NEURONAL APOPTOSIS INDUCED BY HIV-1 TAT PROTEIN AND TNF-ALPHA - POTENTIATION OF NEUROTOXICITY MEDIATED BY OXIDATIVE STRESS AND IMPLICATIONSFOR HIV-1 DEMENTIA

Apoptosis of neurons and non-neuronal cells has been demonstrated in t he brain of AIDS patients with dementia. Previous studies suggest that the apoptotic stimuli are likely to be soluble factors. Several candi dates for the soluble factors that lead to neuronal apoptosis in HIV-1 infection have been proposed, including the HIV-1 Tat protein and TNF -alpha. The mechanisms that lead to neuronal apoptosis in the brain of AIDS patients in vivo, may involve the combined effects of more than one pro-apoptotic factor. In this study, we examine whether exposure o f primary human neurons to the combination of HIV-1 Tat and TNF-alpha can potentiate the induction of neuronal apoptosis compared with expos ure to either factor alone. TNF-alpha was shown to potentiate the indu ction of neuronal apoptosis by HIV-1 Tat via a mechanism that involves increased oxidative stress. Antioxidants inhibited, but did not compl etely abolish the induction of neuronal apoptosis by Tat, suggesting t hat other mechanisms are also likely to be involved. These findings su ggest that soluble HIV-1 Tat and TNF-alpha may play a role in neuronal apoptosis induced by HIV-1 infection of the CNS, particularly when pr esent in combination. Our findings further suggest that one mechanism whereby combinations of pro-apoptotic factors may potentiate the induc tion of neuronal apoptosis in the brain of AIDS patients is by increas ing oxidative stress. Understanding the role of oxidative stress and o ther mechanisms that lead to apoptosis in HIV-1 infection of the CNS m ay advance the development of new therapeutic strategies to prevent ne uronal cell death and improve neurologic function in AIDS patients.