Herpes Simplex Virus

herpes computer virus unidirectional virus Type 1 transmittal at the Molecular Level Research Paper Virology 24 November 2008 schema Herpes simplex computer virus lawsuit 1 (herpes simplex 1) contagion is widespread and gives signifi mountaint disease in humans. The structure, epidemiology, pathogensis and tolerant reaction ar examined in this review, as salutary as specific ways to reduce and pass along pathology and related diseases. The virus natur tout ensembley infects mucosal argonas and begins the search for its target innkeeper kiosk. Upon bandaging to the troops prison cellphone membrane via teams of glycoproteins, the virion is then phagocytosed.Soon the nucleus is seized and all regular array cell mechanisms argon shut off. Replication of herpes simplex 1 is specific encode immediate early, early and late genes. Once the virus comeback make is complete the virus exits epithelial cells near the set of transmittance through a process cognize as cell lysis. Sensory neurons are the specific target of herpes simplex 1, where it tin then extend to the trigeminal ganglia (TG) stoma via neuronal microtubular networks. Both innate and adaptational insubordinate sy pedestals respond to the transmitting with unhomogeneous antibodies, interleukins and interferons.Once the virion reaches the nervous system, the immune responses are otiose to detect it although they try to contain it as best they can. herpes simplex 1 enters a latent stage, usually via latent associated transcripts, not ca victimisation pathogenesis still otiose to fight off by means of the force immune system. pastime a stressful situation or similarly UV activation, herpes simplex 1 travels back slew nerve fibers to re-infect cells near the original internet place of transmittal. This process is known to continue throughout the lifespan of the infect individual, normally without fatalities.When the host immune response is unable to contain the virus in the TG, several(prenominal) associated diseases such(prenominal) as encephalitis and keratits result. Genes involved with virus replication and host genes, to eliminate the virus, book been maneuvered to cause reverse set up and are really utilize as antiviral drugs. Although no vaccine has been approved for use against herpes simplex 1, various attempts fork out been made. This research paper defines the virus transmitting at a molecular level as well as demonstrates modifications of the virus genes to cause reverse personal effects and investigates just a few of the diseases connected with herpes simplex 1.Introduction Herpes simplex viruses typeface 1 and 2 are well known members of the family Herpesviridae, subfamily Alphaherpesvirinae, which cause lifelong, latent infection in humans. Herpes simplex virus type 1 (HSV-1) typically remains the cause of cold sores, gingivostomatitis, and hide lesions in the orofacial area, as well as many obsolescent still fatal condi tions (1). Herpes simplex virus type 2 (HSV-2) is chiefly associated with genital area infection. Worldwide, approximately one third of people screening clinical manifestations of HSV-1 infection (2).HSV-1 is neurotropic, infecting multiple cell types but establishing rotational latency in the trigeminal ganglia (TG). HSV-1 reactivates, in response to certain stimuli such as emotional or physical stress or UV light, and is enthralled along nerve fibers to mucosal or cutaneous regions (1). Infected cells betoken signs of the nucleus changing shape and nucleolus displacement with a constitution of multinucleated giant cells. Cells degenerate, lyse and vesicles of fluid containing the virus locate between the epidermis and cutaneal layer of the skin forming a lesion (2).Although HSV-1 infects a large serving of the population, few actually show symptoms of disease. HSV Structure and Genome HSV-1 is an enveloped double isolated deoxyribonucleic acid (dsDNA) virus consisting of four elements. First, an outer envelope with glycoprotein spikes on its surface. Second, a hide layer including several viral proteins important during HSV-1 infection. Third, an iscosahedral mirid surrounding the last compartment, the electron opaque core containing the dsDNA genome wrapped as a spool. The envelope is made up of 13 different viral glycoproteins embedded in a lipid bilayer.The viral genome of 152 kb, encode the volume of the proteins of the mature virion. Covalently linked L (long) and S (short) components are broken down into unique long (Ul), flanked by ab and ba reiterate segments, and unique short (Us), flanked by ac and ca tell segments. Homologous recombination between terminal repeats results in four linear isomers at equimolar concentrations (see human body 1). All four isomers, including P (prototype), IL (inversion of the L component), IS (inversion of the S component) and ISL (inversion of both the S and the L component), encode 90 unique placement genes essential for viral replication (3).HSV Replication infection is first initialted by the attachment to the host cell glucosaminoglycans, usually heparin sulphate and chondroiton sulphate, with viral glycoprotein C (gC). This bond results in at least five glycoprtoeins, gB, gC, gD, gH and gL, attach to other cell surface receptors, such as Herpesvirus entry intercessor or nectin 1? or ? (4). Fusion of the viral envelope follows, and the de-enveloped tegument capsid is transported to the nuclear digests via the microtubular network, where DNA is released into the nucleus.Nuclear pore complex accepts the viral DNA from the capsid, minimizing the diffusion of DNA to the cytoplasm, and the transfer is completed by nuclear pore proteins (5). The viral genome circularizes upon entering the nucleus, and transcription of the five immediate early genes (IE) is make by the host ribonucleic acid polymerase II. Among the IE genes are ICP0, ICP4, ICP22, ICP27 and ICP47. Host transcript ion, RNA splicing and transport are inhibited during replication, known as host cell shut off. Early (E) viral genes encode enzymes in radical metabolism and viral DNA replication and require the presence of IE genes.Viral E gene products, including viral DNA polymerase, single-stranded DNA-binding protein, origin binding protein and DNA helicase-primase, assemble on the parental viral DNA and gelt DNA synthesis in replication compartments. Three DNA replication origins bind by viral origin-binding protein, separate the DNA strands and beginner viral DNA synthesis. Expression of the late (L) genes begins and produces structural components of the virion. Capsid assembly occurs in the cytoplasm and the associated proteins are then transported to the nucleus.Progeny DNA concatamers are cleaved into monomers and are inserted into the capsid. partitioning and packing of HSV-1 genome requires two cis-acting elements, pac1 and pac2. Next the nucleocapsid matures and egress by base on balls through the Golgi apparatus with the tegument layer and the virion envelope. (3) HSV Latency After infection of the mucosa or epithelial abrasion, HSV-1 enters sensory neurons near the turn up of infection and the tegument and nucleocapsid travel by retrograde axonal transport to cell neuronal soma releasing viral DNA and VP16, when the virus may enter lytic replication or the latent state.Lytic replication results in neuronal cell death as described above. (2,3) During latency the genome circularizes and enters a heavily chromatinated state where no infectious virus is produced and the majority of viral gene expression is silenced. Latency associated transcripts (LAT), mRNA genes, are the only(prenominal) transcripts piece in latent neurons (6). Expression of LATs is not absolutely required for care of latency. Reactivation triggers the virus to be transported in the opposite direction, antrograde, and re-infection occurs at the initial site of infection. HSV and the Immu ne SystemThe immune response to HSV-1 includes both innate and adaptive immune responses. Innate immunity is the first line of defense including native killer (NK) cells, macrophages, dendritic cells, and various cytokines and attendant proteins. Initial response involves secreted proteins, such as defensins and complement proteins. Complement proteins bind HSV antigens resulting in the cleavage of complement molecules. This, followed by the formation of the membrane attack complex, destroys the virus. HSV gC blocks the complement cascade, counteracting the effects of complement.The adaptive immune response is triggered with B cell memory enhance in response to the virus. An antiviral state is induced by infected epithelial cells and resident interferon producing cells (IPCs), secreting interferon ? and ? , priming the surrounding cells for apoptosis. Tumor necrosis factors ? (TNF-? ) is besides produced by IPCs and acts as an autocrine signal stimulating differentiation of ICPs to dendritic cells. They can travel to the lymph nodes to shake CD4+ T cells to produce IFN-? and interleukin 10 (IL-10). After infection and replication, HSV-1 destroys infected cells and travels to sensory neurons.Polymorphonuclear leukocytes, macrophages, NK and ?? TCR+ T cells infiltrate the TG, control the infection and prevent the spread of the virus to rear by cells, including the brain. The adaptive immune response is driven by the innate immune response. Antigen presenting cells migrate from the site of infection to the regional lymph node to present CD4+ and CD8+ T cells and B cells. wanting(p) complement cascades leads to less vigorous memory response to HSV-1. Antibodies against gD and the gH-gL complex are found to protect against HSV-1 and are observe as cross reactive to other strains of HSV.Macrophages engulf viral proteins and cell particles from lysed cells and also secrete cytokines favoring the T helper (Th) cell CD4+ response. CD8+ cytoxic T lymphocytes (CTL) are produced and they react with epitopes displayed on infected cells, which are then targeted for apoptosis. See figure 2. The IE protein ICP 27 contains potent CTL epitopes. The efficacy of gB to induce a CTL response suggests gB is the immunodominant antigen of HSV-1. (2) Beneficial Modifications of Genes Associated with Herpes Simplex Virus type 1 and Relative Associated complaintsOccasionally the immune system is unable to prevent HSV-1 from spreading to surrounding structures such as the eye. optic HSV-1 infection is termed herpetic keratitis, tissue destruction of the eye, and is currently treated with trifluridine or valacyclovir to inhibit HSV-1 DNA polymerase and terminate synthesis of the sugar backbone of viral DNA. The current antiviral compounds require phosphorylation by the infected cell, meaning the antiviral employment cannot take place until the infection has progressed to the point where specific viral deoxythymidine kinase is synthesized.A impudently idea i nvolves helicase-primase inhibitors acting to prevent the unwinding of the double-stranded DNA and the initiation of the new strand synthesis necessary for viral production. Kleymann et al. found a compound, embayment 57-1293, more potent and more effective than valacyclovir and unassociated with systemic toxicity to initiate the described mechanism. (7) A similar study explored the lesion associated with the tissue destruction of the cornea, specifically angiogenesis of stromal keratits (SK).The fibroblast growth factor 2 (FGF-2), a molecule known to stimulate cell growth to contribute to wound healing, was targeted to observe the antiviral action mechanism via its effect on HSV-1 cell entry. FGF-2 inhibits HSV-1 from binding to heparin sulfate, thus hindering entrance into the host cell. Results of this study suggest abrasiveness and clinical SK could be significantly diminished by daily discussion of lesions with FGF-2 protein, overdue to accelerated epithelial wound heali ng. (8) Similarly, HSV-1 can choke the immune response and travel to the brain. HSV-1 encephalitis is the most crushing consequence of HSV and the most ommon cause of fetal encephalitis. Early growth response 1 (Erg-1) is a zinc finger transcription factor evince in neural tissue, and is induced during stress. It regulates growth, apoptosis, angiogenesis and development. Erg-1 is known to regulate several viral genes, including LATs, and is inducible by viral proteins. Erg-1 increases viral replication in infected cells and fatality rate in infected mice. Knockout of Erg-1 expression was shown to reduce the mortality by decreasing the viral loads to tissues in a study conducted by Shis-Heng Chen et al. 9) It has been demonstrated HSV-1 can induce increased activity of central norepinephrine or serotonin neurons, by activating the cell bodies located in the brain stem, following encephalitis. Increased brain stem activity of these neurotransmitters can impair glucocorticoids (GC) negative feedback receptors, activating cytokines IL-1 and TNF? , trim back the binding capacity of said GC receptors. Impaired control of the GC negative feedback regulation upon the hypothalamo-pituitary adrenal axis has been suggested as an important nerve in major depression. (10)Thrombin is a result of the generation of sequential proteolytic enzymes activating circular precursor enzymes and cofactors for blood clotting. HSV-1, HSV-2 and cytomegalovirus have been shown to avoid cellular control of coagulation initiation through the organic expression of procoagulant phospholipids and tissue factor. This allows the unregulated generation of thrombin because tissue factor can bind ciruculating factor VIIa, forming a cofactor-enzyme complex directly on the virus. Tenase activity has been credited to HSV-1 encoded gC, which accelerates the FVIIa-dependent activation of FX.FXa associates with its cofactor V to convert prothrombin to thrombin. collection of FX and FV leading to thrombin generation has been demonstrated on the virus surface. Herpes virus genomic material has been associated with atherosclerosis plaque, thrombosis and atherosclerosis due to the unregulated production of thrombin. (11) It is well known NK cells aid in the fight against HSV-1 infection. Severe herpetic infections have been seen in NK -deficient patients, as well as early infiltrations of herpetic lesions by NK cells. This due to damage of HLA class 1 expression by HSV-1 and the lysis of HSV-1 infected targets by NK cells.E. Estefania et al. presented a study suggesting clinical symptoms of HSV-1 infection being more likely to happen among humans expressing the NK cell receptors KIR2DL2 and KIR2DS2. The genes encoding the receptors appear to increase the risk of recurrent infection, where the lack of the receptors is shown to protect from the disease. (1) finding HSV-1 can cause severe recurrent disease in humans and establish lifelong infection in their hosts. some(prenomina l) antiviral approaches have been considered to counteract the effects of HSV-1 throughout the body so far no vaccine, to cure the infection from its host, has been accepted.Acyclovir, and its ester derivative valacyclovir, as well as penciclovir and its prodrug famciclovir, are the latest approved antiviral medications to battle HSV-1 infection. Several other strategies are currently under investigation such as potential therapeutic vaccines, cidofovir, and aqueous extracts in Africa. Past attempts of vaccines have utilize viral vectors, DNA vaccination, recombinant bacteria, cytokines to manipulate the immune response, novel adjuvants, innovative pitch shot systems and different routes of inoculation. Most of which have been successful in lab mice but none have been approved for human use.Therapeutic vaccines target symptomatic individuals, using DNA vaccines encoding various cytokines used to intentionally bias the immune system toward Th1 or Th2 responses. Different boosts wi th different cytokine adjuvants may be used to induce proper immune response. (2) Extracts from the eastern cape of Africa, Aloe ferox and Withania somnifera, confirmed morphologic changes indicative of cytopathic effects that retard the replication and spread of HSV-1. (12) Furthermore, a haematopoietic stem cell transplant recipient developed mucosal HSV-1 infection, and while under acyclovir treatment, later showed resistance to the antiviral.After developing haemorrhagic cystitis due to polyomavirus BK, cidofovir was prescribed and the patient profited from the broad spectrum anti-DNA virus activity with the slicing of HSV-1 lesions. (13) In conclusion, as described above the mechanisms by which HSV-1 hijacks and hides out in its host, have been studied to great detail and are routinely manipulated. The particularly complex structure, as well as precise means by which each gene in the large genome is trip and carries out its genes products, intrigue many scientists which c ontinue to investigate and attempt a formidable vaccine against the virus.Studies among mice have proven effective, although HSV-1 is a really host specific infection, thus making trials of acceptable anitvirals and vaccines extremely difficult. The only slightly acceptable element of HSV-1 infection is, in rare cases where no reoccurrences is shown, and moreover there are many instances of asymptomatic carriers. ravage incidence such as transferring HSV-1 to a neonate during rake and schizophrenics showing decreased prefrontal grey matter due to HSV-1, are just a pinch of the terrifying effects of this virus, remaining in host TG until a stressful situation comes along. 14,15) Herpes Simplex Virus type 1 Genome (Figure 1) 00 Herpes Simplex Virus Type 1 Infection (Figure 2) Works Cited 1. )Estefania, E, et al. Influence of KIR gene diversity on the social class of HSV-1 infection resistance to the disease is associated with the absence of KIR2DL2 and KIR2DS2. Tissue Antigens 70 . 1 (July 2007) 34-41. MEDLINE. EBSCO. Library name, City, State abbreviation. 19 Nov. 2008 . 2. )Ferenczy, Michael W. Prophylactic Vaccine Strategies and the Potential of Therapeutic Vaccines Against Herpes Simplex Virus. afoot(predicate) Pharmaceutical Design 13. 9 July 2007) 1975-1988. Academic Search Premier. EBSCO. Library name, City, State abbreviation. 19 Nov. 2008 . 3. )Shen, Y, and J Nemunaitis.. Herpes simplex virus 1 (HSV-1) for cancer treatment. genus Cancer Gene Therapy 13. 11 (07 Nov. 2006) 975-992. MEDLINE. EBSCO. Library name, City, State abbreviation. 19 Nov. 2008 . 4. )Clement, Christian, et al. A novel role for phagocytosis-like inhalation in herpes simplex virus entry. Journal of Cell biota 174. 7 (25 Sep. 2006) 1009-1021. Academic Search Premier. EBSCO. Library name, City, State abbreviation. 4 Sep. 2008 . 5. )Newcomb, William W, Frank P Booy, and Jay C Brown. Uncoating the herpes simplex virus genome. Journal Of Molecular Biology 370. 4 (20 July 2007) 63 3-642. MEDLINE. EBSCO. Library name, City, State abbreviation. 3 Sep. 2008 . 6. )Ramachandran, Srividya, and Paul R Kinchington.. Potential prophylactic and therapeutic vaccines for HSV infections. Current Pharmaceutical Design 13. 19 (2007) 1965-1973. MEDLINE. EBSCO. Library name, City, State abbreviation. 22 Nov. 2008 . 7. )Kaufman, Herbert E, et al. Efficacy of a helicase-primase inhibitor in animal models of ocular herpes simplex virus type 1 infection. Journal Of Ocular Pharmacology And Therapeutics The Official Journal Of The Association For Ocular Pharmacology And Therapeutics 24. 1 (Feb. 2008) 34-42. MEDLINE. EBSCO. Library name, City, State abbreviation. 19 Nov. 2008 . 8. )Kim, Bumseok, et al. Application of FGF-2 to Modulate Herpetic Stromal Keratitis. Current midpoint Research 31. 12 (Dec. 2006) 1021-1028. Academic Search Premier. EBSCO. Library name, City, State abbreviation. 19 Nov. 2008 . 9. )Chen S, Yao H, Chen I, Shieh B, Li C, Chen S.Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice. Journal of Clinical investigating serial online. October 2008118(10)3470-3477. Available from Academic Search Premier, Ipswich, MA. Accessed November 22, 2008. 10. )Bener, Dafna, et al. Glucocorticoid Resistance following Herpes Simplex-1 Infection Role of Hippocampal Glucocorticoid Receptors. Neuroendocrinology 85. 4 (Apr. 2007) 207-215. Academic Search Premier. EBSCO. Library name, City, State abbreviation. 19 Nov. 2008 . 11. )Thrombin paper 12. )Kambizi, L. , et al. Anti-viral effects of aqueous extracts of Aloe Xerox and Withania somnifera on herpes simplex virus type 1 in cell culture. South African Journal of cognition 103. 9/10 (Sep. 2007) 359-360. Academic Search Premier. EBSCO. Library name, City, State abbreviation. 10 Sep. 2008 . 13. )Andrei, G, et al. Dual infection with polyomavirus BK and acyclovir-resistant herpes simplex virus successfully treated with cidofovir in a bone marrow trans plant recipient. Transplant Infectious Disease An Official Journal Of The Transplantation Society 9. 2 (June 2007) 126-131. MEDLINE. EBSCO. Library name, City, State abbreviation. 19 Nov. 2008 . 14. )Brown, Elizabeth L. , et al. Effect of maternal herpes simplex virus (HSV) serostatus and HSV type on risk of neonatal herpes. Acta Obstetricia & Gynecologica Scandinavica 86. 5 (May 2007) 523-529. Academic Search Premier. EBSCO. Library name, City, State abbreviation. 17 Sep. 2008 . 15. )Prasad, K. M. R. , et al. Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia. Molecular Psychiatry 12. 1 (Jan. 2007) 105-113. Academic Search Premier. EBSCO. Library name, City, State abbreviation. 1 Oct. 2008 .