Methamphetamine, Innate Immunity and HIV

 描述（由申请人提供）：甲基苯丙胺（METH）是美国艾滋病毒感染者中最常滥用的药物之一。甲基苯丙胺的使用与艾滋病毒感染者的最坏健康结果有关，因为甲基苯丙胺对病毒感染的免疫反应产生不利影响。虽然METH已被表明是艾滋病毒疾病发展的一个促进因素，但METH对艾滋病毒的作用机制仍有待确定。我们的体外研究表明，METH可以增强HIV复制和损害细胞内的先天免疫。因此，我们提出了使用来自独特且充分表征的研究受试者的临床标本的进一步研究，研究METH对RIG-I/TLR 3信号传导介导的抗HIV活性的体内和离体影响。我们假设METH抑制原代免疫细胞（CD 4 +T细胞，单核细胞）和CNS细胞（星形胶质细胞，小胶质细胞）的细胞内先天免疫，促进HIV感染和神经元损伤。我们提出了三个具体的目标来解决这个假设：在目标1中，我们将确定在有或没有慢性HIV感染的METH使用者中外泌体衍生的HIV限制性miRNA和免疫活化标志物的血浆水平。在目标2中，我们将确定METH对RIG-I/TLR 3信号传导介导的针对HIV的先天免疫的离体和体外作用。我们还将研究METH对RIG-I/TLR 3信号传导和HIV感染的作用机制。在目标3中，我们将确定星形胶质细胞RIG-I/TLR 3信号传导对小胶质细胞中HIV复制（胶质细胞-胶质细胞相互作用）的影响以及METH对星形胶质细胞RIG-I/TLR 3信号传导介导的抗HIV作用和神经元细胞保护的影响。这些拟议的结合体内、离体和体外方法的新型研究具有临床意义和相关性，因为它们将揭示以前未识别的METH对HIV和中枢神经系统作用的机制。此外，拟议的研究将确定新的免疫学标志物，用于监测甲基苯丙胺使用对艾滋病毒疾病发展的影响。

 DESCRIPTION (provided by applicant): Methamphetamine (METH) is one of the most commonly abused drugs among HIV-infected individuals in the United States. METH use is associated with the worst health outcomes in HIV-infected individuals, as METH adversely impacts immunological responses to viral infections. Although METH has been indicated as a facilitating factor in the development of HIV disease, the mechanism(s) of METH actions on HIV remains to be determined. Our in vitro studies showed that METH could enhance HIV replication and impair intracellular innate immunity. Thus, we proposed further studies using the clinical specimens from the unique and well-characterized study subjects, investigating the in vivo and ex vivo impact of METH on RIG- I/TLR3 signaling-mediated anti-HIV activities. We hypothesize that METH suppresses intracellular innate immunity in primary immune cells (CD4+T cells, monocytes) and CNS cells (astrocytes, microglia), facilitating HIV infection and neuronal injury. We propose three specific aims to address this hypothesis: In aim 1, we will determine the plasma levels of exosome- derived HIV restriction miRNAs and immune activation markers in METH users with or without chronic HIV infection. In aim 2, we will determine the ex vivo and in vitro effects of METH on RIG-I/TLR3 signaling-mediated innate immunity against HIV. We will also examine the mechanisms involved in the actions of METH on RIG-I/TLR3 signaling and HIV infection. In aim 3, we will determine the effect of astroglial RIG-I/TLR3 signaling on HIV replication in microglia (glia-glia interaction) as well as the impact of METH on astroglial RIG-I/TLR3 signaling-mediated anti-HIV effect and neuronal cell protection. These proposed novel studies with combinational in vivo, ex vivo and in vitro approaches are clinically significant and relevant, as they will reveal previously unidentified mechanisms for the METH actions on HIV and the CNS. In addition, the proposed studies will identify the novel immunological markers for monitoring the impact of METH use on the development of HIV disease.