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. The ability of HSV to establish lifelong latency renders it resistant to cure and represents a major hurdle in the prevention of herpetic diseases, the majority of which result from recrudescence of the virus from latency. Three pivotal aspects of the pathogenesis of HSV will be studied in this application. First, we will examine mechanisms by which the viral genes US 11 and ICP34.5 can subvert the host's innate and adaptive immune responses and play key roles in pathogenesis. Second, we will examine how they, and other genes important for pathogenesis, alter host and viral gene expression in vitro and in vivo. Finally, we will develop a novel system using bioluminescence imaging to study how the innate immune response and other immune factors contribute to limiting the spread and tropism of the virus. The interplay of such viral and host factors at various stages in the HSV lifecycle remains poorly 5understood. A better understanding, at the molecular level, of both viral and host factors involved in HSV pathogenesis is in complete accordance with stated high priority research goals of May 2001 Report of the Corneal Diseases Program of the National Eye Institute.
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