PATHOGENESIS OF CMV RETINITIS

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Cytomegalovirus (CMV) retinitis is the most frequent ophthalmic opportunistic infection in patients with AIDS. Although the clinical and histopathologic features of AIDS-related CMV retinitis have been extensively described, the pathogenesis of this disease is poorly understood. Our proposal explores the pathogenesis of CMV retinitis is terms of a new mouse model of the disease developed in our laboratory. We hypothesize that murine CMV (MCMV) retinitis with features similar to AIDS-related CMV retinitis will develop in adult C57BL/6 mice suffering from murine acquired immune deficiency syndrome (MAIDS), an immunosuppressive disorder produced by a mixture of murine retroviruses that parallels HIV-l-induced AIDS in humans. We predict that this animal model of CMV retinitis can be used to address several fundamental, clinically-relevant questions that relate to the pathogenesis and treatment of CMV retinitis in a setting of retrovirus-induced immunosuppression. We will evaluate this hypothesis and prediction by first performing a series of experiments designed to characterize the evolution of disease. Specifically, we will explore the histopathologic and virologic features of retinitis at various stages of MAIDS, examine the nature of the retinal inflammation associated with the disease, and identify the cell(s) of the retina that are susceptible to MCMV infection. Additional studies will focus on the effect of immunomodulators on the tempo and severity of retinitis. These will include MAIDS-induced immunosuppression, depletion of specific immune cell subsets and adoptive transfer of virus-specific effectors, and the effect of antiretrovirus drugs that are known to induce bone marrow toxicity in humans. Finally, we will investigate the effect of ganciclovir on MCMV retinitis and identify the cell(s) of the retina that serve as reservoirs for virus during treatment with this antiviral. The long term goal of this research project is to define the pathogenetic events that occur during the evolution of CMV retinitis in persons immunosuppressed by retrovirus infection, so that more innovative therapeutic approaches can be developed for improved treatment of this devastating sight-threatening disease.