zed from abstract) Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in the US, with more that 200,000 cases per year. 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. The unique regulatory switch between lytic and latent infection is poorly understood. The broad goals of this proposal are to elucidate host and viral factors involved in the various stages of latency. To this end, recombinant viruses will be created with lesions in DNA replication and latency-related genes are tested in a mouse ocular model for their ability to establish and reactivate from latency in mice. These studies will be performed in conjunction with knockout mice with lesions in host genes such as interferons, which may play key roles in controlling HSV infection. This will allow the elucidation of the possible interplay between host and viral genes. In addition, the PI will engineer a transgenic mouse line which will allow us to specifically target viral genes for deletion during latency in the mouse. Viruses will therefore be wild-type during infection, but genetically altered during latency. This entirely novel approach to the field of herpes pathogenesis will allow us to dissect the precise roles for certain viral genes during the stages of the life cycle of the virus. A better understanding of both viral and host factors and their interplay in HSV pathogenesis will allow further insight into the mechanisms by which HSV can persist for the lifetime of its host and indicate novel therapeutic approaches and targets for control of this blinding disease.
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