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：
10700148
负责人：
Viviana A Simon
金额：
$ 21.13万
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/10700148
关键词：
Anatomy Astrocytes Autopsy Biological Markers Biological Models Blood - brain barrier anatomy Blood Vessels Brain Cell Cycle Arrest Cell Line Cell Proliferation Cell Separation Cell Survival Cells Central Nervous System Central Nervous System Infections Characteristics Clonal Expansion Data Development Disease Environment Flow Cytometry Gene Expression Profile Gliosis Growth Factor HIV HIV Infections HIV-associated neurocognitive disorder HIV/AIDS Hand Highly Active Antiretroviral Therapy Human Immune Infection Inflammatory Investigation Kinetics Knowledge Link Macrophage Maintenance Maps Measurement Measures Microglia Microscopy Mitogens Molecular Mus Nerve Degeneration Neurocognitive Deficit Neurodegenerative Disorders Patients Persons Phenotype Play Population Productivity Proliferating Proteins Provirus Integration Proviruses RNA Splicing Reporter Role Sampling Surveys Testing Therapeutic Time Tissues Transcript Vascular Endothelial Growth Factors Viral Virus Virus Replication biomarker identification brain cell brain tissue cell immortalization driving force experimental study high reward high risk insight latent HIV reservoir latent infection link protein migration 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.

高度活跃的抗逆转录病毒疗法有效地靶向病毒复制，但无法消除前期病毒长寿细胞群体。我们对人脑中艾滋病毒持久性的了解仍然有限。小胶质细胞是中枢神经系统的常驻免疫细胞。我们的初步数据表明HIV感染原代人小胶质细胞导致增殖（称为小胶质细胞增多）。我们的记者艾滋病毒媒介称为pmorpheus的工具包可以使用显微镜和流式细胞术方法。我们假设HIV感染诱导潜在感染的小胶质细胞的克隆膨胀。该提案利用了我们的基于pmorpheus的主要人类小胶质细胞模型系统，以实验检验该假设。我们建议研究生产力从验尸大脑分离的人原代小胶质细胞中深度的潜在艾滋病毒感染组织（AIM 1）并鉴定生物标志物和艾滋病毒相关的细胞重新布线特征小胶质细胞增多（AIM 2）。在此高风险/高奖励R21应用中概述的实验不会仅在我们对主要人类艾滋病毒潜伏期的理解中填补关键知识差距小胶质细胞，但也了解小胶质细胞增多和神经脱位的生物标志物。