DESCRIPTION (provided by applicant): In 2003, an estimated 2.3 million Americans were active cocaine users. The US is currently experiencing an epidemic of cocaine use entangled with HIV-1 infection. The central nervous system (CNS) is a common target for both HIV-1 and cocaine. Astrocytes, integral components of the CNS, are reported to be susceptible to HIV-1 infection. Upon activation, astrocytes release a number of immunoregulatory products that foster the immunopathogenesis of HIV-1 infection. Signal transduction via mitogen-activated protein kinases (MAP kinases) play a significant role in cellular immune responses. The role of cocaine on MAP kinases in the context of susceptibility to HIV-1 infection has not yet been delineated in normal human astrocytes (NHA). Consequently, the following aim is proposed: Cocaine acts as a co-factor in the neuropathogenesis HIV-1 infection. Further, we propose that cocaine mediates these effects by enhancing HIV-1 infection via the modulation of MAP kinases. We also propose to investigate the effect of cocaine on the proteomic profile of un-infected and HIV-1 infected NHA. Elucidating the molecular mechanisms of cocaine- mediated enhancement of HIV-1 infection in NHA that lead to HIV-1 disease progression and the identification of associated unique proteins may help to develop novel therapeutic strategies in drug using HIV-1 infected subjects.