Herpes Simplex Virus

Herpes Simplex Virus Type 1 Infection at the Molecular Level Research Paper Virology 24 November 2008 Abstract Herpes simplex virus type 1 (HSV-1) infection is widespread and causes significant disease in humans. The structure, epidemiology, pathogensis and immune response are examined in this review, as well as specific ways to reduce and eliminate pathology and related diseases. The virus naturally infects mucosal areas and begins the search for its target host cell. Upon binding to the host cell membrane via teams of glycoproteins, the virion is then phagocytosed.Soon the nucleus is seized and all regular host cell mechanisms are shut off. Replication of HSV-1 is specific encoding immediate early, early and late genes. Once the virus replication process is complete the virus exits epithelial cells near the site of infection through a process known as cell lysis. Sensory neurons are the specific target of HSV-1, where it can then travel to the trigeminal ganglia (TG) stoma via neur onal microtubular networks. Both innate and adaptive immune systems respond to the infection with various antibodies, interleukins and interferons.Once the virion reaches the nervous system, the immune responses are unable to detect it although they try to contain it as best they can. HSV-1 enters a latent stage, usually via latent associated transcripts, not causing pathogenesis but unable to fight off by means of the host immune system. Following a stressful situation or similarly UV activation, HSV-1 travels back down nerve fibers to re-infect cells near the original site of infection. This process is known to continue throughout the lifespan of the infected individual, normally without fatalities.When the host immune response is unable to contain the virus in the TG, several associated diseases such as encephalitis and keratits result. Genes involved with virus replication and host genes, to eliminate the virus, have been maneuvered to cause reverse effects and are currently use d as antivirals. Although no vaccine has been approved for use against HSV-1, various attempts have been made. This research paper defines the virus infection at a molecular level as well as demonstrates modifications of the virus genes to cause reverse effects and investigates just a few of the diseases connected with HSV-1.Introduction Herpes simplex viruses type 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 skin lesions in the orofacial area, as well as many rare but fatal conditions (1). Herpes simplex virus type 2 (HSV-2) is primarily associated with genital area infection. Worldwide, approximately one third of people display clinical manifestations of HSV-1 infection (2).HSV-1 is neurotropic, infecting multiple cell types but establishing 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 transported along nerve fibers to mucosal or cutaneous regions (1). Infected cells show signs of the nucleus changing shape and nucleolus displacement with a formation of multinucleated giant cells. Cells degenerate, lyse and vesicles of fluid containing the virus locate between the epidermis and dermal layer of the skin forming a lesion (2).Although HSV-1 infects a large percentage of the population, few actually show symptoms of disease. HSV Structure and Genome HSV-1 is an enveloped double stranded DNA (dsDNA) virus consisting of four elements. First, an outer envelope with glycoprotein spikes on its surface. Second, a tegument layer including several viral proteins important during HSV-1 infection. Third, an iscosahedral capsid 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 g lycoproteins embedded in a lipid bilayer.The viral genome of 152 kb, encode the majority 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 b’a’ repeated segments, and unique short (Us), flanked by ac and c’a’ repeated segments. Homologous recombination between terminal repeats results in four linear isomers at equimolar concentrations (see figure 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 transcription 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, binding to other cell surface receptors, such as Herpesvirus entry mediator or nectin 1? or ? (4). Fusion of the viral envelope follows, and the de-enveloped tegument capsid is transported to the nuclear pores 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 done by the host RNA polymerase II. Among the IE genes are ICP0, ICP4, ICP22, ICP27 and ICP47. Host transcription, RNA splicing and transport are inhibited during replication, known as host cell shut off. Early (E) viral genes encode enzymes in nucleotide 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 start DNA synthesis in replication compartments. Three DNA replication origins bind by viral origin-binding protein, separate the DNA strands and initiate 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. Cleavage and packing of HSV-1 genome requires two cis-acting elements, pac1 and pac2. Next the nucleocapsid matures and egress by passing 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 site 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 en ter 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 transcripts found in latent neurons (6). Expression of LATs is not absolutely required for maintenance 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 Immune SystemThe immune response to HSV-1 includes both innate and adaptive immune responses. Innate immunity is the first line of defense including natural killer (NK) cells, macrophages, dendritic cells, and various cytokines and complement 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 enhanced 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 also produced by IPCs and acts as an autocrine signal stimulating differentiation of ICPs to dendritic cells. They can travel to the lymph nodes to stimulate 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. Deficient 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 observed 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 As sociated DiseasesOccasionally the immune system is unable to prevent HSV-1 from spreading to surrounding structures such as the eye. Ocular 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 activity cannot take place until the infection has progressed to the point where specific viral thymidine kinase is synthesized.A new idea involves 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, BAY 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 as sociated 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 activity 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 severity and clinical SK could be significantly diminished by daily treatment of lesions with FGF-2 protein, due to accelerated epithelial wound healing. (8) Similarly, HSV-1 can surpass the immune response and travel to the brain. HSV-1 encephalitis is the most devastating consequence of HSV and the most ommon cause of fetal encephalitis. Early growth response 1 (Erg-1) is a zinc finger transcription factor expressed in neural tissue, and is induced during stress. It regulates growth, apoptosis, angiogenesis and development. Erg-1 is known to regulate several vi ral genes, including LATs, and is inducible by viral proteins. Erg-1 increases viral replication in infected cells and mortality 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? , reducing 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 aspect in major depression. (10)Thrombin is a result of the generation of sequential proteolytic enzymes activating circular precursor enzymes and cofactors for bloo d clotting. HSV-1, HSV-2 and cytomegalovirus have been shown to avoid cellular control of coagulation initiation through the constitutive 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. Assembly 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) Conclusion HSV-1 can cause severe recurrent disease in humans and establish lifelong infection in their hosts. Several antiviral approaches have been considered to counteract the effects of HSV-1 throughout the body yet 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 utilized viral vectors, DNA vaccination, recombinant bacteria, cytokines to manipulate the immune response, novel adjuvants, innovative delivery 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 with 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 morphological changes indicative of cytopathic effects that retard the replication and spread of HSV-1. (12) Furthermore, a hematopoietic stem cell transplant recipient developed mucosal HSV-1 infection, and while under acyclovir treatment, later show ed resistance to the antiviral.After developing hemorrhagic cystitis due to polyomavirus BK, cidofovir was prescribed and the patient profited from the broad spectrum anti-DNA virus activity with the disappearance 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 detailed means by which each gene in the large genome is activated and carries out its genes products, intrigue many scientists which continue to investigate and attempt a formidable vaccine against the virus.Studies among mice have proven effective, although HSV-1 is a very 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. Devastating incidence such as transferring HSV-1 to a neonate during delivery 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. â€Å"Influence of KIR gene diversity on the course 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. â€Å"Prophylactic Vaccine Strategies and the Potential of Therapeutic Vaccines Against Herpes Simplex Virus. † Current Pharmaceutical Design 13. 9 July 2007): 1975-1988. Academic Search Premier. EBSCO. 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