Mechanisms of Cocaine-Induced HIV-1 infection in NHA

描述(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。美国目前正在经历一场与HIV-1感染有关的可卡因使用流行病。中枢神经系统(CNS)是HIV-1和可卡因的共同目标。星形胶质细胞是中枢神经系统的组成部分，据报道易受HIV-1感染。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。丝裂原活化蛋白激酶(MAP)的信号转导在细胞免疫反应中发挥着重要作用。在正常人类星形胶质细胞(NHA)中，可卡因对MAP激酶的作用在HIV-1感染易感性的背景下尚未被描述。因此，提出了以下目标：可卡因在HIV-1感染的神经发病机制中起辅助作用。此外，我们认为可卡因通过调节MAP激酶来增强HIV-1的感染，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蛋白质组的影响。阐明可卡因在NHA中促进HIV-1感染从而导致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感染者的药物治疗策略。

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.