Role of miRNAs in Methamphetamine/HIV-mediated Immune Activation

摘要 慢性免疫激活是HIV疾病进展的主要因素。微生物易位的细菌产物 可能是慢性HIV感染中全身免疫激活的原因。但 负责慢性免疫激活的机制仍有待确定。鉴于滥用药物 虽然甲基苯丙胺是艾滋病毒感染的主要原因之一，但研究甲基苯丙胺（METH）的使用是否是至关重要的， HIV感染者中经常滥用药物，与HIV感染相关的全身性 炎症和慢性免疫激活。我们假设METH的使用导致炎症和免疫反应， 通过诱导炎症和神经毒性miRNA激活，促进HIV复制， BBB/CNS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 血浆中几种关键的微生物成分和免疫激活标记物的水平， 艾滋病毒感染。我们还将测量这些受试者中炎症/神经毒性miRNA的血浆水平; 2，我们将研究METH使用者的单核细胞和T淋巴细胞是否表达更高水平的 与非METH使用者相比，炎症/神经毒性miRNAs。我们还将调查METH是否具有 与微生物制品的协同作用对增强巨噬细胞的HIV感染以及来自 METH使用者比对照受试者更容易感染HIV;在目标3中，我们将检查 METH和/或HIV对脑组织和CSF中炎性和神经毒性miRNA表达的影响 来自患有或不患有HIV相关神经认知障碍（HAND）的受试者。此外，我们将机械地 研究炎性/神经毒性miRNA（let-7、miR-17、-20 a、-21、-132、-146 a）在BBB中的作用， 神经元损伤这些提出的研究结合了体外（目的3）、离体（目的2）和体内（目的1，2， 3)这些方法具有临床相关性和重要性，并将确定以前未识别的生物标志物， METH使用介导的全身性炎症/免疫激活和BBB/CNS损伤的机制。

Abstract Chronic immune activation is a major factor of HIV disease progression. Bacterial products of microbial translocation from the gut are likely to be a cause of systemic immune activation in chronic HIV infection. However, the mechanism(s) responsible for chronic immune activation remain to be determined. Given that drugs of abuse contribute greatly to HIV infection, it is crucial to study whether use of methamphetamine (METH), one of the most commonly abused drugs among HIV-infected individuals, is associated with HIV infection-related systemic inflammation and chronic immune activation. We hypothesize that METH use result in inflammation and immune activation through induction of the inflammatory and neurotoxic miRNAs, which facilitate HIV replication and the BBB/CNS injury. We propose three specific aims to address this hypothesis. In Aim 1, we will determine the plasma levels of several key microbial components and immune activation markers in METH users with or without HIV infection. We will also measure the plasma levels of inflammatory/neurotoxic miRNAs in these subjects; In Aim 2, we will study whether monocytes and T lymphocytes from METH users express higher levels of the inflammatory/neurotoxic miRNAs than those from non-METH users. We will also investigate whether METH has synergetic effect with the microbial products on enhancing HIV infection of macrophages and whether the cells from METH users are more susceptible to HIV infection than those from control subjects; In Aim 3, we will examine the effects of METH and/or HIV on the expression of inflammatory and neurotoxic miRNAs in the brain tissues and CSF from subjects with or without HIV-associated neurocognitive disorder (HAND). In addition, we will mechanistically investigate the role of inflammatory/neurotoxic miRNAs (let-7, miR-17, -20a, -21, -132, -146a) in the BBB and neuronal injury. These proposed studies with combinational in vitro (Aim 3), ex vivo (Aim 2), and in vivo (Aims 1, 2, 3) approaches are clinically relevant and significant, and will determine previously unrecognized biomarkers and mechanisms for METH use-mediated systemic inflammation/immune activation and impairment of the BBB/CNS.