Methamphetamine and HIV: Defective immunity with CD8 T cell dysfunction

描述(申请人提供)：我们的总体目标是了解甲基苯丙胺(Meth)是如何导致功能性免疫系统异常的，这些变化如何改变对病毒感染的反应，以及由Meth引起的独特的T细胞功能障碍如何导致对艾滋病毒的免疫缺陷以及全身和中枢神经系统(CNS)疾病的增加。我们的实验包括五个具体目标，通过啮齿类动物的基本机制，系统和逐步地工作，到非人类灵长类动物的高度可翻译的实验。我们将了解到有关Meth对免疫系统的调节及其对宿主对HIV反应的调节的新信息。除了体内研究，我们还将对T细胞中的信号进行定量磷酸蛋白质组学研究，以确定Meth改变CD8 T细胞功能的分子机制。这些联合研究将揭示在模拟人类体内Meth滥用和HIV感染的互补系统中的机械交叉流，从而能够识别由于Meth和HIV的交叉而受到干扰的细胞网络和信号事件。

DESCRIPTION (provided by applicant): Our overall goal is to understand the means by which methamphetamine (Meth) induces functional immune system abnormalities, how these changes alter the response to viral infection, and how the unique pattern of T cell dysfunction resulting from Meth leads to defective immunity to HIV with increased systemic and central nervous system (CNS) disease. Our experiments comprise five specific aims, working systematically and progressively through basic mechanisms in rodents to highly translatable experiments in nonhuman primates. We will learn new information regarding the regulation of the immune system by Meth and its modulation of the host response to HIV. In addition to in vivo studies, we will perform quantitative phosphoproteomics of the signaling in T cells to identify the molecular mechanism whereby Meth alters CD8 T cell function. These combined studies will reveal mechanistic crosscurrents in complementary systems modeling Meth abuse and HIV infection in humans, allowing the identification of the networks of cells and signaling events which are perturbed due to the intersection of Meth and HIV.