Exosomes in tobacco-and HIV-mediated neurotoxcity

吸烟在艾滋病毒感染人群中非常普遍，并且已知会加剧艾滋病毒 发病机制艾滋病毒感染脑细胞，如小胶质细胞和巨噬细胞，已知会导致艾滋病毒- 相关的神经认知障碍（HAND）在50%的HIV+人群中。由于烟草成分，主要是 苯并（a）芘（BaP）也会引起神经毒性，它们一起可能会进一步加剧HIV-1的神经毒性。 吸烟者感染细胞外囊泡，特别是外泌体（30-100 nm），其重要性日益增加 作为肿瘤治疗的生物标志物和载体，已被认为在HIV中起关键作用 发病机制最近的研究表明，从HIV感染的单核细胞分泌的外泌体整合了 邻近未感染的单核细胞，并促进HIV感染。然而，关于它的作用， 烟草介导的HIV发病机制和神经毒性中的外来体。该提案的长期目标是 确定烟草/HIV诱导的巨噬细胞/小胶质细胞外泌体的关键成分， 负责加剧艾滋病毒的发病机制和神经毒性。我们在这份提案中的目标是确定 单核细胞源性巨噬细胞（MDM）中的外泌体因子及其相关机制 烟草介导的HIV复制增加和神经毒性。核心假设是外泌体 组分，特别是与氧化应激途径相关的组分，在暴露于 烟草成分是HIV复制和神经毒性的关键介质。我们将测试假设， 如下具体目标1：确定CSC/BaP和艾滋病毒对艾滋病的贡献和潜在机制， 调节外泌体/外泌体AOE从MDM的分泌：我们的工作假设是， CSC/BaP和HIV通过减少外泌体和外泌体AOE的分泌， 合成.具体目标2：确定生物多样性的贡献和基本机制 外泌体/外泌体AOE对MDM中HIV复制和神经毒性的影响。我们的假设是 来自CSC/BaP治疗的MDM的外来体增加了HIV复制， CSC/BaP和HIV一起对神经元细胞的神经毒性增加。成功完成后 根据拟议的研究，我们将确定来自CSC/BaP处理的MDM的外泌体AOE是 对HIV发病机制和神经毒性至关重要。这一结果将为理解 吸烟介导的HIV发病机制和神经毒性。获得的知识将提供 评价外泌体作为HIV感染者治疗的生物标志物和/或新型载体的动机 吸烟者。

Tobacco smoking is highly prevalent in the HIV-infected population, and is known to exacerbate HIV pathogenesis. HIV infection to the brain cells such as microglia and macrophages are known to cause HIV- associated neurocognitive disorder (HAND) in 50% of the HIV+ population. Since tobacco constituents, mainly benzo(a)pyrene (BaP), also cause neurotoxicity, together they may further exacerbate neurotoxicity in HIV- infected smokers. Extracellular vesicles, especially exosomes (30-100 nm), which are gaining importance as biological markers and carriers for cancer therapies, have been proposed to play a critical role in HIV pathogenesis. Recent studies indicate that exosomes secreted from HIV-infected monocytes integrate with adjacent uninfected monocytes and facilitate HIV infection. However, there is nothing known about the role of exosomes in tobacco-mediated HIV pathogenesis and neurotoxicity. The long-term goal of this proposal is to identify the key components of tobacco/HIV-induced exosomes from macrophage/microglia that are responsible for exacerbated HIV pathogenesis and neurotoxicity. Our objective in this proposal is to identify exosomal factors in monocyte-derived macrophages (MDM) and underlying mechanism that are responsible for tobacco-mediated increased HIV replication and neurotoxicity. The central hypothesis is that exosomal components, especially related to oxidative stress pathway, that are released from MDM upon exposure to tobacco constituents are the key mediator for HIV replication and neurotoxicity. We will test the hypothesis as follows. Specific Aim 1: Determine the contribution, and underlying mechanism, of CSC/BaP and HIV in regulating secretion of exosomes/exosomal AOEs from MDM: Our working hypothesis is that exposure of CSC/BaP and HIV to MDM decreases secretion of exosomes and exosomal AOEs through their decreased synthesis. Specific Aim 2: Determine the contribution and underlying mechanism of exosomes/exosomal AOEs towards HIV replication in MDM and neurotoxicity. Our working hypothesis is that exosomes, which are derived from CSC/BaP-treated MDM, increase HIV replication, and exposure of CSC/BaP and HIV together to neuronal cells increases neurotoxicity. Upon successful completion of the proposed research, we will have established that exosomal AOEs derived from CSC/BaP-treated MDM are critical for HIV pathogenesis and neurotoxicity. Such outcome will open a new avenue in understanding the mechanisms of smoking-mediated HIV pathogenesis and neurotoxicity. The knowledge obtained will provide an incentive to evaluate exosomes as biological markers and/or novel carriers for therapies in HIV-infected smokers.