The human immunodeficiency virus associated dementia complex (ADC) follows progressive viral infection and immunosuppression in a significant proportion of infected individuals. The mechanisms for disease, in measure, revolve around viral infection and immune activation of brain mononuclear phagocytes (macrophages and microglia). Studies from our laboratory support distinctive role for each cell type in disease. This component of the program project grant will investigate indirect mechanisms of HIV neuropathogenesis utilizing age-matched human microglia and blood-derived monocytes to examine the neurotoxic responses elicited following immune activation and HIV-1 infection. The mechanisms for viral entry, the chemotactic factors that underlie monocyte penetration into brain and the elucidation of the biological and molecular events in which mononuclear phagocytes induce neural injury will be explored. The hypothesis being tested is that functional differences exist between the two phagocytic cell types and that microglial cells are a principle participant in HIV-1 associated neuropathological injury. The laboratory has now gained significant expertise together with other project responses, it utilizing molecular and biochemical approaches for identifying HIV-induced neurotoxins and in developing small animal model systems for ADC. Such experimental systems will be utilized in determining the precise role played by mononuclear phagocytes in ADC.