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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VISB (01))
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University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
United States
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Chien, Hsin; Alston, Christine I; Dix, Richard D (2018) Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression. J Virol 92:
Alston, Christine I; Dix, Richard D (2017) Reduced frequency of murine cytomegalovirus retinitis in C57BL/6 mice correlates with low levels of suppressor of cytokine signaling (SOCS)1 and SOCS3 expression within the eye during corticosteroid-induced immunosuppression. Cytokine 97:38-41
Blalock, Emily L; Chien, Hsin; Dix, Richard D (2013) Murine cytomegalovirus downregulates interleukin-17 in mice with retrovirus-induced immunosuppression that are susceptible to experimental cytomegalovirus retinitis. Cytokine 61:862-75
Cousins, Scott W; Espinosa-Heidmann, Diego G; Miller, Daniel M et al. (2012) Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization. PLoS Pathog 8:e1002671
Blalock, Emily L; Chien, Hsin; Dix, Richard D (2012) Systemic reduction of interleukin-4 or interleukin-10 fails to reduce the frequency or severity of experimental cytomegalovirus retinitis in mice with retrovirus-induced immunosuppression. Ophthalmol Eye Dis 4:79-90
Chien, Hsin; Dix, Richard D (2012) Evidence for multiple cell death pathways during development of experimental cytomegalovirus retinitis in mice with retrovirus-induced immunosuppression: apoptosis, necroptosis, and pyroptosis. J Virol 86:10961-78
Buckner, Anissa E; Dix, Richard D (2006) Nicotine treatment alters NF-kappaB expression in human cytomegalovirus-infected ARPE-19 cells. Curr Eye Res 31:191-8
Dix, R D; Cousins, S W (2005) Cell-mediated cytotoxicity of murine cytomegalovirus-infected target cells allows for release of residual infectious virus. Arch Virol 150:797-803
Dix, Richard D; Cousins, Scott W (2004) Susceptibility to murine cytomegalovirus retinitis during progression of MAIDS: correlation with intraocular levels of tumor necrosis factor-alpha and interferon-gamma. Curr Eye Res 29:173-80
Dix, R D; Ekworomadu, C O; Hernandez, E et al. (2004) Perforin knockout mice, but not mice with MAIDS, show protection against experimental cytomegalovirus retinitis after adoptive transfer of immune cells with a functional perforin cytotoxic pathway. Arch Virol 149:2235-44

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