Methamphetamine and HIV interactions in the regulation of glial activation

描述（由申请人提供）：HIV-1暴露与甲基苯丙胺（Methe）滥用相关。这两个因素协同作用，加重neuroAIDS症状和疾病进展。Meth对先天免疫细胞的重要影响之一是改变活性氧（ROS）的平衡并诱导炎症标志物，如CCR 5和RANTES。这些变化被认为是多巴胺依赖性的，但我们已经观察到ROS和CCR 5都可以在无多巴胺系统中诱导。有趣的是，中枢神经系统中的ROS可以信号传导NF κ B水平和磷酸化的增加，并直接诱导炎症分子启动子的激活。另一方面，也诱导ROS的HIV达特已显示出增强由甲基苯丙胺和其他滥用药物诱导的神经胶质活化和神经元损伤。HIV达特而不是Meth在体外增加巨噬细胞中的几种TATA盒结合组分，表明它可以对启动子中携带TATA盒启动子结构域的炎性分子的启动子具有调节作用。我们推测，在HIV达特存在下，由Meth-induced ROS触发的转录信号与TATA盒依赖性调节机制相互作用。我们建议探索ROS诱导的通路在Meth和达特上调星形胶质细胞和小胶质细胞上的CCR 5和RANTES中的作用，旨在确定多巴胺非依赖性机制中的参与者。我们还将研究TATA盒结合元件的诱导是否是HIV达特调节CNS中ROS和炎症标志物、影响免疫细胞浸润和干扰药物相关刻板行为的能力的基础。使用原始的方法，我们希望揭示一个基本的机制，艾滋病毒和甲基之间的相互作用，在中枢神经系统病理的恶化，这将打开一个新的调查线与翻译的范围。

DESCRIPTION (provided by applicant): HIV-1 exposure is associated with methamphetamine (Meth) abuse. These two factors synergize in aggravating neuroAIDS symptoms and disease progression. One of the important consequences of Meth on innate immune cells is to change the balance of reactive oxygen species (ROS) and induce inflammatory markers, such as CCR5 and RANTES. These changes are believed to be dopamine-dependent, but we have observed that both ROS and CCR5 can be induced in dopamine-free systems. Interestingly, ROS in the CNS can signal the increase of NFkB levels and phosphorylation, and directly induce activation of promoters of inflammatory molecules. On the other hand, HIV Tat, which also induces ROS, has been shown to potentiate glial activation and neuronal damage induced by Meth and other drugs of abuse. HIV Tat, but not Meth, increases several TATA-box binding components in macrophages in vitro, suggesting that it can have a modulatory effect on promoters of inflammatory molecules that bear a TATA-box promoter domain in the promoter. We hypothesize that transcriptional signaling triggered by Meth-induced ROS interact with a TATA-box-dependent modulatory mechanism in the presence of HIV Tat. We propose to explore the role of ROS-induced pathways in the upregulation of CCR5 and RANTES on astrocytes and microglia by Meth and Tat, aiming to identify the players in a dopamine-independent mechanism. We will also investigate whether the induction of TATA-box binding elements is at the basis of the ability of HIV Tat to modulate ROS and inflammatory markers in the CNS, affect immune cell infiltration and interfere with drug-related stereotypic behaviors. Using an original approach we expect to unveil a basic mechanism of interaction between HIV and Meth in the aggravation of CNS pathology, which will open a new line of investigation with a translational reach.