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

描述（由申请人提供）：非法药物，如甲基苯丙胺（METH）改变免疫功能，降低宿主抵抗力。甲基苯丙胺滥用与感染易感性增强之间存在关联;然而，其潜在机制在很大程度上尚不清楚。METH滥用者中HIV-1感染的高发病率和METH对免疫系统的潜在影响强调了METH-HIV-1共病的临床意义。免疫应答缺陷可导致外周器官和中枢神经系统（CNS）HIV-1感染加速。初步数据表明，氧化应激是METH诱导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，METH暴露eliminates氧化应激在T细胞和T细胞受体刺激后显示T细胞增殖和减少细胞因子的产生。暴露于METH的T细胞表现出控制免疫细胞活化和T细胞表面标志物的基因的调节。因此，我们推测METH在T淋巴细胞中引起的氧化应激抑制免疫应答，损害T细胞活化和增殖，导致HIV-1感染的进展加快。使用体外系统和长期暴露于METH的HIV-1脑炎动物模型的组合，我们将解决以下问题：（1）METH诱导的氧化应激对T细胞功能的潜在影响是什么？(2)与METH相关的氧化应激介导的T细胞免疫应答受损的潜在机制是什么？(3)T细胞功能障碍如何影响CNS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传导抑制剂将被用来描绘参与这些影响的途径。我们认为，拟议的工作是非常重要的，因为他们将发现新的机制介导的HIV-1和METH滥用对免疫的综合影响，并提出基于这些调查的治疗方法。甲基苯丙胺是一种高度成瘾的兴奋剂，被数百万美国人滥用，已知会改变免疫功能，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甲基苯丙胺滥用与艾滋病毒1型感染发病率增加之间存在关联。然而，甲基苯丙胺滥用与HIV-1感染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。该提案旨在了解METH滥用和HIV-1感染背景下免疫功能障碍的假定机制。

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.