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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：
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
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/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

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.

项目总结