasm.^[16]^[17]

The late proteins transcribed are used in the capsid formation and forming the receptors on the surface of the virus. The packaging of the viral particles, which include the genome, core and the capsid, occur in the nucleus. In the nucleus, cleavage of genome concatemers occurs and these are placed into pre-formed capsids. HSV-1 undergoes a process of primary and secondary envelopment. It acquires a primary envelope by budding into the inner nuclear membrane. 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.^[18]

Latent infection

HSV may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia.^[1] During latent infection of a cell, HSV 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 for the virus, which allows later recurrences to produce further infections.

A protein found in neurons may bind to Herpes DNA and regulate latency. Recent studies have found that the Herpes DNA contains a sequence that is involved in silencing the expression of a gene associated with lytic infection, ICP4. The sequence contains elements which bind to human nerve cell protein factors: the human neuronal protein Neuronal Restrictive Silencing Factor (NRSF), and human Repressor Element Silencing Transcription Factor (REST). When the proteins are able to bind to the viral DNA elements, histone deacytalization occurs atop the ICP4 gene sequence.^[19]^[20]

Reactivation

The virus can be reactivated due to the effects of other illnesses such as cold and influenza, excema, menstruation, emotional and physical stress, exposure to bright sunlight, gastric upset, fatigue or injury, consequently resulting in the appearance of surface sores.

Treatment

Antimicrobial Regimen

Genital Herpes^[21]

1.First Clinical Episode of Genital Herpes

Preferred Regimen (1): Acyclovir 400 mg PO tid for 7–10 days
Preferred Regimen (2): Acyclovir 200 mg PO five times a day for 7–10 days
Preferred Regimen (3): Valacyclovir 1 g PO bid for 7–10 days
Preferred Regimen (4): Famciclovir 250 mg PO tid for 7–10 days
Note:Treatment can be extended if healing is incomplete after 10 days of therapy.

2.Established HSV-2 Infection

2.1 Suppressive Therapy for Recurrent Genital Herpes

Preferred Regimen (1): Acyclovir 400 mg PO bid
Preferred Regimen (2): Valacyclovir 500 mg PO qd
Preferred Regimen (3): Valacyclovir 1 g PO qd
Preferred Regimen (4): Famciclovir 250 mg PO bid
Note(1):Daily therapy with Acyclovir for as long as 6 years and with Valacyclovir OR Famciclovir for 1 year
Note(2):Valacyclovir 500 mg qd might be less effective than other Valacyclovir OR Acyclovir dosing regimens in persons who have very frequent recurrences (i.e., ≥10 episodes per year).

2.2 Episodic Therapy for Recurrent Genital Herpes

Preferred Regimen (1): Acyclovir 400 mg PO tid for 5 days
Preferred Regimen (2): Acyclovir 800 mg PO bid for 5 days
Preferred Regimen (3): Acyclovir 800 mg PO tid for 2 days
Preferred Regimen (4): Valacyclovir 500 mg PO bid for 3 days
Preferred Regimen (5): Valacyclovir 1 g PO qd for 5 days
Preferred Regimen (6): Famciclovir 125 mg PO bid for 5 days
Preferred Regimen (7): Famciclovir 1 g PO bid for 1 day
Preferred Regimen (8): Famciclovir 500 mg once, followed by 250 mg PO bid for 2 days

3. Severe Disease (disseminated infection, pneumonitis, or hepatitis) or CNS complications (e.g., meningoencephalitis).

Preferred Regimen: Acyclovir 5–10 mg/kg IV q8h for 2–7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy. HSV encephalitis requires 21 days of intravenous therapy. Impaired renal function warrants an adjustment in acyclovir dosage.

4. Special Considerations

4.1 HIV Infection

4.1.1 Daily Suppressive Therapy in Persons with HIV

Preferred Regimen (1): Acyclovir 400–800 mg PO bid /tid
Preferred Regimen (2): Valacyclovir 500 mg PO bid
Preferred Regimen (3): Famciclovir 500 mg PO bid

4.1.2 Episodic Infection in Persons with HIV

Preferred Regimen (1): Acyclovir 400 mg PO tid for 5–10 days
Preferred Regimen (2): Valacyclovir 1 g PO bid for 5–10 days
Preferred Regimen (3): Famciclovir 500 mg PO bid for 5–10 days
Note: For severe HSV disease, initiating therapy with Acyclovir 5–10 mg/kg IV q8 h might be necessary.

4.2 Genital Herpes in Pregnancy

Suppressive therapy of pregnant women with recurrent genital herpes
Preferred Regimen (1): Acyclovir 400–800 mg PO bid /tid
Preferred Regimen (2): Valacyclovir 500 mg PO bid
Note:Treatment recommended starting at 36 weeks of gestation.

4.3 Neonatal Herpes

Known or suspected neonatal herpes

Preferred Regimen: Acyclovir 20 mg/kg IV q 8 h
Note (1): Treatment for 14 days if disease is limited to the skin and mucous membranes, or
Note (2): Treatment for 21 days for disseminated disease and that involving the central nervous system.

4.4 Acyclovir-resistant genital herpes

Preferred Regimens: Foscarnet 40–80 mg/kg IV q8 h until clinical resolution is attained
Alternative Regimen (1): Cidofovir 5 mg/kg IV once weekly might also be effective.
Alternative Regimen (2): Imiquimod topical preparations should be applied to the lesions qd for 5 consecutive days.

4.5 Management of Sex Partners

Preferred Regimen (1): Acyclovir 400 mg PO tid for 7–10 days
Preferred Regimen (2): Acyclovir 200 mg PO five times a day for 7–10 days
Preferred Regimen (3): Valacyclovir 1 g PO bid for 7–10 days
Preferred Regimen (4): Famciclovir 250 mg PO tid for 7–10 days
Note:The sex partners of persons who have genital herpes can benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated

4.6 Allergy, Intolerance, and Adverse Reactions

Allergic and other adverse reactions to oral Acyclovir, Valacyclovir, and Famciclovir are rare. Desensitization to acyclovir has been described.

Vaccine research

Herpevac, a vaccine for HSV-2 is currently (as of February 2007) undergoing clinical testing in women in the United States and Canada.^[22]^[23] Previous studies have determined that this vaccine is approximately 70% effective in women, but does not prevent the disease in men.^[24]

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed. ed.). McGraw Hill. pp. 555&ndash, 62. ISBN 0838585299.
↑ "Herpes simplex". DermNet NZ — New Zealand Dermatological Society. 2006-09-16. Retrieved 2006-10-15.
↑ ^3.0 ^3.1 Mettenleiter TC, Klupp BG, Granzow H (2006). "Herpesvirus assembly: a tale of two membranes". Curr. Opin. Microbiol. 9 (4): 423–9. doi:10.1016/j.mib.2006.06.013. PMID 16814597.
↑ ^4.0 ^4.1 ^4.2 ^4.3 ^4.4 McGeoch DJ, Rixon FJ, Davison AJ (2006). "Topics in herpesvirus genomics and evolution". Virus Res. 117 (1): 90–104. doi:10.1016/j.virusres.2006.01.002. PMID 16490275.
↑ Rajcáni J, Andrea V, Ingeborg R (2004). "Peculiarities of herpes simplex virus (HSV) transcription: an overview". Virus Genes. 28 (3): 293–310. PMID 15266111.
↑ Search in UniProt Knowledgebase (Swiss-Prot and TrEMBL) for: HHV1
↑ Matis J, Kúdelová M (2001). "Early shutoff of host protein synthesis in cells infected with herpes simplex viruses". Acta Virol. 45 (5–6): 269–77. PMID 12083325.
↑ Wyrwicz LS, Ginalski K, Rychlewski L (2007). "HSV-1 UL45 encodes a carbohydrate binding C-type lectin protein". Cell Cycle. 7 (2). PMID 18256535.
↑ 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. PMID 16014918.
↑ ^10.0 ^10.1 Subramanian RP, Geraghty RJ (2007). "Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B". Proc. Natl. Acad. Sci. U.S.A. 104 (8): 2903–8. doi:10.1073/pnas.0608374104. PMID 17299053.
↑ Cardone G, Winkler DC, Trus BL, Cheng N, Heuser JE, Newcomb WW, Brown JC, Steven AC (2007 May 10). "Visualization of the herpes simplex virus portal in situ by cryo-electron tomography". Virology. 361 (2): 426-34. PMID 17188319. Check date values in: |date= (help)
↑ Trus BL, Cheng N, Newcomb WW, Homa FL, Brown JC, Steven AC (2004 Nov). "Structure and polymorphism of the UL6 portal protein of herpes simplex virus type 1". Journal of Virology. 78 (22): 12668-71. PMID 15507654. Check date values in: |date= (help)(Article: [1])
↑ Nellissery JK, Szczepaniak R, Lamberti C, Weller SK (2007 Jun 20). "A putative leucine zipper within the HSV-1 UL6 protein is required for portal ring formation". Journal Virology. PMID 17581990. Check date values in: |date= (help)
↑ Newcomb WW, Booy FP, Brown JC (2007). "Uncoating the herpes simplex virus genome". J. Mol. Biol. 370 (4): 633–42. doi:10.1016/j.jmb.2007.05.023. PMID 17540405.
↑ Adang LA, Parsons CH, Kedes DH (2006). "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". J. Virol. 80 (20): 10073–82. doi:10.1128/JVI.01156-06. PMID 17005685.
↑ 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. PMID 16940547.
↑ Skepper JN, Whiteley A, Browne H, Minson A(2001)."Herpes Simplex Virus Nucleocapsids Mature to Progeny Virions by an Envelopment-Deenvelopment-Reenvelopment Pathway".J.Virol.75(12):5697-5702
↑ Granzow H, Klupp BG, Fuchs W, Veits J, Osterrieder N, Mettenleiter TC (2001)."Egress of Alphaherpesviruses:Comparative Ultrastructural Study". J. Virol.75(8):3675-3684
↑ 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. PMID 17555596.
↑ 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.
↑ Workowski, Kimberly A.; Bolan, Gail A. (2015-06-05). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 64 (RR-03): 1–137. ISSN 1545-8601. PMID 26042815.
↑ Baker T (2006-06-13). "First herpes vaccine under study". Press release. Medical College of Georgia. Retrieved 2007-06-17.
↑ "Herpevac Trial for Women". NIH. Retrieved 2007-07-09.
↑ "Major Herpes Vaccine Trial Launched in Women". 2002-11-20. Retrieved 2007-07-09.

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Template:WikiDoc Sources

[Sherris-1] 1.0 ^1.1 ^1.2 ^1.3 Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed. ed.). McGraw Hill. pp. 555&ndash, 62. ISBN 0838585299.

[2] "Herpes simplex". DermNet NZ — New Zealand Dermatological Society. 2006-09-16. Retrieved 2006-10-15.

[pmid16814597-3] 3.0 ^3.1 Mettenleiter TC, Klupp BG, Granzow H (2006). "Herpesvirus assembly: a tale of two membranes". Curr. Opin. Microbiol. 9 (4): 423–9. doi:10.1016/j.mib.2006.06.013. PMID 16814597.

[pmid16490275-4] 4.0 ^4.1 ^4.2 ^4.3 ^4.4 McGeoch DJ, Rixon FJ, Davison AJ (2006). "Topics in herpesvirus genomics and evolution". Virus Res. 117 (1): 90–104. doi:10.1016/j.virusres.2006.01.002. PMID 16490275.

[pmid15266111-5] Rajcáni J, Andrea V, Ingeborg R (2004). "Peculiarities of herpes simplex virus (HSV) transcription: an overview". Virus Genes. 28 (3): 293–310. PMID 15266111.

[6] Search in UniProt Knowledgebase (Swiss-Prot and TrEMBL) for: HHV1

[pmid12083325-7] Matis J, Kúdelová M (2001). "Early shutoff of host protein synthesis in cells infected with herpes simplex viruses". Acta Virol. 45 (5–6): 269–77. PMID 12083325.

[pmid18256535-8] Wyrwicz LS, Ginalski K, Rychlewski L (2007). "HSV-1 UL45 encodes a carbohydrate binding C-type lectin protein". Cell Cycle. 7 (2). PMID 18256535.

[pmid16014918-9] 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. PMID 16014918.

[Subramanian_17299053-10] 10.0 ^10.1 Subramanian RP, Geraghty RJ (2007). "Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B". Proc. Natl. Acad. Sci. U.S.A. 104 (8): 2903–8. doi:10.1073/pnas.0608374104. PMID 17299053.

[pmid17188319-11] Cardone G, Winkler DC, Trus BL, Cheng N, Heuser JE, Newcomb WW, Brown JC, Steven AC (2007 May 10). "Visualization of the herpes simplex virus portal in situ by cryo-electron tomography". Virology. 361 (2): 426-34. PMID 17188319. Check date values in: |date= (help)

[pmid15507654-12] Trus BL, Cheng N, Newcomb WW, Homa FL, Brown JC, Steven AC (2004 Nov). "Structure and polymorphism of the UL6 portal protein of herpes simplex virus type 1". Journal of Virology. 78 (22): 12668-71. PMID 15507654. Check date values in: |date= (help)(Article: [1])

[Nellissery_2007-13] Nellissery JK, Szczepaniak R, Lamberti C, Weller SK (2007 Jun 20). "A putative leucine zipper within the HSV-1 UL6 protein is required for portal ring formation". Journal Virology. PMID 17581990. Check date values in: |date= (help)

[pmid17540405-14] Newcomb WW, Booy FP, Brown JC (2007). "Uncoating the herpes simplex virus genome". J. Mol. Biol. 370 (4): 633–42. doi:10.1016/j.jmb.2007.05.023. PMID 17540405.

[PMID_17005685-15] Adang LA, Parsons CH, Kedes DH (2006). "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". J. Virol. 80 (20): 10073–82. doi:10.1128/JVI.01156-06. PMID 17005685.

[pmid16940547-16] 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. PMID 16940547.

[17] Skepper JN, Whiteley A, Browne H, Minson A(2001)."Herpes Simplex Virus Nucleocapsids Mature to Progeny Virions by an Envelopment-Deenvelopment-Reenvelopment Pathway".J.Virol.75(12):5697-5702

[18] Granzow H, Klupp BG, Fuchs W, Veits J, Osterrieder N, Mettenleiter TC (2001)."Egress of Alphaherpesviruses:Comparative Ultrastructural Study". J. Virol.75(8):3675-3684

[PMID17555596-19] 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. PMID 17555596.

[pmid17502875-20] 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.

[21] Workowski, Kimberly A.; Bolan, Gail A. (2015-06-05). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 64 (RR-03): 1–137. ISSN 1545-8601. PMID 26042815.

[22] Baker T (2006-06-13). "First herpes vaccine under study". Press release. Medical College of Georgia. Retrieved 2007-06-17.

[23] "Herpevac Trial for Women". NIH. Retrieved 2007-07-09.

[24] "Major Herpes Vaccine Trial Launched in Women". 2002-11-20. Retrieved 2007-07-09.

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@@ Line 1: / Line 1: @@
-'''For patient information on congenital herpes, click [[Congenital herpes (patient information)|here]]'''
 {{Taxobox | color=violet
 | name = ''Herpes simplex virus''
@@ Line 36: / Line 34: @@
 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"/>
-{{clr}}
-{| class = "prettytable" style = "width:90%; float:centre; font-size:90%; margin-left:40px"
+{| class = "prettytable" style = "width: 80%; font-size: 90%;"
 |-
 | 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"/>
@@ Line 190: / Line 188: @@
 The virus can be reactivated due to the effects of other illnesses such as cold and influenza, excema, menstruation, emotional and physical stress, exposure to bright sunlight, gastric upset, fatigue or injury, consequently resulting in the appearance of surface sores.
-== Anti-viral medication ==
+==Treatment==
-=== Nucleoside analogs ===
+===Antimicrobial Regimen===
+:* '''Genital Herpes'''<ref>{{Cite journal| issn = 1545-8601| volume = 64| issue = RR-03| pages = 1–137| last1 = Workowski| first1 = Kimberly A.| last2 = Bolan| first2 = Gail A.| title = Sexually transmitted diseases treatment guidelines, 2015| journal = MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control| date = 2015-06-05| pmid = 26042815}}</ref>
-Treatment is available in the form of antiviral medications such as [[Nucleoside analogues|nucleoside analogs]], which reduce the duration of symptoms of a herpex 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.
+::* 1.'''First Clinical Episode of Genital Herpes'''
+:::* Preferred Regimen (1): [[Acyclovir]] 400 mg PO tid for 7–10 days
-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.
+:::* Preferred Regimen (2): [[Acyclovir]] 200 mg PO five times a day for 7–10 days
+:::* Preferred Regimen (3): [[Valacyclovir]] 1 g PO bid for 7–10 days
-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>
+:::* Preferred Regimen (4): [[Famciclovir]] 250 mg PO tid  for 7–10 days
+:::* Note:Treatment can be extended if healing is incomplete after 10 days of therapy.
-{|padding="6" border="1"
+::* 2.'''Established HSV-2 Infection '''
-!Oral Prodrug<br>
+:::* 2.1 '''Suppressive Therapy for Recurrent Genital Herpes'''
-!Drug
+::::* Preferred Regimen (1): [[Acyclovir]] 400 mg PO bid
-!Analog of [[Nucleoside]]
+::::* Preferred Regimen (2): [[Valacyclovir]] 500 mg PO qd
-!Nucleoside Family
+::::* Preferred Regimen (3): [[Valacyclovir]] 1 g PO qd
-|-
+::::* Preferred Regimen (4): [[Famciclovir]] 250 mg PO bid
-|[[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'')
+::::* Note(1):Daily therapy with [[Acyclovir]] for as long as 6 years and with [[Valacyclovir]]  {{or}} [[Famciclovir]] for 1 year
-|[[Penciclovir]]<br>(1.5% oral, IV, locally topical)<br>(''Denavir'', ''Fenistil'')
+::::* Note(2):[[Valacyclovir]] 500 mg qd might be less effective than other [[Valacyclovir]] {{or}} [[Acyclovir]] dosing regimens in persons who have very frequent recurrences (i.e., ≥10 episodes per year).
-|rowspan="3"|<math>\Bigg\}</math>[[guanosine]]
+:::* 2.2 '''Episodic Therapy for Recurrent Genital Herpes'''
-|rowspan="3"|[[purine]]
+::::* Preferred Regimen (1): [[Acyclovir]] 400 mg PO tid for 5 days
-|-
+::::* Preferred Regimen (2): [[Acyclovir]] 800 mg PO bid for 5 days
-| [[Valaciclovir]]<br>(55% oral)<br>(''Valtrex'')
+::::* Preferred Regimen (3): [[Acyclovir]] 800 mg  PO tid for 2 days
-| [[Aciclovir]]<br>(10-20% oral)<br>(''Zovirax'', ''Zovir'')
+::::* Preferred Regimen (4): [[Valacyclovir]] 500 mg PO bid for 3 days
-|-
+::::* Preferred Regimen (5): [[Valacyclovir]] 1 g PO qd for 5 days
-| [[Valganciclovir]]<br>(60% oral)<br>(''Valcyte'')
+::::* Preferred Regimen (6): [[Famciclovir]] 125 mg  PO bid  for 5 days
-| [[Ganciclovir]]<br>(5% oral, IV, locally intraocular)<br>(''Cytovene'', ''Cymevene'')
+::::* Preferred Regimen (7): [[ Famciclovir]] 1 g PO bid  for 1 day
-|-
+::::* Preferred Regimen (8): [[Famciclovir]] 500 mg once, followed by 250 mg  PO bid  for 2 days
-| [[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)
+::* 3. '''Severe Disease''' (disseminated infection, pneumonitis, or hepatitis) or CNS complications (e.g., meningoencephalitis).
-| &nbsp;
+:::* Preferred Regimen: [[ Acyclovir]] 5–10 mg/kg IV q8h  for 2–7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy. HSV encephalitis requires 21 days of intravenous therapy. Impaired renal function warrants an adjustment in acyclovir dosage.
-| [[thymidine]]
+::* 4. '''Special Considerations'''
-| [[pyrimidine]]
+:::* 4.1 '''HIV Infection'''
-|}
+::::* 4.1.1 '''Daily Suppressive Therapy in Persons with HIV'''
+:::::* Preferred Regimen (1): [[Acyclovir]] 400–800 mg PO bid /tid
-=== Fusion inhibitors ===
+:::::* Preferred Regimen (2): [[Valacyclovir]] 500 mg  PO bid
-Fusion inhibitors prevent "fusion" of the viral envelope with the cell membrane.  This prevents [[viral entry]] to the cell.
+:::::* Preferred Regimen (3): [[Famciclovir]] 500 mg PO bid
-* [[Docosanol]]
+::::* 4.1.2 '''Episodic Infection in Persons with HIV'''
+:::::* Preferred Regimen (1): [[Acyclovir]] 400 mg  PO tid  for 5–10 days
+:::::* Preferred Regimen (2): [[Valacyclovir]] 1 g PO bid for 5–10 days
+:::::* Preferred Regimen (3): [[Famciclovir]] 500 mg  PO bid for 5–10 days
+:::::* Note: For severe HSV disease, initiating therapy with [[Acyclovir]] 5–10 mg/kg IV q8 h might be necessary.
+:::* 4.2 '''Genital Herpes in Pregnancy'''
+::::* Suppressive therapy of pregnant women with recurrent genital herpes
+::::* Preferred Regimen (1): [[Acyclovir]] 400–800 mg PO bid /tid
+::::* Preferred Regimen (2): [[Valacyclovir]] 500 mg  PO bid
+::::* Note:Treatment recommended starting at 36 weeks of gestation.
+:::* 4.3 '''Neonatal Herpes '''
+::::* Known or suspected neonatal herpes
-=== Helicase-primase inhibitors ===
+::::* Preferred Regimen: [[Acyclovir]] 20 mg/kg IV q 8 h
-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=Crumpacker CS, Schaffer PA |title=New anti-HSV therapeutics target the helicase-primase complex |journal=Nat. Med. |volume=8 |issue=4 |pages=327-8 |year=2002 |pmid=11927930 |doi=10.1038/nm0402-327 |url=http://www.nature.com/nm/journal/v8/n4/full/nm0402-327.html}}</ref>
+::::* Note (1): Treatment for 14 days if disease is limited to the skin and mucous membranes, or
+::::* Note (2): Treatment for 21 days for disseminated disease and that involving the central nervous system.
-=== Dietary supplements ===
+:::* 4.4 '''Acyclovir-resistant genital herpes'''
-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 />
+::::* Preferred Regimens: [[Foscarnet ]] 40–80 mg/kg IV q8 h until clinical resolution is attained
+::::* Alternative Regimen (1): [[Cidofovir]] 5 mg/kg  IV once weekly might also be effective.
-=== Other anti-viral medication ===
+::::* Alternative Regimen (2): Imiquimod topical preparations should be applied to the lesions qd for 5 consecutive days.
-[[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).
+:::* 4.5 '''Management of Sex Partners'''
+::::* Preferred Regimen (1): [[Acyclovir]] 400 mg PO tid for 7–10 days
-[[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.
+::::* Preferred Regimen (2): [[Acyclovir]] 200 mg PO five times a day for 7–10 days
+::::* Preferred Regimen (3): [[Valacyclovir]] 1 g PO bid for 7–10 days
-=== Drug Resistance ===
+::::* Preferred Regimen (4): [[Famciclovir]] 250 mg PO tid  for 7–10 days
-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>.
+::::* Note:The sex partners of persons who have genital herpes can benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated
-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%.
+:::* 4.6 '''Allergy, Intolerance, and Adverse Reactions'''
+::::* Allergic and other adverse reactions to oral [[Acyclovir]], [[Valacyclovir]], and [[Famciclovir]] are rare. Desensitization to acyclovir has been described.
 == Vaccine research ==
@@ Line 267: / Line 277: @@
 [[zh:单纯疱疹病毒]]
-{{SIB}}
+[[Category:Infectious Disease Project]]
 [[Category:Herpesviruses]]
 [[Category:Sexually transmitted diseases]]
-[[Category:Infectious disease]]
 [[pl:Wirus opryszczki pospolitej]]