Human immunodeficiency virus (HIV)-associated dementia (HAD) follows progressive viral infection and immunosuppression in a significant proportion of affected persons. The mechanism for disease, in large measure, revolves around viral infection and immune activation of brain macrophages and microglia. Preliminary studies from the applicant's laboratory suggest that there are distinctive roles for each cell type in the disease. The proposed studies will compare virus-cell interactions in HIV-1-infected monocyte-derived macrophages and in human microglia as a function of donor age and viral strain. The mechanisms for viral entry, the chemotactic factors that underlie monocyte penetrance into brain, and the biological differences between monocytes and microglia in producing neural injury will be assessed. The hypothesis being tested is that functional differences in effector cell function exist between the two cell types, and that microglial cells are a principal participant in HIV-1-associated neuropathological injury. The applicant's laboratory has significant expertise in isolating and propagating monocytes and microglia, in delineating macrophage effector cell responses following viral infection/immune activation, in utilizing molecular and biochemical approaches for identifying HIV-induced neurotoxins, in developing a small animal model systems for HAD, and in utilizing sensitive assays to determine neuronal injury/death. With all of the existing technology, the applicant wishes to determine the precise role that mononuclear phagocytes (both macrophages and microglia) play in HAD. The following specific aims are proposed: 1. To compare monocyte/microglia effector cell responses following viral infection and immune activation. Cell responses to be examined include phagocytosis, antigen presentation, intracellular killing and effector cell secretions. 2. To analyze the composition of soluble factors secreted by macrophages/microglia, their effects on neuronal function, and the viral and cellular control mechanisms that affect their production. 3. To utilize a SCID mouse model system for HIV encephalitis to test the importance of chemokine receptors, mechanisms for spreading viral infection, neurotoxic activities of specific factors identified in Specific Aims #1 and #2, and determine the functional differences between monocytes and microglia in the pathogenesis of HAD.
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