Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010568-14
Application #
7684584
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Shen, Grace L
Project Start
1994-07-01
Project End
2012-08-31
Budget Start
2009-09-01
Budget End
2012-08-31
Support Year
14
Fiscal Year
2009
Total Cost
$345,187
Indirect Cost

  Institution

Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302

  Publications

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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