HIV innate sensing in glial cells and inflammation

神经胶质细胞和炎症中的艾滋病毒先天感知

• 批准号: 10484086
• 负责人: Joao Filipe Inacio Mamede
• 金额: $ 26.02万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484086
• 关键词: Activities of Daily Living; Adaptor Signaling Protein; Address; Astrocytes; Binding Proteins; Biological; Blood; Blood Cells; Brain; Capsid; Cells; Chronic; Clinical; Complement 1q; Complex; Consequences of HIV; Cyclic GMP; Cytoplasm; DNA; Data; Dementia; Detection; Encephalitis; Event; Exhibits; Future; Genes; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Health; Heart; Homeostasis; Hour; IRF3 gene; Imaging Device; Immune response; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Interferons; Knowledge; Lead; Mediating; Microglia; Molecular; Myeloid Cells; Natural Immunity; Neuraxis; Neurocognitive Deficit; Neuroglia; Neurons; Nuclear Translocation; Pathway interactions; Pattern; Pattern recognition receptor; Penetration; Persons; Phagocytes; Phenotype; Play; Process; Production; Reverse Transcription; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Therapeutic; Tissues; Viral; Viral Proteins; Virus Assembly; Virus-like particle; Work; antiretroviral therapy; base; biochemical tools; brain cell; cytokine; ds-DNA; induced pluripotent stem cell; innate immune sensing; neurocognitive disorder; neuroinflammation; novel; particle; pathogen; polyglutamine; receptor

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.

项目摘要 即使在联合抗逆转录病毒治疗(Cart)的时代，艾滋病毒携带者(Plwh)也表现出广泛的 一系列神经认知障碍统称为艾滋病毒相关神经认知障碍(HAND)。 大脑中的炎症是手部的一个特征，但在手推车中驱动这种炎症的机制 时代并不完全清楚。CART在大脑中的渗透率低于其他组织，也可能导致 非感染性颗粒的产生。在这两种情况下，病毒的先天感知可能在胶质细胞中被触发。 细胞(小胶质细胞和星形胶质细胞)介导持续性炎症。我们将评估先天机制 神经胶质细胞的感官。根据我们的工作，我们假设cGAS/STING的激活是天生的 在胶质细胞中检测到HIV颗粒或病毒样颗粒后，感觉通路强大而持久，导致 炎性细胞因子的产生，进而导致持续性的神经炎症。具体来说，我们 将确定艾滋病毒进入后事件对神经胶质细胞先天免疫感觉的影响(目标1)和 直接或通过确定HIV介导的星形胶质细胞先天感知的生物学后果 与小胶质细胞的串扰(目标2)。我们将在我们的研究中使用IPSC来源的小胶质细胞和星形胶质细胞以及 先进的分子、生化和成像工具，以解决我们的总体假设。我们的工作将 定义一种新的途径，可能推动和/或促成CART时代的持续性神经炎症， 它可以提供有针对性的战略，以改善和/或减少艾滋病毒相关的神经炎症。