Role of miRNAs in Methamphetamine/HIV-mediated Immune Activation

摘要 慢性免疫激活是HIV疾病进展的一个主要因素。微生物易位的细菌产物 来自肠道的病毒很可能是慢性艾滋病毒感染中全身免疫激活的一个原因。然而， 慢性免疫激活的机制(S)尚不清楚。考虑到滥用毒品 很大程度上导致艾滋病毒感染，因此研究是否使用甲基苯丙胺(冰毒)是至关重要的 在HIV感染者中经常滥用药物，与HIV感染相关的全身 炎症和慢性免疫激活。我们假设冰毒的使用会导致炎症和免疫 通过诱导炎症和神经毒性miRNAs激活，促进艾滋病毒复制和 血脑屏障/中枢神经系统损伤。我们提出了三个具体目标来解决这一假设。在目标1中，我们将确定 有无冰毒吸毒者血浆几种关键微生物成分和免疫激活标志物的水平 艾滋病毒感染。我们还将测量这些受试者血浆中炎性/神经毒性miRNAs的水平； 2，我们将研究冰毒使用者的单核细胞和T淋巴细胞是否表达更高水平的 炎性/神经毒性miRNAs比非冰毒使用者的miRNAs少。我们还将调查冰毒是否有 与微生物产品在增强巨噬细胞感染HIV方面的协同效应以及细胞是否来自 冰毒使用者比对照组更容易感染艾滋病毒；在目标3中，我们将检查 冰毒和/或HIV对脑组织和脑脊液中炎性和神经毒性miRNAs表达的影响 来自患有或不患有艾滋病毒相关神经认知障碍(手)的受试者。此外，我们将机械地 探讨炎性/神经毒性miRNAs(let-7、miR-17、-20a、-21、-132、-146a)在血脑屏障中的作用 神经元损伤。这些建议的研究包括体外(目标3)、体外(目标2)和体内(目标1、2、 3)方法具有临床相关性和重要意义，将确定以前未被识别的生物标记物和 冰毒介导的全身炎症/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.