The objective of this application is to determine the role of apoptosis in HIV-1 dementia. The Investigator has preliminary data suggesting neuronal apoptosis in brains of patients with HIV-1 dementia. She concludes that apoptosis is likely to be an important cause of neuronal loss in this disorder. She and her coworkers have shown that specific strains of HIV-1 are required to induce apoptosis in primary human fetal brain cultures. Their immunocytochemical studies suggest that restricted astrocyte infection may be one factor which distinguishes HIV-1 isolates which induce neuronal apoptosis, possibly by producing or amplifying the effects of neurotoxic factors. A peptide inhibitor of the ICE protease family inhibits apoptosis in HIV-1-infected primary brain cultures, suggesting that the ICE family is involved in mediating HIV-1-induced neuronal apoptosis. In the proposed research, the Investigator and her coworkers will address several questions which are fundamental to understanding the role of apoptosis in HIV-1 dementia. In vitro studies in primary brain cultures will be complemented by studies of brain tissue from AIDS patients to correlate results with clinical dementia in vivo. HIV-1 brain isolates which induce neuronal apoptosis in vitro will be identified and their correlation with clinical dementia will be determined. The role of restricted astrocyte infection in HIV-induced apoptosis in the CNS will also be examined. Primary brain cultures will be used to determine the role of the ICE protease family in HIV-induced neuronal apoptosis and examine their potential as therapeutic targets.
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