The two most common pathogens in the CNS of AIDS patients at autopsy are HIV and CMV, with HIV present in 40-50% and CMV in 20-30% of all brains in our study. Since both CMV and HIV can cause a diffuse encephalitis, differential diagnosis is difficult in life. CMV retinitis (CMV-R) is the most common and readily diagnosed manifestation of CMV, developing in 20- 30% of all AIDS patients. Usually infection is extensive at presentation and while treatment temporarily restricts damage, CMV reactivations occur and blindness may result. Our data suggest that CMV-R can be used as a marker of CMV infection in the brain and neurocognitive impairment. If so, early detection or prediction of CMV-R could facilitate treatment to prevent blindness and encephalitis. While virtually all HIV infected individuals are latently infected with CMV, why CMV becomes a life threatening disease in some and remains subclinical in others, is unknown. To investigate whether susceptibility to overt CMV disease was dependent on host immune response, we examined CMV specific T-cell proliferation and HLA type prospectively. Most individuals who developed CMV-R had a history of low T-cell proliferative responses to CMV antigens (but not HIV) compared to matched controls. With respect to immunogenetics, HLA-DR7 was significantly increased and HLA- B44,51 slightly increased in CMV-R patients. Presence of these 3 HLA alleles also correlated with low CMV specific proliferation responses in asymptomatic HIV infected individuals. We now hypothesize that CMV mediates neurocognitive deficits in AIDS and that those individuals most susceptible to CMV-R and encephalitis could be identified early in HIV disease by immunologic and immunogenetic testing. We propose to examine the predictive value of low immune response for CMV- R by assaying those with more than 100 CD4 T-cells and monitoring for development of CMV-R. The association of HLA-DR-7, B44, and B51 will be investigated by following those already HLA typed individuals and typing a set of those who develop retinitis. We will also initiate experiments to test the hypothesis that HLA-DR7 is associated with low proliferation response by comparing T-cell recognition of antigens presented with DR7 to the same antigens presented by other DR alleles. To investigate whether low proliferative response to CMV reflects inability to respond to antigen or absence of CMV reactivation, proliferation will be examined concurrently with CMV viremia (PCR of peripheral blood lymphocytes for CMV DNA) for a set of individuals with 100-200 CD4 T-cells. Information as to the presence of viremia will also permit comparison of T-cell proliferation, HLA alleles, and viremia, for detection and prediction of CMV-R. The results of these experiments should improve understanding of host and virus interaction and CMV neuropathogenesis in AIDS, and help establish criteria to predict high or low risk of CMV-R.