VIROLOGIC AND IMMUNOLOGIC STUDIES MURINE CMV RETINITIS

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DESCRIPTION (Applicant's Description): Even though much known about the course and treatment of CMV retinitis in immunosuppressed human patients, many aspects of the pathogenesis of CMV retinitis remain to be deciphered. Understanding the pathogenesis of CMV retinitis continues to be an important area of investigation since even though the incidence of new cases of CMV retinitis decreased in patients on highly active antiretroviral therapy (HAART) and several antivirals with anti-CMV activity are widely available, the number of new cases of CMV retinitis has begun to slowly increase again at many centers. The studies proposed in this application will use the BALB/c mouse model of MCMV retinitis and will focus on those aspects of retinitis in the mouse that appear to be relevant to understanding the pathogenesis of CMV retinitis in human patients - latency and reactivation in the eye, the role of the blood-retinal barrier (BRB) and whether intravenously injected virus-infected cells enter and infect the retina, and finally, the role of infected RPE in causing apoptosis of apparently uninfected retinal cells. The first Specific Aim is to define the site(s) of latency in the eye and whether the route that is used for ocular injection plays a role in determining the sites at which MCMV becomes latent. The second Specific Aim is to determine if MCMV can spread to and replicate in the retina of immunosuppressed mice following disruption of the BRB and intravenous injection of MCMV-infected mononuclear cells or MCMV. The third Specific Aim is to determine the mechanism by which infection of the RPE results in apoptosis of the overlying retina. By using the mouse model to provide new information about how MCMV causes infection of the retina, the results of these studies may provide new insight into the mechanisms of CMV infection of the retina in human patients, which, in turn, might lead to new therapies for preventing infection or reducing its harmful effects.