Retinal pathology is frequent in patients with the acquired immunodeficiency syndrome (AIDS) induced by the immunodeficiency virus (HIV). This proposal is based on the hypothesis that retinal damage in AIDS is initiated through HIV infection of vascular endothelial cells and secondarily to HIV infection of Muller cells. HIV infected endothelial and Muller cells may then have altered functions (eg, change in blood- retina-barrier or cytokine production. These functional changes may increase retinal susceptibility to further HIV and cytomegalovirus (CMV) infection with resultant retinal necrosis, or may on their own lead to cell destruction. HIV and CMV may coexist in the same cell and mutually enhance viral transcription. This study will test the above hypothesis (1) by analyzing and comparing the distribution and localization of HIV in retina of HIV infected versus combined HIV and CMV infected patients; (2) by using cytokines on endothelial and Muller cell cultures to determine whether these growth factors can regulate susceptibility to HIV; and (3) by exposing HIV infected endothelial and Muller cells to CMV to determine the role of HIV on susceptibility to CMV. AIDS retinal disease is an excellent model system because it provides two unique situations. Firstly, retinal tissue at different stages of a disease is only available in disease processes such as AIDS, where the retinal disease is independent of other lethal clinical manifestations. This disease enables the identification of the progressive changes from early to late disease induced by HIV, Secondly, the retina provides a simple, clearly defined structure, with morphologically and functionally defined cell types. The retina is therefore the ideal structure for a definitive analysis of cytokine and viral effects on endothelial and glial cells in AIDS retinitis. By understanding the cells and growth factors involved in AIDS retina disease, the mechanism of retinal cell destruction will be better understood, thereby leading to more effective forms of therapy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008144-02
Application #
3265333
Study Section
Special Emphasis Panel (ARR (V4))
Project Start
1989-08-01
Project End
1992-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Doheny Eye Institute
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Hofman, F M; Chen, P; Incardona, F et al. (1999) HIV-1 tat protein induces the production of interleukin-8 by human brain-derived endothelial cells. J Neuroimmunol 94:28-39
Duchini, A; Govindarajan, S; Santucci, M et al. (1996) Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 44:474-82
Hofman, F M; Dohadwala, M M; Wright, A D et al. (1994) Exogenous tat protein activates central nervous system-derived endothelial cells. J Neuroimmunol 54:19-28
Hofman, F M; Wright, A D; Dohadwala, M M et al. (1993) Exogenous tat protein activates human endothelial cells. Blood 82:2774-80
Chen, T C; Hinton, D R; Apuzzo, M L et al. (1993) Differential effects of tumor necrosis factor-alpha on proliferation, cell surface antigen expression, and cytokine interactions in malignant gliomas. Neurosurgery 32:85-94
Merrill, J E; Kono, D H; Clayton, J et al. (1992) Inflammatory leukocytes and cytokines in the peptide-induced disease of experimental allergic encephalomyelitis in SJL and B10.PL mice. Proc Natl Acad Sci U S A 89:574-8
Wu-Hsieh, B A; Lee, G S; Franco, M et al. (1992) Early activation of splenic macrophages by tumor necrosis factor alpha is important in determining the outcome of experimental histoplasmosis in mice. Infect Immun 60:4230-8
Hofman, F M; Hinton, D R (1992) Tumor necrosis factor-alpha in the retina in acquired immune deficiency syndrome. Invest Ophthalmol Vis Sci 33:1829-35
Schneider, J; Hofman, F M; Apuzzo, M L et al. (1992) Cytokines and immunoregulatory molecules in malignant glial neoplasms. J Neurosurg 77:265-73
Wong, V L; Hofman, F M; Ishii, H et al. (1991) Regional distribution of thrombomodulin in human brain. Brain Res 556:1-5