METH-induced T cell Dysfunction: Role in HIV-1 Immunopathogenesis

描述(申请人提供)：非法药物，如甲基苯丙胺(冰毒)会改变免疫功能，降低宿主抵抗力。冰毒滥用与感染易感性增加之间存在关联；然而，潜在的机制在很大程度上尚不清楚。冰毒滥用者中HIV-1感染的高发病率以及冰毒对免疫系统的潜在影响，突显了冰毒-HIV-1共病的临床意义。免疫应答缺陷可导致HIV-1在外周器官和中枢神经系统(CNS)加速感染。初步数据表明，氧化应激是冰毒引起免疫功能障碍的可能原因之一。事实上，我们的初步研究表明，冰毒暴露会引起T细胞的氧化应激，在T细胞受体的刺激下，显示T细胞增殖并减少细胞因子的产生。暴露在冰毒中的T细胞表现出控制免疫细胞激活和T细胞表面标志的基因的调节。因此，我们推测，冰毒引起的T淋巴细胞氧化应激抑制免疫反应，损害T细胞的激活和增殖，从而促进HIV-1感染的进展。利用体外系统和长期接触冰毒的HIV-1脑炎动物模型，我们将解决以下问题：(1)冰毒诱导的氧化应激对T细胞功能的潜在影响？(2)与冰毒相关的氧化应激介导的T细胞免疫反应受损的机制是什么？(3)T细胞功能障碍如何影响中枢神经系统内外对HIV-1感染的适应性免疫系统反应？抗氧化剂和特定的信号抑制剂将被用来描述参与这些效应的途径。我们认为，拟议的工作具有非常重要的意义，因为它们将揭示调节艾滋病毒-1和冰毒滥用对免疫的联合影响的新机制，并在这些研究的基础上提出治疗方法。甲基苯丙胺是一种高度上瘾的兴奋剂，被数百万美国人滥用，众所周知会改变免疫功能，增加感染的易感性。流行病学研究表明，越来越多的证据表明，滥用冰毒与艾滋病毒-1感染发病率增加之间存在联系。然而，滥用冰毒与艾滋病毒-1感染的易感性或其进展之间的明显因果关系在很大程度上是未知的。这项建议旨在了解在冰毒滥用和HIV-1感染背景下免疫功能障碍的可能机制。

DESCRIPTION (provided by applicant): Illicit drugs such as methamphetamine (METH) alter immune functions and decreases host resistance. There is an association between METH abuse and enhanced susceptibility to infections; however, underlying mechanisms are largely unknown. High incidence of HIV-1 infection in METH abusers and potential effects of METH on immune system underscore clinical significance of METH-HIV-1 co-morbidity. Defective immune responses could lead to the accelerated HIV-1 infection in the peripheral organs and central nervous system (CNS). Preliminary data point to the oxidative stress as one of possible causes of METH induced immune dysfunction. Indeed, our preliminary studies indicate that METH exposure elicits oxidative stress in T cells and upon T-cell receptor stimulation show T cell proliferation and decreases cytokine production. T cells exposed to METH demonstrate modulation of genes controlling in immune cell activation and T cell surface markers. Therefore, we hypothesize that the oxidative stress caused by METH in T lymphocytes dampens immune responses, impairs T cell activation and proliferation leading to enhanced progression of HIV-1 infection. Using a combination of in vitro systems and animal model for HIV-1 encephalitis chronically exposed to METH, we will address the following questions: (1) What are the potential implications of METH- induced oxidative stress on T cell functions? (2) What are the mechanisms underlying impaired T cell immune responses mediated by oxidative stress associated with METH? (3) How does T cell dysfunction affect the adaptive immune system responses to HIV-1 infection in and outside of CNS? Antioxidants and specific signaling inhibitors will be utilized to delineate pathways involved in these effects. We believe that the proposed works are highly significant as they will uncover novel mechanisms mediating combined effects of HIV-1 and METH abuse on immunity and propose therapeutic approaches based on these investigations. PUBLIC HEALTH RELEVANCE Methamphetamine is a highly addictive stimulant abused by millions of Americans and is known to alter immune function and increase susceptibility to infection. Epidemiological studies indicate growing evidence of the association between METH abuse and an increased incidence of HIV-1 infections. However, the apparent causal interrelationship between METH abuse and susceptibility to HIV-1 infection or its progression are largely unknown. This proposal aims to understand putative mechanisms of immune dysfunctions in the setting of METH abuse and HIV-1 infection.