ASTROCYTE APOPTOSIS INDUCED BY HIV-1 TRANSACTIVATION OF THE C-KIT PROTOONCOGENE

HIV-1 infection of the central nervous system (CNS) frequently causes dementia and other neurological disorders. The mechanisms of CNS injur y in HIV-1 infection are poorly understood. Apoptosis of neurons and a strocytes is induced by HIV-1 infection ira vitro and in brain tissue from AIDS patients, but the apoptotic stimuli have not been identified . We report herein that HIV-1 infection of primary brain cultures indu ces the receptor tyrosine kinase protooncogene c-kit and that high lev els of c-Kit expression are associated with astrocyte apoptosis. Overe xpression of c-Kit in an astrocyte-derived cell line in the absence of HIV-1 induces rapid apoptotic death. The apoptotic mechanism requires the c-Kit tyrosine kinase domain. The mechanism of c-kit induction by HIV-1 involves transactivation of the c-kit promoter by the HIV-1 Nef protein. These studies demonstrate that c-Kit can induce astrocyte ap optosis and suggest that this mechanism may play a role in CNS injury caused by HIV-1 infection. We propose that c-Kit can serve dual functi ons as a growth factor receptor or apoptosis inducer.