HIV latency driven microgliosis

高效抗逆转录病毒疗法有效地靶向病毒复制，但未能消除病毒感染 长寿的细胞群。我们对艾滋病毒在人脑中的持久性的了解仍然有限。小胶质细胞是 常驻中枢神经系统的先天免疫细胞。我们的初步数据表明，艾滋病毒感染 原代人类小胶质细胞的死亡导致增殖(称为小胶质细胞增生症)。本报记者艾滋病病毒传播媒介 名为pMorpheus的工具包允许使用 显微镜和流式细胞术的方法。我们假设HIV感染通过以下方式诱导小胶质细胞增多 潜伏感染小胶质细胞的克隆性扩增。该提案充分利用了我们基于pMorpheus的主要功能 人类小胶质细胞模型系统对这一假说进行实验验证。我们建议对Products进行调查 人死后脑内分离的原代小胶质细胞中HIV的深度潜伏感染 组织(目标1)，并鉴定HIV相关的生物标志物和细胞重连特征 小胶质细胞增多症(目标2)。此高风险/高回报R21应用程序中概述的实验将不会 只填补我们对HIV潜伏期在原发人类中建立的理解中的关键知识空白 小胶质细胞也是小胶质细胞增多症和神经退行性变的生物标志物。

Highly active antiretroviral therapy effectively targets viral replication but fails to eliminate proviruses in long-lived cell populations. Our knowledge of HIV persistence in the human brain remains limited. Microglia are the resident innate immune cells of the central nervous system. Our preliminary data indicate that HIV infection of primary human microglia cells results in proliferation (termed microgliosis). Our reporter HIV vector toolkit termed pMorpheus allows examination of latency establishment at the single cell level using microscopy and flow cytometry approaches. We hypothesize that HIV infection induces microgliosis by clonal expansion of latently infected microglia cells. This proposal leverages our pMorpheus based primary human microglia model system to experimentally test this hypothesis. We propose to investigate productive and latent HIV infections in depth in human primary microglia cells isolated from post-mortem brain tissues (Aim 1) and to identify biomarkers and cellular rewiring characteristic of HIV associated microgliosis (Aim 2). The experiments outlined in this high risk/high reward R21 application will not only fill critical knowledge gaps in our understanding of HIV latency establishment in primary human microglia cells but also inform on biomarkers of microgliosis and neuro-degeneration.