Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in developed countries, with more than 200,000 cases per year in the USA. HSV can cause a variety of ocular diseases in humans ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis to necrotizing stromal keratitis. In addition, HSV commonly causes cold sores, genital sores, and is a leading cause of viral encephalitis. The life cycles of HSV and other neurotropic herpesviruses are characterized by a lytic phase of infection at peripheral sites such as the cornea and skin during which all virus genes are expressed, and a latent phase of infection in neurons, during which gene expression is extremely limited. Latency represents a lifelong source of virus which can reactivate periodically causing severe ocular and other mucocutaneous damage, and the ability to establish lifelong latency renders HSV resistant to cure. ? ? One hallmark of the neurotropic herpesviruses is their ability to rapidly shut off macromolecular synthesis in the cells that they infect. For HSV type 1 (HSV-1) and HSV-2 the gene responsible for this shutoff is the product of the UL41 gene known as the virion host shutoff protein or vhs. All of the neurotropic herpesviruses have a homolog of the UL41 gene, although the reason for this gene conservation among viruses that establish latency in neurons is not known. Our previously funded studies have shown that vhs activity plays an essential role in infection and damage of the eye, in the development of periocular disease, and in the establishment of latency. We have defined a domain of vhs that is critical for its interaction with VP16 and thereby regulates both its the packaging and activity. We have also shown that vhs activity can alter that magnitude of immune responses to HSV. In addition we have shown that viruses deficient in vhs are effective vaccines for the prevention of recurrent herpetic infections. These accomplishments are in complete accordance with the stated research goals of the Corneal Diseases Program of the NEI. ? ? The objectives of this proposal are to build upon our previous findings and further investigate the mechanisms of action of the multifunctional vhs protein and its impact upon pathogenesis and ocular disease. We address the hypothesis is that vhs helps render HSV resistant to interferon through its ability to alter the activity of the interferon-induced kinase PKR. In addition, we test the hypothesis that vhs activity alters the recognition of virus-infected cells through control of antigen presentation, thereby shaping the adaptive immune response in favor of the virus. Finally we will identify the domains of vhs, which are important for the interaction of HSV with neurons, the site of latency for the virus, and identify how HSV and vhs alter gene expression patterns in neurons. We reason that a better definition of the mechanisms and domains of vhs function will provide targets for therapeutic intervention against HSV ocular disease, as well as aiding in the design of HSV vaccines. ? ?
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