mechanisms of HIV and drug abuse pathogenesis in CNS

描述（由申请人提供）：甲基苯丙胺（冰毒）是一种精神兴奋剂，在美国已经超过可卡因的使用。药物滥用，特别是使用冰毒，是艾滋病毒感染和疾病进展的一个危险因素。冰毒增加HIV/SIV病毒载量并加剧HIV相关神经认知障碍（HAND）。甲基苯丙胺导致中枢神经系统发病机制增强的细胞和分子机制尚不完全清楚。虽然许多研究直接评估了冰毒和HIV病毒毒素对神经元的影响，但星形胶质细胞在冰毒/HIV合并症中的作用尚未得到充分研究。星形胶质细胞占中枢神经系统细胞的70%，并发挥维持中枢神经系统稳态的重要功能。我们证明甲基安非他明诱导星形胶质细胞中的HIV复制，抑制-catenin信号传导，并导致谷氨酸转运网络失调。甲基介导的-catenin信号的抑制尤其重要，因为这一途径对细胞间的通讯、生存和增殖至关重要，我们发现它调节兴奋性氨基酸转运蛋白2 (EAAT2)，这是一种主要的谷氨酸转运蛋白，负责星形胶质细胞约90%的谷氨酸摄取。本应用将集中于甲基安非他明和-catenin信号在甲基安非他明/HIV共发病中的毒理学、功能和潜在的治疗方法。具体来说，我们建议确定冰毒诱导HIV生产性复制的机制（Aim 1/病毒学）；测定Meth/ -catenin轴对星形胶质细胞功能的影响（Aim 2/function）；并评估-catenin途径的小分子调节剂克服冰毒对HIV和星形胶质细胞功能的影响的能力（目标3/治疗学）。总的来说，这些研究将为HIV/Meth共发病提供新的机制见解，并通过靶向-catenin通路的细胞保护特性来加速药物治疗的发展，这些药物治疗可以靶向Meth和HIV加重的神经发病机制。

DESCRIPTION (provided by applicant): Methamphetamine (Meth) is a psychostimulant that has exceeded cocaine use in the US. Drug abuse in general and Meth use in particular is a risk factor for HIV acquisition and disease progression. Meth enhances HIV/SIV viral load and exacerbates HIV associated neurocognitive disorders (HAND). The cellular and molecular mechanisms by which Meth leads to heightened pathogenesis in the CNS are not entirely clear. While a number of studies have directly assessed the impact of Meth and HIV viral toxins in neurons, the role of astrocytes, which make up to 70% of cells in the CNS and perform vital functions to maintain CNS homeostasis, is understudied in Meth/HIV co-morbidity. We demonstrate that Meth induces HIV replication in astrocytes, inhibits -catenin signaling, and leads to dysregulation in the glutamate transport network. Meth-mediated inhibition of -catenin signaling is particularly important because this pathway is critical for cell-to-cell communication survival, proliferation, and we show that it regulates Excitatory Amino Acid Transporter 2 (EAAT2), the predominate glutamate transporter responsible for ~90% of glutamate uptake by astrocytes. This application will focus on the virology, function, and potential therapeutics in th axis between Meth and -catenin signaling in Meth/HIV co-morbidity. Specifically, we propose to identify the mechanism by which Meth induces HIV productive replication (Aim 1/virology); determine the impact of Meth/ -catenin axis on the function of astrocytes (Aim 2/function); and assess the ability of small molecule modulators of the -catenin pathway to overcome Meth effects on HIV and function of astrocytes (Aim 3/therapeutics). Collectively, these studies will provide novel mechanistic insights into HIV/Meth co-morbidity and expedite the development of pharmacotherpies that can target Meth and HIV exacerbated neuropathogenesis by targeting the cellular protective properties of the -catenin pathway. PUBLIC HEALTH RELEVANCE: Methamphetamine is a drug that is often abused in the HIV+ population. It leads to risky behavior that increases the chances for HIV infection. Once HIV infected, Meth abusers have worse neurocognitive impairment than HIV+ non Meth abusers. We propose to study mechanisms at the cellular and molecular level to understand how Meth and HIV lead to worse clinical outcome than either factor alone. Understanding these pathways is a critical first step to devise novel strategies to treat this co-morbid condition.