My watch list
my.bionity.com  
Login  

Herpes simplex virus



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)

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 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).

Additional recommended knowledge

Contents

Transmission

Main article: Herpes simplex

HSV is transmitted by cccccc 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

The human herpes viruses all share some common properties. One shared property is virus structure and herpes viruses are composed of relatively large double-stranded, linear DNA genomes encoding 100-200 genes encased within an icosahedral protein cage called the capsid which is itself wrapped in a lipid bilayer membrane called the envelope. This particle is known as the virion.[3]

Cellular entry

  Entry of HSV into the host cell involves interactions of several viral glycoproteins with cell surface receptors. The virus particle is covered by an envelope which, when bound to specific receptors on the cell surface, will fuse with the 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 cell surface bring the two 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.[4] In the case of Herpes virus, initial interactions occur when glycoprotein C, on the surface of the viral envelope, binds to a cell surface particle, heparan sulfate. Glycoprotein D binds specifically to the herpesvirus entry mediator receptor (HVEM), thus providing a strong, fixed attachment to the host cell. These interactions bring the membrane surfaces into mutual proximity and allow for other surface glycoproteins to interact. Once bound to the HVEM, glycoprotein D changes its conformation and interacts with glycoproteins H and L, which form a complex. The interaction of these membrane proteins results in the hemifusion state. Afterward, glycoprotein B interaction with the glycoprotein H and L complex creates an entry pore.[4] Glycoprotein B interacts with host cell surface glycosaminoglycans.

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.[5] Each icosahedral capsid contains a single portal, located in one vertex.[6][7] The DNA exits the capsid in a single linear segment.[8]

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.[9] 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.[10][11]

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.[12]

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.[13][14]

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.

Anti-viral medication

Nucleoside analogs

Treatment is available in the form of antiviral medications such as nucleoside analog, which reduce the duration of symptoms and accelerate healing.

Nucleoside analogs are molecules which possess a similarity to natural nucleotides - the building-blocks of DNA and RNA. Because the replicating virus incorporates these analogs into viral DNA, the genetic material produced contains defects and mutations. As a result, the subsequent generation of virus produced is damaged and reduced in number.

Oral Prodrug
Drug Analog of Nucleoside Nucleoside Family
Famciclovir[15]
(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[16] (BVDU)   thymidine pyrimidine

Treatment should begin at the first symptoms of an outbreak for best results as far as duration and healing; should treatment begin before the lesions appear, it is possible that the outbreak can be averted. Another option is the use of daily suppressive therapy, in which antivirals are taken every day over the course of years. Suppressive therapy reduces frequency of symptoms and recurrence of outbreaks. In addition, suppressive therapy reduces subclinical shedding, lowering the risk of transmission through sexual contact or kissing.

Of these, Ganciclovir is known to have cytotoxic effects on infected cells but Acyclovir is not known to have this effect.[17]

Fusion inhibitors

Fusion inhibitors prevent "fusion" of the viral envelope with the cell membrane. This prevents viral entry to the cell.

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.[18]

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.[19] 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."[15]

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).

Butylated hydroxytoluene (BHT), commonly available as a food preservative, has been shown in vitro to inactivate enveloped viruses including herpes.[20][21] In-vivo studies of topical application to animals confirmed the anti-viral activity of BHT during outbreaks.[22] BHT has not been clinically tested and approved to treat herpes in humans.

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%.

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.[23][24] Previous studies have determined that this vaccine is approximately 70% effective in women, but does not prevent the disease in men.[25]

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. ^ 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. ^ 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.
  5. ^ 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). PMID 17188319.
  6. ^ 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). PMID 15507654.(Article: [1])
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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
  12. ^ 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
  13. ^ 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.
  14. ^ 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.
  15. ^ a b Learn About Herpes: Treatment. American Social Health Association. Retrieved on 2007-07-09.
  16. ^ 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.
  17. ^ 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.
  18. ^ Crumpacker CS, Schaffer PA (2002). "New anti-HSV therapeutics target the helicase-primase complex". Nat. Med. 8 (4): 327-8. doi:10.1038/nm0402-327. PMID 11927930.
  19. ^ Cold Sores. Healthnotes. Retrieved on 2007-07-09.
  20. ^ Snipes W, Person S, Keith A, Cupp J (1975). "Butylated hydroxytoluene inactivated lipid-containing viruses". Science 188 (4183): 64-6. PMID 163494.
  21. ^ 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.
  22. ^ 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.
  23. ^ Baker T. "First herpes vaccine under study", Press release, Medical College of Georgia, 2006-06-13. Retrieved on 2007-06-17. 
  24. ^ Herpevac Trial for Women. NIH. Retrieved on 2007-07-09.
  25. ^ Major Herpes Vaccine Trial Launched in Women (2002-11-20). Retrieved on 2007-07-09.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Herpes_simplex_virus". A list of authors is available in Wikipedia.
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE