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: 10055497
• 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/10055497
• 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 HIV相关的神经认知障碍(HAND)代表了一系列导致显著 艾滋病毒携带者的发病率。虽然艾滋病毒相关性痴呆症的流行率 自引入抗逆转录病毒疗法(ART)以来显著减少，较温和的手部形式相当 在艺术上在个人中很常见。分子、细胞和病毒在该病发病机制中的作用 手语仍然不能完全理解。艾滋病毒很容易感染中枢神经系统(CNS)的小胶质细胞， 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到 未受感染的细胞。脑器官发育的最新进展为解剖病毒细胞提供了一种手段 以及中枢神经系统中可能与手的发育相关的细胞-细胞相互作用，包括机制 病毒的细胞间传播。我们实验室一直在研究IPSC来源的小胶质细胞，以确定 HIV是如何附着和感染这种细胞的。Siglec-1是一种干扰素(干扰素)诱导的分子，与 到HIV-1脂双层上的神经节苷脂，导致随后病毒的内化和形成- 单核细胞来源的巨噬细胞中的包含室(VCC)，促进病毒向T细胞的传播 细胞。在这个项目中，我们将确定Siglec-1在调节HIV与IPSC来源的相互作用中的作用 小胶质细胞，包括它在小胶质细胞感染和未感染的小胶质细胞、T细胞、 巨噬细胞，以及潜在的星形胶质细胞。新型SIGLEC1基因敲除IPSC品系将被用来提供新的 对Siglec-1在中枢神经系统感染和炎症中的洞察。然后，实验将扩展到大脑 器官模型，以及HIV小胶质细胞捕获和小胶质细胞感染对大脑的贡献 在2D和3D器官中都评估了炎症。芬太尼对HIV感染者的影响 小胶质细胞和有机体将被分析，并可能改变干扰素信号和艾滋病毒传播的动力学和 中枢神经系统组织中的炎症。总之，这些研究将为手部疾病的发病机制提供新的见解。 并为这一重要的疾病组确定新的治疗目标。