Prevention of HIV and drug abuse-induced brain pathology by targeting mitochondria

摘要 滥用毒品，如甲基苯丙胺(冰毒)，可以与特定的抗精神病药物协同工作 逆转录病毒疗法和残留病毒在感染艾滋病毒的大脑中复制，以推动艾滋病毒相关 脑部病理和神经认知功能障碍。这项提议的中心假设是 艾滋病毒大脑的生命周期受到接触冰毒的影响，这有助于 HIV进入大脑，建立感染和潜伏期，以及特定的抗- 逆转录病毒药物，有助于神经免疫激活和神经炎症反应。 我们将通过关注艾滋病毒的新的和以前未被探索的方面来评估这些事件 血脑屏障(BBB)的生物学。根据我们的初步数据，我们认为类似于通行费的 受体2和4(TLR2/4)是冰毒脑血管毒性的关键参与者，导致 拆解TJ蛋白复合体，促进艾滋病毒进入大脑(目标1)。接下来，我们将 冰毒诱导HIV复制增强的机制及潜伏期的建立 血脑屏障周细胞感染(目标2)。我们的开创性发现表明血脑屏障周细胞 允许感染艾滋病毒。在目前的提案中，我们将继续这一新颖的研究，重点是 冰毒在这些细胞的主动和潜伏感染中的作用。因为冰毒、艾滋病毒和抗逆转录病毒 药物共同的线粒体功能障碍是其脑血管的主要机制之一 毒性，该提案的一个重要部分将致力于探索新的纳米技术 旨在以线粒体为靶点进行治疗保护(目标3)。因此，我们将提供创新的 预防脑血管毒性和神经免疫激活的治疗策略， 这是由艾滋病毒感染大脑中的冰毒和特定的抗逆转录病毒药物驱动的。 这项拟议的研究不仅具有很高的创新性，而且很可能导致 为临床提供新的翻译知识。这个应用程序将学习小说和以前的 脑部感染发生的未知机制和发病机制 艾滋病毒，在药物滥用和抗逆转录病毒战略的背景下。在药物滥用方面有专业知识 研究、血脑屏障生物学、艾滋病毒感染和线粒体靶向，我们处于独特的地位 执行提议的、高度创新的项目。

Abstract Drugs of abuse, such as methamphetamine (METH), can work in concert with specific anti- retroviral therapeutics and residual viral replication in HIV-infected brain, to drive the HIV-related brain pathology and neurocognitive dysfunction. The central hypothesis of this proposal is that HIV brain life cycle is influenced by exposure to METH, which facilitates the entry of HIV into the brain, establishing infection and latency, and, along with specific anti- retroviral drugs, contribute to neuroimmune activation and neuroinflammatory reactions. We will evaluate these events by focusing on novel and previously unexplored aspects of HIV biology at the blood-brain barrier (BBB). Based on our preliminary data, we propose that toll-like receptors 2 and 4 (TLR2/4) are critical players of cerebrovascular toxicity of METH, leading to dissembling of TJ protein complexes and facilitated HIV entry into the brain (Aim 1). We will next evaluate the mechanisms of METH-induced enhanced HIV replication and establishment of latent infection in BBB pericytes (Aim 2). Our pioneering findings indicated that BBB pericytes are permissive to HIV infection. In the current proposal, we will continue this novel research by focusing on the role of METH in active and latent infection in these cells. Because METH, HIV, and anti-retroviral drugs share mitochondrial dysfunction as one of the primary mechanisms of their cerebrovascular toxicity, an important part of the proposal will be devoted to exploring novel nanotechnologies aimed to target mitochondria for therapeutic protection (Aim 3). Thus, we will provide innovative therapeutic strategies to protect against cerebrovascular toxicity and neuroimmune activation, which are driven by METH and specific anti-retroviral drugs in HIV-infected brain. The proposed research is not only highly innovative, but it is likely to lead to the development of new translational knowledge for the clinic. This application will study novel and previously unrecognized mechanisms and pathogenesis underlying the development of brain infection by HIV, in the context of drug abuse and anti-retroviral strategies. With expertise in drug abuse research, BBB biology, HIV infection, and mitochondria targeting, we are uniquely positioned to perform the proposed, highly innovative project.