Mechanisms of Cocaine-Induced HIV-1 infection in NHA

描述（由申请人提供）：2003年，估计有230万美国人是活跃的可卡因使用者。美国目前正在经历可卡因使用与HIV-1感染交织的流行病。中枢神经系统（CNS）是HIV-1和可卡因的共同靶点。星形胶质细胞，中枢神经系统的组成部分，据报道是易受HIV-1感染。在激活后，星形胶质细胞释放一些免疫调节产物，促进HIV-1感染的免疫发病机制。有丝分裂原活化蛋白激酶（MAP激酶）的信号转导在细胞免疫应答中起着重要作用。在正常人类星形胶质细胞（NHA）中，可卡因对MAP激酶在HIV-1感染易感性中的作用尚未被描述。因此，提出以下目标：可卡因在HIV-1感染的神经发病机制中起辅助因素的作用。此外，我们提出可卡因通过调节MAP激酶来增强HIV-1感染，从而介导这些效应。我们还建议研究可卡因对未感染和HIV-1感染的NHA蛋白质组学的影响。阐明可卡因介导的NHA中HIV-1感染增强导致HIV-1疾病进展的分子机制以及相关独特蛋白的鉴定可能有助于开发利用HIV-1感染受试者的新治疗策略。

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.