Viral retinitis induced by HIV is associated with vascular lesions, leading to the degeneration of endothelial cells, focal occlusion of small vessels, and infection by opportunistic pathogens (e.g., CMV). The process by which HIV causes these pathological conditions is not well understood. The Principal Investigator and her associates have shown that in the retina in AIDS patients: (1) HIV-positive macrophages are distributed perivascularly; (2) tumor necrosis factor-alpha (TNF) is present; and (3) prominent gliosis is apparent. In preliminary data, the researchers have established endothelial cell cultures derived from the retina, and have evidence that TNF, interleukin-1 (IL-1), and the HIV-derived TAT protein can induce changes in endothelial cell functions. Based on the previous studies and preliminary data, the Investigator now postulates that the mechanism by which HIV is disseminated on the retina and causes the pathology in AIDS retinitis is, at least in part, mediated by cytokines and viral proteins released by HIV-infected macrophages. She proposes to study the mechanism by which inflammatory cytokines and the TAT protein derived from HIV-infected cells regulate endothelial cell function by altering the blood- retina barrier, using both in vitro cell cultures and AIDS retina tissues. For this purpose she and her colleagues established endothelial cell cultures derived from the retina (REC) that (1) are homogeneous, (2) retain central nervous system endothelial cell properties, and (3) respond to growth factors in vitro. Using the REC model, these researchers will characterize now the effects of the TAT protein on endothelial cell function as measured by adhesion molecule expression, cytokine production, TNF receptor modulation, permeability alteration, and coagulation factor secretion; they will relate these data to adhesion molecule expression and TNF receptor modulation found in situ in cryostat sections of AIDS tissues. The researchers will then determine how the TAT protein modulates the function of REC cultures activated by TNF and IL-1, exogenous cytokines of particular interest because they are secreted by HIV-infected cells and because they activate REC, according to preliminary data. Further, the researchers will determine whether TAT protein affects the susceptibility of REC to CMV infection and how tat protein modulates the activities of CMV-infected REC.
