HIV latency driven microgliosis

HIV潜伏期驱动的小胶质细胞增生

基本信息

批准号：
10618696
负责人：
Viviana A Simon
金额：
$ 25.35万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2022-09-07 至 2024-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618696
关键词：
AIDS/HIV problem Anatomy Astrocytes Autopsy Biological Markers Biological Models Blood - brain barrier anatomy Blood Vessels Brain Cell Cycle Arrest Cell Line Cell Proliferation Cell Survival Cells Central Nervous System Infections Characteristics Clonal Expansion Data Development Disease Environment Flow Cytometry Gene Expression Profile Growth Factor HIV HIV Infections HIV-associated neurocognitive disorder Highly Active Antiretroviral Therapy Human Immune Infection Inflammatory Investigation Kinetics Knowledge Link Maintenance Measurement Measures Microglia Microscopy Mitogens Molecular Mus Nerve Degeneration Neuraxis Neurocognitive Deficit Neurodegenerative Disorders Patients Persons Phenotype Play Population Primary Infection Proteins Proviruses RNA Splicing Reporter Role Sampling Surveys Testing Therapeutic Time Tissues Transcript VEGFA gene Vascular Endothelial Growth Factors Viral Virus Virus Replication base brain cell brain tissue cell immortalization driving force experimental study high reward high risk insight latent HIV reservoir latent infection link protein macrophage neurotoxic prevent promoter protein biomarkers self-renewal single cell sequencing vector

项目摘要

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.

高活性抗逆转录病毒疗法可有效靶向病毒复制，但无法消除原病毒长寿的细胞群。我们对人类大脑中艾滋病毒持续存在的了解仍然有限。小胶质细胞是中枢神经系统的固有先天免疫细胞。我们的初步数据表明，艾滋病毒感染原代人小胶质细胞的减少导致增殖（称为小胶质细胞增生）。我们的记者 HIV 载体称为 pMorpheus 的工具包允许使用以下方法检查单细胞水平上的潜伏期建立显微镜和流式细胞术方法。我们假设 HIV 感染通过以下方式诱发小胶质细胞增生：潜伏感染的小胶质细胞的克隆扩增。该提案利用了我们基于 pMorpheus 的初级人类小胶质细胞模型系统通过实验检验了这一假设。我们建议调查生产性从死后大脑中分离出的人类原代小胶质细胞中的潜伏性艾滋病毒感染组织（目标 1）并识别与 HIV 相关的生物标志物和细胞重连特征小胶质细胞增生（目标 2）。此高风险/高回报 R21 应用程序中概述的实验不会仅填补了我们对初级人类艾滋病毒潜伏期建立理解的关键知识空白小胶质细胞还提供小胶质细胞增生和神经变性的生物标志物信息。