Herpes simplex virus

From Wikipedia, the free encyclopedia

Herpes simplex virus
TEM micrograph of a 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 (HWJ-1)
Herpes simplex virus 2 (HWJ-2)
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 humans.[1] Eight members of herpesviridae infect humans to cause a variety of illnesses including cold sores, chickenpox or varicella, shingles or herpes zoster (VZV), cytomegalovirus (CMV), and various cancers, 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 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 sores or fever blisters, whereas HSV-2 is more often associated with genital herpes.

An infection by a herpes simplex virus is marked by watery blisters in the skin or mucous membranes of the mouth, lips or 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 in the cell bodies of nerves 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.[2]

Herpes is contagious if the carrier is producing and 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.

Contents

[edit] Transmission

Main article: Herpes simplex

HSV is transmitted during close contact with an infected person who is shedding virus from the skin, in saliva or in secretions 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.[3] In addition, vertical transmission of HSV may occur between mother and child during childbirth, which can be fatal to the infant.[4] 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.[1]

[edit] Microbiology

[edit] 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.[5] HSV-1 and HSV-2 each contain at least 74 genes (or open-reading frames, ORFs) within their genomes,[6] although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.[7] 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 (UL) and the short unique region (US). Of the 74 known ORFs, UL contains 56 viral genes, whereas US contains only 12.[6] Transcription of HSV genes is catalyzed by RNA polymerase II of the infected host.[6] 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.[6]

Five proteins from (UL) form the viral capsid; UL6, UL18, UL35, UL38 and the major capsid protein UL19.[5]

The open reading frames (ORFs) of HSV-1[8][6]
Gene Protein Function/description Gene Protein Function/description
UL1 Glycoprotein L [2] Surface and membrane UL38 UL38; VP19C [3] Capsid assembly and DNA maturation
UL2 UL2 [4] Uracil-DNA glycosylase UL39 UL39 [5] Ribonucleotide reductase (Large subunit)
UL3 UL3 [6] unknown UL40 UL40 [7] Ribonucleotide reductase (Small subunit)
UL4 UL4 [8] unknown UL41 UL41; VHS [9] Tegument protein; Virion host shutoff[9]
UL5 UL5 [10] DNA replication UL42 UL42 [11] DNA polymerase processivity factor
UL6 UL6 [12] Processing and packaging DNA UL43 UL43 [13] Membrane protein
UL7 UL7 [14] Virion maturation UL44 Glycoprotein C [15] Surface and membrane
UL8 UL8 [16] DNA helicase/primase complex-associated protein UL45 UL45 [17] Membrane protein; C-type lectin[10]
UL9 UL9 [18] Replication origin-binding protein UL46 VP11/12 [19] Tegument proteins
UL10 Glycoprotein M [20] Surface and membrane UL47 UL47; VP13/14 [21] Tegument protein
UL11 UL11 [22] virion exit and secondary envelopment UL48 VP16 (Alpha-TIF) [23] Virion maturation; activate IEGs by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'.
UL12 UL12 [24] Alkaline exonuclease UL49 UL49A [25] Envelope protein
UL13 UL13 [26] Serine-threonine protein kinase UL50 UL50 [27] dUTP diphosphatase
UL14 UL14 [28] Tegument protein UL51 UL51 [29] Tegument protein
UL15 Terminase [30] Processing and packaging of DNA UL52 UL52 [31] DNA helicase/primase complex protein
UL16 UL16 [32] Tegument protein UL53 Glycoprotein K [33] Surface and membrane
UL17 UL17 [34] Processing and packaging DNA UL54 IE63; ICP27 [35] Transcriptional regulation
UL18 VP23 [36] Capsid protein UL55 UL55 [37] Unknown
UL19 VP5 [38] Major capsid protein UL56 UL56 [39] Unknown
UL20 UL20 [40] Membrane protein US1 ICP22; IE68 [41] Viral replication
UL21 UL21 [42] Tegument protein[11] US2 US2 [43] Unknown
UL22 Glycoprotein H [44] Surface and membrane US3 US3 [45] Serine/threonine-protein kinase
UL23 Thymidine kinase [46] Peripheral to DNA replication US4 Glycoprotein G [47] Surface and membrane
UL24 UL24 [48] unknown US5 Glycoprotein J [49] Surface and membrane
UL25 UL25 [50] Processing and packaging DNA US6 Glycoprotein D [51] Surface and membrane
UL26 P40; VP24; VP22A [52] Capsid protein US7 Glycoprotein I [53] Surface and membrane
UL27 Glycoprotein B [54] Surface and membrane US8 Glycoprotein E [55] Surface and membrane
UL28 ICP18.5 [56] Processing and packaging DNA US9 US9 [57] Tegument protein
UL29 UL29 [58] Major DNA-binding protein US10 US10 [59] Capsid/Tegument protein
UL30 DNA polymerase [60] DNA replication US11 US11; Vmw21 [61] Binds DNA and RNA
UL31 UL31 [62] Nuclear matrix protein US12 ICP47; IE12 [63] Inhibits MHC class I pathway by preventing binding of antigen to TAP
UL32 UL32 [64] Envelope glycoprotein RS1 ICP4; IE175 [65] Activates gene transcription
UL33 UL33 [66] Processing and packaging DNA ICP0 ICP0; IE110; α0 [67] E3 ubiquitin ligase that activates viral gene transcription and counteracts the interferon response
UL34 UL34 [68] Inner nuclear membrane protein LRP1 LRP1 [69] Latency-related protein
UL35 VP26 [70] Capsid protein LRP2 LRP2 [71] Latency-related protein
UL36 UL36 [72] Large tegument protein RL1 RL1; ICP34.5 [73] Neurovirulence factor. Antagonizes PKR by de-phosphorylating eIF4a.
UL37 UL37 [74] Capsid assembly LAT none [75] Latency-associated transcript

[edit] Cellular entry

A simplified diagram of HSV replication
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.[12] 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.[12] Glycoprotein B interacts with glycosaminoglycans on the surface of the host cell.

[edit] 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.[13] Each icosahedral capsid contains a single portal, located in one vertex.[14][15] The DNA exits the capsid in a single linear segment.[16]

[edit] 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 another member of the herpes virus family, KSHV, 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. 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 transcription. The virion host shutoff protein (VHS or UL41) is very important to viral replication.[9] 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.[18][19]

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, 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.[20]

[edit] 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 of the virus, which allows later recurrences to produce further infections.

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 an important transactivator of genes associated with lytic infection in HSV-1.[21] 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 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.[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]

[edit] Reactivation

The 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.

[edit] Anti-viral medication

[edit] Nucleoside analogs

Oral Prodrug
 Drug Analog of Nucleoside Nucleoside Family
Famciclovir[25]
(bioavailability: 75% oral)
(trade names: Famvir)		 Penciclovir
(1.5% oral, IV, locally topical)
(Denavir, Fenistil)		 \Bigg\}guanosine purine
Valaciclovir
(55% oral)
(Valtrex)		 Aciclovir
(10-20% oral)
(Zovirax, Zovir)
Valganciclovir
(60% oral)
(Valcyte)		 Ganciclovir
(5% oral, IV, locally intraocular)
(Cytovene, Cymevene)
Brivudine[26] (BVDU)   thymidine pyrimidine

Treatment is available in the form of antiviral medications such as 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 nucleotides - the building-blocks of DNA and RNA. Active herpes simplex virus will 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 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.[27]

[edit] 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.[28]

[edit] 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.[29]

[edit] 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.[30] 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."[25]

[edit] 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.[31]

Butylated hydroxytoluene (BHT), commonly available as a food preservative, has been shown in vitro to inactivate enveloped viruses including herpes.[32][33] In-vivo studies of topical application to animals confirmed the anti-viral activity of BHT during outbreaks.[34] 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.[35]

[edit] Drug resistance

Resistance of HSVes in cell culture has been reported for nucleosides in the range of 10-2 to 10-4 and for Helicase-Primase inhibitors in the range of 10-4 to 10-6. 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%.

[edit] Vaccine research

Main article: 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.[36][37] Previous studies have determined that this vaccine is approximately 70% effective in women, but does not prevent the disease in men.[38]

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.[39]

[edit] References

  1. ^ a b c d Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology, 4th ed., McGraw Hill, 555–62. ISBN 0838585299. 
  2. ^ Herpes simplex. DermNet NZ — New Zealand Dermatological Society (2006-09-16). Retrieved on 2006-10-15.
  3. ^ Gupta R, Warren T, Wald A (2007). "Genital herpes". Lancet 370 (9605): 2127–37. doi:10.1016/S0140-6736(07)61908-4. PMID 18156035. 
  4. ^ Kimberlin DW (2007). "Herpes simplex virus infections of the newborn". Semin. Perinatol. 31 (1): 19–25. doi:10.1053/j.semperi.2007.01.003. PMID 17317423. 
  5. ^ a b 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. 
  6. ^ a b c d e 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. 
  7. ^ Rajcáni J, Andrea V, Ingeborg R (2004). "Peculiarities of herpes simplex virus (HSV) transcription: an overview". Virus Genes 28 (3): 293–310. PMID 15266111. 
  8. ^ Search in UniProt Knowledgebase (Swiss-Prot and TrEMBL) for: HHV1
  9. ^ a b 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. 
  10. ^ Wyrwicz LS, Ginalski K, Rychlewski L (2007). "HSV-1 UL45 encodes a carbohydrate binding C-type lectin protein". Cell Cycle 7 (2). PMID 18256535. 
  11. ^ 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. 
  12. ^ a b 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. 
  13. ^ Cardone G, Winkler DC, Trus BL, Cheng N, Heuser JE, Newcomb WW, Brown JC, Steven AC (May 2007). "Visualization of the herpes simplex virus portal in situ by cryo-electron tomography". Virology 361 (2): 426–34. doi:10.1016/j.virol.2006.10.047. PMID 17188319. 
  14. ^ 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. doi:10.1128/JVI.78.22.12668-12671.2004. PMID 15507654. (Article: [1])
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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
  20. ^ 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
  21. ^ 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. 
  22. ^ 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. 
  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. 
  24. ^ Roizman B, Gu H, Mandel G (2005). "The first 30 minutes in the life of a virus: unREST in the nucleus". Cell Cycle 4 (8): 1019–21. PMID 16082207. 
  25. ^ a b Learn About Herpes: Treatment. American Social Health Association. Retrieved on 2007-07-09.
  26. ^ Ciucci A, Lafrate EM, Manzini S, Giachetti A (1997). "Mechanism of antiviral action of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) : direct evidence with 14-C-BVDU in herpes simplex virus-infected cells". Antiviral Chemistry & Chemotherapy 8: 565–71. 
  27. ^ Rubsam LZ, Davidson BL, Shewach DS (1998). "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". Cancer Res. 58 (17): 3873–82. PMID 9731497. 
  28. ^ Leung DT, Sacks SL (2004). "Docosanol: a topical antiviral for herpes labialis". Expert Opin Pharmacother 5 (12): 2567–71. doi:10.1517/14656566.5.12.2567. PMID 15571473. 
  29. ^ Kleymann et al (2002). "New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease". Nat. Med. 8 (4): 392–8. doi:10.1038/nm0402-392. PMID 11927946. 
  30. ^ Cold Sores. Healthnotes. Retrieved on 2007-07-09.
  31. ^ Shafran SD, Sacks SL, Aoki FY, et al (1997). "Topical undecylenic acid for herpes simplex labialis: a multicenter, placebo-controlled trial". J. Infect. Dis. 176 (1): 78–83. PMID 9207352. 
  32. ^ Snipes W, Person S, Keith A, Cupp J (1975). "Butylated hydroxytoluene inactivated lipid-containing viruses". Science 188 (4183): 64–6. PMID 163494. 
  33. ^ Coohill TP, Babich M, Taylor WD, Snipes W (1980). "A comparison of herpes simplex virus plaque development after viral treatment with anti-DNA or antilipid agents". Biophys. J. 30 (3): 517–21. PMID 6266532. 
  34. ^ Richards JT, Katz ME, Kern ER (1985). "Topical butylated hydroxytoluene treatment of genital herpes simplex virus infections of guinea pigs". Antiviral Res. 5 (5): 281–90. PMID 2998276. 
  35. ^ Molecular Therapy - Abstract of article: 801. RNA Gene Therapy Targeting Herpes Simplex Virus
  36. ^ Baker T. "First herpes vaccine under study", Press release, Medical College of Georgia, 2006-06-13. Retrieved on 2007-06-17. 
  37. ^ Herpevac Trial for Women. NIH. Retrieved on 2007-07-09.
  38. ^ Major Herpes Vaccine Trial Launched in Women (2002-11-20). Retrieved on 2007-07-09.
  39. ^ Major Herpes Vaccine Breakthrough (2008). Retrieved on 2008-05-17.

[edit] External links