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: 10399644
• 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/10399644
• 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）代表了一系列导致严重的认知障碍的疾病。 艾滋病毒感染者的发病率。虽然艾滋病毒相关痴呆症的患病率 自抗逆转录病毒疗法（ART）引入以来，HAND的发病率显著下降， 在接受ART治疗的个体中很常见。 手仍然不完全理解。HIV容易感染中枢神经系统（CNS）的小胶质细胞，并且 有来自动物模型的证据表明，小胶质细胞感染发生在急性感染的数天内。小胶质 是移动的，并经常与CNS内的其他细胞相互作用，可能介导HIV的传播， 未感染的细胞脑类器官发育的最新进展提供了一种解剖病毒细胞的手段 以及中枢神经系统中可能与HAND发生相关的细胞间相互作用，包括机制 病毒在细胞间传播。我们的实验室一直在研究iPSC衍生的小胶质细胞，以确定 艾滋病毒是如何附着并感染这种细胞的Siglec-1是一种干扰素（IFN）诱导型分子， HIV-1脂双层上的神经节苷脂，导致随后的内化和病毒的形成- 单核细胞衍生的巨噬细胞中的VCC，并促进病毒向T细胞的传播 细胞在这个项目中，我们将定义Siglec-1在介导HIV与iPSC衍生的HIV相互作用中的作用。 小胶质细胞，包括其在感染小胶质细胞和转感染未感染的小胶质细胞，T细胞， 巨噬细胞和潜在的星形胶质细胞。新的SIGLEC 1敲除iPSC系将用于提供新的 Siglec-1在CNS感染和炎症中的作用实验将扩展到大脑 类器官模型，以及HIV的小胶质细胞捕获和小胶质细胞感染对脑血管疾病的贡献。 在2D和3D类器官中评估炎症。芬太尼暴露对HIV感染者的影响 将分析小胶质细胞和类器官，并可能改变IFN信号传导和HIV传播的动力学， CNS组织炎症。总之，这些研究将为HAND的发病机制提供新的见解， 并为这组重要的疾病确定新的治疗靶点。