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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要即使在联合抗逆转录病毒疗法 (cART) 时代，艾滋病毒感染者 (PLWH) 也表现出广泛的一系列神经认知障碍统称为 HIV 相关神经认知障碍 (HAND)。大脑炎症是 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，也可能导致产生非感染性颗粒。在这两种情况下，病毒的先天感知可能会在神经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中的传感。根据我们的工作，我们假设 cGAS/STING 的激活与生俱来在神经胶质细胞中检测到 HIV 颗粒或病毒样颗粒后，传感途径强而持久，导致炎症细胞因子的产生，进而导致持续的神经炎症。具体来说，我们将确定 HIV 进入后事件对神经胶质细胞先天免疫感应的影响（目标 1）以及直接或通过星形胶质细胞确定 HIV 介导的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 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总体假设。我们的工作将定义了一种在 cART 时代可能驱动和/或促成持续性神经炎症的新途径，这可以为改善和/或减少艾滋病毒相关神经炎症的针对性策略提供信息。