Immunopathogenesis of HIV-1 Infection: Role of Methamphetamine

描述(申请人提供)：美国目前正经历着甲基苯丙胺(Meth)作为娱乐毒品的严重流行，截至2005年7月，Meth作为街头或俱乐部毒品的使用已超过可卡因。最近的研究还表明，在Meth使用者中，HIV-1感染的流行率很高。血单核细胞来源的树突状细胞(DC)是抵御HIV-1感染的第一道防线，也是注射吸毒者HIV-1的最初靶点。虽然已经有证据表明Meth使用者存在免疫功能障碍，但Meth使用者中HIV-1感染的免疫发病机制的分子基础尚未阐明。此外，在使用Meth的人群中，滥用Meth对导致HIV-1疾病进展的DC活动的影响尚未得到检验。目前的应用集中在新的，基于DC的免疫治疗和/或翻译研究策略，以防止艾滋病毒-1感染的易感性和进展在使用人群的Meth。因此，拟议的实验将检验以下假设：冰毒是HIV-1感染发病机制中的一个辅助因素，它与某些HIV-1蛋白协同作用于DC功能，从而导致受感染宿主的免疫系统调节失调。此外，我们认为Meth通过几种机制介导这些对DC的影响，包括：1)下调各种共刺激分子、趋化因子(DC成熟、有效的抗原呈递、细胞迁移和T细胞增殖所必需的)的表达，以及相互上调已知促进HIV-1感染的HIV-1进入辅助受体(CCR5和CXCR4)；2)上调抑制T细胞免疫功能的吲哚胺2，3双加氧酶(IDO)；以及3)上调DC上存在的DC特异性的、CD4非依赖的病毒附着受体DC-SIGN。此外，我们将通过研究信号转导通路和使用Meth特异性siRNA和受体抑制剂来确定Meth介导DC功能失调的机制(S)。我们的初步研究表明，Meth显著下调共刺激分子的表达，抑制HIV-1协同受体DC-SIGN和IDO的3种趋化因子的表达，这些作用似乎是通过丝裂原激活蛋白(MAP)激酶的失调而介导的。结果数据将根据HIV-1疾病状态、CD4计数、HIV-1病毒载量和Meth使用情况进行分层。这些研究可能导致新的抗HIV-1治疗或翻译研究策略，如靶向CD4非依赖性病毒附着受体DCSIGN，或设计IDO、DC-SIGN、CCR5/CXCR4和特定的多巴胺受体的抑制剂，或在使用和不使用HIV-1的高危人群中刺激共刺激和(3)趋化因子分子的表达。

DESCRIPTION (provided by applicant): The US is currently experiencing a serious epidemic of methamphetamine (Meth) use as a recreational drug and as of July 2005, Meth use has surpassed cocaine use as a street or club drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. Blood monocyte derived dendritic cells (DC) are the first line of defense against HIV-1 infection and are the initial target of HIV-1 in injection drug users. Although evidence of immune dysfunctions has been reported in Meth users, the molecular basis of the immunopathogenesis of HIV-1 infection in Meth users has not been delineated. Further, the effects of Meth abuse on the activities of DC that lead to HIV-1 disease progression in the Meth using population has not been examined. The current application focuses on novel, DC based immunotherapeutic and/or translational research strategies against susceptibility to and progression of HIV-1 infections in Meth using populations. Consequently, the following hypothesis will be tested by the proposed experiments: Meth is a co-factor in the pathogenesis of HIV-1 infections by acting in synergy with certain HIV-1 proteins on DC functions subsequently leading to dysregulation of the immune system of the infected host. Further, we propose that Meth mediates these effects on DC through several mechanisms including: 1) down regulating the expression of various costimulatory molecules, chemokines (that are necessary for DC maturation, effective antigen presentation, cell migration, and T cell proliferation), and a reciprocal upregulation of HIV-1 entry coreceptors (CCR5 and CXCR4) that are known to facilitate HIV-1 infection; 2) upregulating indolamine 2,3 dioxygenase (IDO) that suppresses T cell immune functions; and 3) upregulating the DC-specific, CD4 independent virus attachment receptor, DC-SIGN, present on DC. Further, we shall determine the mechanism(s) of Meth mediated dysregulation of DC functions by examining signal transduction pathways and using Meth specific siRNA and receptor inhibitors. Our preliminary studies show that Meth significantly downregulates the expression of costimulatory molecules and HIV-1 suppressing (3-chemokines with a reciprocal upregulation of HIV-1 coreceptors, DC-SIGN and IDO, and these effects appear to be mediated via dysregulation of mitogen-activated protein (MAP) kinases. Resultant data will be stratified on the basis of HIV-1 disease status, CD4 counts, HIV-1 viral load and Meth use. These studies may lead to novel anti-HIV-1 therapeutic or translational research strategies such as targeting the CD4 independent virus attachment receptor, DCSIGN, or devising inhibitors of IDO, DC-SIGN, CCR5/CXCR4 and specific dopamine receptors or stimulating the expression of costimulatory-and (3-chemokine molecules in high risk Meth using and non using HIV-1 infected subjects.