Exosomes in tobacco-and HIV-mediated neurotoxcity

吸烟在感染艾滋病毒的人群中非常普遍，众所周知，吸烟会加剧艾滋病毒 发病机制。HIV感染脑细胞，如小胶质细胞和巨噬细胞，已知会导致HIV- 50%的HIV+人群患有相关的神经认知障碍(HAND)。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艾滋病毒的神经毒性- 被感染的烟民。细胞外小泡，特别是外体(30-100 nm)，它正变得越来越重要 作为癌症治疗的生物标记物和载体，已被提出在艾滋病毒中发挥关键作用 发病机制。最近的研究表明，从感染艾滋病毒的单核细胞分泌的外切体与 邻近未受感染的单核细胞，并促进艾滋病毒感染。然而，我们对此一无所知。 外切体在烟草介导的HIV发病机制和神经毒性中的作用。这项提议的长期目标是 鉴定烟草/HIV诱导的巨噬细胞/小胶质细胞外切体的关键成分 对加剧艾滋病毒的致病作用和神经毒性负责。我们在这项提案中的目标是确定 单核细胞来源的巨噬细胞(MDM)的外体因子及其相关机制 用于烟草介导的艾滋病毒复制和神经毒性增加。中心假说是外显体 与氧化应激途径有关的成分，当暴露在空气中时，从MDM释放 烟草成分是艾滋病毒复制和神经毒性的关键媒介。我们将对该假设进行如下测试 下面是。具体目标1：确定CSC/BaP和艾滋病毒在#年的贡献和基本机制 调节MDM外体/外体AOES的分泌：我们的工作假设是暴露于 CSC/BaP和HIV对MDM的作用是通过减少外切体和外切体AOES的分泌来实现的 综合。具体目标2：确定以下方面的贡献和基本机制 胞外体/胞外体对MDM中HIV复制和神经毒性的影响。我们的工作假设是 来自CSC/BaP处理的MDM的外切体增加了艾滋病毒的复制，并暴露于 CSC/BaP和HIV共同作用对神经细胞增加神经毒性。在成功完成 建议的研究，我们将已经确定来自CSC/BaP治疗的MDM的外体AOES是 对HIV的致病机制和神经毒性至关重要。这样的结果将为理解 吸烟介导的HIV致病机制和神经毒性。所获得的知识将提供 激励评价外切体作为HIV感染者治疗的生物标志物和/或新载体 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.