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

• 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
• 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

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.

项目摘要 艾滋病毒相关的神经认知疾病（手）代表一系列疾病 患有艾滋病毒（PLWH）的人的发病率。虽然与HIV相关痴呆的患病率具有 自引入抗逆转录病毒疗法（ART）以来，较轻的手很大 在艺术的个人中常见。分子，细胞和病毒对发病机理的贡献 手保持不完全理解。 HIV容易感染中枢神经系统（CNS）的小胶质细胞，并 有动物模型的证据表明，小胶质细胞感染发生在急性感染的几天之内。小胶质细胞 是流动的，并且经常与中枢神经系统内的其他细胞相互作用，可能会介导HIV传播到 未感染的细胞。脑器官发育的最新进展提供了一种剖析病毒细胞的方法 以及可能与手发展有关的中枢神经系统中的细胞细胞相互作用，包括机制 病毒的细胞细胞传播。我们的实验室一直在研究IPSC衍生的小胶质细胞，以定义 HIV如何附着并感染这种细胞类型。 SIGLEC-1是一个连接的干扰素（IFN）诱导分子 在HIV-1脂质双层上进行神经胶质，导致随后的内在化和形成病毒 在单核细胞衍生的巨噬细胞中包含隔室（VCC），并促进病毒传播到T 细胞。在这个项目中，我们将定义SIGLEC-1在调解与IPSC衍生的HIV相互作用中的作用 小胶质细胞，包括其在小胶质细胞感染中的作用和对未感染的小胶质细胞，T细胞的转染的作用 巨噬细胞，有可能针对星形胶质细胞。新颖的Siglec1淘汰IPSC线将被用来提供新的 对中枢神经系统感染和炎症中SIGLEC-1的见解。然后将实验扩展到大脑 器官模型，以及小胶质捕获HIV和小胶质细胞感染对脑的贡献 在2D和3D器官中评估的炎症。 HIV感染的芬太尼暴露的影响 将分析小胶质细胞和类器官，并可能改变IFN信号传导以及HIV扩散的动力学和 中枢神经系统组织的炎症。这些研究将共同​​提供有关手发病机理的新见解， 并确定这一重要疾病组的新型治疗靶标。