HIV innate sensing in glial cells and inflammation

项目摘要 即使在联合抗逆转录病毒治疗（cART）的时代，艾滋病毒感染者（PLWH）也表现出广泛的 神经认知障碍谱统称为HIV相关的神经认知障碍（HAND）。 大脑中的炎症是HAND的一个标志，但在CART中驱动这种炎症的机制 时代并不完全清楚。cART对大脑的渗透率低于其他组织，也可能导致 产生非传染性颗粒。在这两种情况下，神经胶质细胞中的病毒先天感应可能被触发， 细胞（小胶质细胞和星形胶质细胞）介导持续性炎症。我们将评估先天性 神经胶质细胞中的感知。基于我们的工作，我们假设cGAS/STING先天性激活 在检测到神经胶质细胞中的HIV颗粒或病毒样颗粒后，传感途径是强大和持久的， 炎症细胞因子的产生，这反过来又会导致持续的神经炎症。我们特别 将确定HIV进入后事件对神经胶质细胞先天免疫感应的影响（目的1）， 确定HIV介导的星形胶质细胞先天感知的生物学后果，直接或通过 与小胶质细胞的串扰（aim 2）。我们将在我们的研究中使用iPSC衍生的小胶质细胞和星形胶质细胞， 复杂的分子、生化和成像工具来解决我们的整体假设。我们的工作将 定义了一种新的途径，可以驱动和/或有助于在cART时代持续的神经炎症， 这可以为改善和/或减少HIV相关神经炎症的靶向策略提供信息。

Project Summary Even in the era of combination antiretroviral therapy (cART), people living with HIV (PLWH) exhibit a broad spectrum of neurocognitive disorders collectively termed HIV-Associated Neurocognitive Disorders (HAND). Inflammation in the brain is a hallmark of HAND, yet the mechanisms that drive this inflammation in the cART era are not entirely clear. cART penetration into the brain is lower than in other tissues and can also lead to production of noninfectious particles. Under these two scenarios, viral innate sensing may be triggered in glial cells (microglia and astrocytes) to mediate persistent inflammation. We will assess mechanisms of innate sensing in glial cells. Based on our body of work, we hypothesize that the activation of the cGAS/STING innate sensing pathway is strong and lasting after detection of HIV particles or virus like particles in glial cells, leading to inflammatory cytokine production which, in turn, will result in persistent neuroinflammation. Specifically, we will determine the impact of HIV post-entry events on innate immune sensing in glial cells (aim 1) and determine the biologic consequence of HIV-mediated innate sensing on astrocytes, either directly or through cross-talk with microglia (aim 2). We will use iPSC-derived microglia and astrocytes in our studies as well as sophisticated molecular, biochemical, and imaging tools to address our overall hypotheses. Our work will define a novel pathway that may drive and/or contribute to persistent neuroinflammation in the era of cART, which can inform targeted strategies to ameliorate and/or reduce HIV-associated neuroinflammation.