HIV-associated dementia complex develops in 20% of AIDS patients and has been linked to release of neurotoxic metabolites and cytokines by infected macrophages and microglia in the brain. Recently, macrophage infection has also been associated with release of certain chemokines, both in vitro and in the brain of ADC. Little is known about the role of chemokines and chemokine receptor interactions in the pathogenesis of ADC. The Principal Investigator and his associates have demonstrated functional chemokine receptors on human neurons in vitro and chemokine receptors on neurons and microglia in vivo. Further, they found that chemokines modulated certain neuronal glial function in vitro and that CNS HIV strains differ in their abilities to induce chemokines in macrophages. To test the hypothesis that chemokines induced by HIV-1 within the CNS contribute to the pathogenesis of ADC through chemokine receptor/ligand interaction, the Investigator proposes three specific aims: (1) to determine the distribution of selected chemokine receptors in CNS cell type, and to identify specific chemokine production within the CNS, by analysis of primary glial cells cultured from human brain, cerebrospinal fluid from HIV-1 infected patients, and autopsied brain specimens; (2) to define the effects of specific chemokines on functional neurotransmitter pathways and other relevant functions in neurons and glia, determining the effects of chemokines on neurotransmitter uptake and enzyme expression, glial cell chemotaxis, and neuronal calcium fluxes; (3) to analyze differences between primary CNS isolates for patients with and without ADC in inducing chemokine production.
