Methamphetamine and HIV interactions in the regulation of glial activation

描述(申请人提供)：接触HIV-1与滥用甲基苯丙胺(Meth)有关。这两个因素在加重神经艾滋病症状和疾病进展方面协同作用。Meth对天然免疫细胞的重要影响之一是改变ROS平衡，诱导炎性标志物，如CCR5和RANTES。这些变化被认为是多巴胺依赖的，但我们观察到ROS和CCR5都可以在无多巴胺的系统中诱导。有趣的是，中枢神经系统中的ROS可以发出NFkB水平升高和磷酸化的信号，并直接诱导炎症分子启动子的激活。另一方面，HIV Tat也能诱导ROS，已被证明可以增强Meth和其他滥用药物诱导的神经胶质细胞激活和神经元损伤。HIV Tat，但不是Meth，在体外增加了巨噬细胞中几个TATA盒结合成分，这表明它可以对炎症分子的启动子具有调制作用，这些启动子中带有TATA盒启动子结构域。我们假设，在HIV Tat存在的情况下，由Meth诱导的ROS触发的转录信号与TATA盒依赖的调制机制相互作用。我们建议探索ROS诱导的通路在Meth和Tat上调星形胶质细胞和小胶质细胞CCR5和RANTES中的作用，旨在确定多巴胺非依赖性机制中的参与者。我们还将调查TATA盒结合元件的诱导是否基于HIV TAT调节中枢神经系统中的ROS和炎症标志物的能力，影响免疫细胞的渗透，并干扰与药物相关的刻板印象行为。使用一种原创性的方法，我们希望揭示HIV和Meth在中枢神经系统病理加重中相互作用的基本机制，这将开辟一条具有翻译覆盖范围的新的调查路线。

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.