Role of Siglec-1 in HIV Interactions with Microglia and Astrocytes

Siglec-1 在 HIV 与小胶质细胞和星形胶质细胞相互作用中的作用

基本信息

批准号：
10206089
负责人：
PAUL W. SPEARMAN
金额：
$ 49.53万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10206089
关键词：
3-Dimensional AIDS dementia Animal Model Astrocytes Biological Models Brain CD4 Positive T Lymphocytes Cell Communication Cell Line Cell membrane Cells Central Nervous System Infections Cerebrum Clustered Regularly Interspaced Short Palindromic Repeats DNA Development Dimensions Disease Event Exposure to Fentanyl Fluorescence Microscopy Gangliosides Gene Expression Gene Expression Profiling Goals HIV HIV-1 HIV-associated neurocognitive disorder In Vitro Individual Infection Inflammation Interferons Knock-out Laboratories Lead Lipid Bilayers Measurement Measures Mediating Microglia Modeling Molecular Morbidity - disease rate Morphine Myeloid Cells Neuraxis Neurocognitive Deficit Neuroglia Neurons Opiate Addiction Opioid Organoids Pathogenesis Persons Play Prevalence Production Reporter Reporting Role Signal Transduction System T-Lymphocyte Tissues United States Viral Viral reservoir Virion Virus acute infection antiretroviral therapy cell type cytokine differential expression experimental study induced pluripotent stem cell insight knockout gene live cell microscopy macrophage monocyte neurotoxic new therapeutic target novel particle sialic acid binding Ig-like lectin sialoadhesin transcriptomics transmission process two-dimensional uptake viral transmission

项目摘要

Project Summary HIV-associated neurocognitive disorders (HAND) represent a spectrum of disorders that cause significant morbidity in persons living with HIV (PLWH). While the prevalence of HIV-associated dementia has significantly decreased since the introduction of antiretroviral therapy (ART), milder forms of HAND are quite common among individuals on ART. The molecular, cellular, and viral contributions to the pathogenesis of HAND remain incompletely understood. HIV readily infects microglia of the central nervous system (CNS), and there is evidence from animal models that microglial infection occurs within days of acute infection. Microglia are mobile and frequently interact with other cells within the CNS, potentially mediating transmission of HIV to uninfected cells. Recent advances in cerebral organoid development provide a means of dissecting virus-cell and cell-cell interactions in the CNS that may be relevant to the development of HAND, including mechanisms of cell-cell transmission of virus. Our laboratory has been studying iPSC-derived microglia in order to define how HIV attaches to and infects this cell type. Siglec-1 is an interferon (IFN)-inducible molecule that attaches to gangliosides on the HIV-1 lipid bilayer, leading to subsequent internalization and formation of the virus- containing compartment (VCC) in monocyte-derived macrophages and facilitating transmission of virus to T cells. In this project, we will define the role of Siglec-1 in mediating HIV interactions with iPSC-derived microglia, including its role in infection of microglia and trans-infection to uninfected microglia, T cells, macrophages, and potentially to astrocytes. Novel SIGLEC1 knockout iPSC lines will be utilized to provide new insights into Siglec-1 in CNS infection and inflammation. Experiments will then be extended to cerebral organoid models, and the contribution of microglial capture of HIV and microglial infection to cerebral inflammation assessed in both 2D and 3D organoids. The effects of fentanyl exposure of HIV-infected microglia and organoids will be analyzed, and may alter IFN signaling and the dynamics of HIV spread and inflammation in CNS tissues. Together, these studies will provide new insights into the pathogenesis of HAND, and identify novel therapeutic targets for this important group of disorders.

项目概要 HIV 相关神经认知障碍 (HAND) 是一系列可导致严重后果的疾病。 HIV 感染者 (PLWH) 的发病率。虽然艾滋病毒相关痴呆症的患病率已自引入抗逆转录病毒疗法 (ART) 以来，HAND 的发病率显着下降，较温和的 HAND 形式相当在 ART 个体中很常见。分子、细胞和病毒对发病机制的贡献 HAND 仍然不完全理解。 HIV很容易感染中枢神经系统（CNS）的小胶质细胞，并且动物模型的证据表明，小胶质细胞感染发生在急性感染后的几天内。小胶质细胞是可移动的并经常与中枢神经系统内的其他细胞相互作用，可能介导艾滋病毒传播未感染的细胞。大脑类器官发育的最新进展提供了一种解剖病毒细胞的方法 CNS 中可能与 HAND 发展相关的细胞间相互作用，包括机制病毒的细胞间传播。我们的实验室一直在研究 iPSC 衍生的小胶质细胞，以便定义 HIV如何附着并感染这种细胞类型。 Siglec-1 是一种干扰素 (IFN) 诱导型分子，可附着在 HIV-1脂质双层上的神经节苷脂，导致病毒随后内化和形成- 单核细胞衍生的巨噬细胞中含有区室（VCC）并促进病毒传播至 T 细胞。在这个项目中，我们将定义 Siglec-1 在介导 HIV 与 iPSC 衍生的相互作用中的作用小胶质细胞，包括其在小胶质细胞感染和转感染未感染小胶质细胞、T 细胞、巨噬细胞，并可能影响星形胶质细胞。新型 SIGLEC1 敲除 iPSC 系将用于提供新的深入了解 Siglec-1 在中枢神经系统感染和炎症中的作用。然后实验将扩展到大脑类器官模型，以及小胶质细胞捕获 HIV 和小胶质细胞感染对大脑的贡献在 2D 和 3D 类器官中评估炎症。芬太尼暴露对艾滋病毒感染者的影响小胶质细胞和类器官将被分析，并可能改变 IFN 信号传导和 HIV 传播的动态中枢神经系统组织的炎症。总之，这些研究将为 HAND 的发病机制提供新的见解，并确定这一类重要疾病的新治疗靶点。