Pathogenesis of CMV Retinitis

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DESCRIPTION: Human cytomegalovirus (HCMV) retinitis remains a significant ophthalmologic problem in patients with HIV/AIDS. Three specific aims are proposed to continue study of the basic pathophysiologic pathways and mechanisms that mediate retinal infection and retinal destruction during evolution of AIDS-related HCMV retinal. These aims will use a clinically relevant mouse model of murine CMV (MCMV) retinitis novel to our laboratory in which MCMV is inoculated subretinally into C57BL/6 mice with MAIDS, a murine retrovirus-induced immunodeficiency syndrome. The first aim will determine if quantification of loss of the perforin cytotoxic pathway is a better predictor for susceptibility to MCMV retinitis than quantification of absolute numbers of peripheral lymphocytes during MAIDS progression. Subsequent experiments of this aim will focus on measurement of the perforin cytotoxic pathway in HIV/AIDS patients with or without HCMV retinitis using an innovative RT-PCR assay for human perforin mRNA. The second aim will determine the pathway by which perforin-mediated cytotoxicity is suppressed during MAIDS to allow susceptibility to MCMV retinitis. These experiments will focus on interleukin-4 which is upregulated during MAIDS and thought to shift cytotoxic T-cell killing from a dominant perforin pathway to a dominant Fas/FasL pathway. The third aim will determine the contribution of tumor necrosis factor-a (TNF-a)-induced apoptosis in mediating retinal tissue destruction during MAIDS-related MCMV retinitis with special attention to retinal neurons not infected with virus. The proposed studies will provide new insights into the virologic, immunologic, and pathogenetic events that operate during evolution of retinal disease in the unique setting of retrovirus-induced immuno-suppression, information needed to develop new diagnostic strategies to better predict onset of HCMV retinitis in HIV/AIDS patients and to develop rational therapeutic strategies to better manage this sight-threatening disease in the clinical setting.