Multiscale analysis of HIV-1-induced small T cell syncytia

HIV-1诱导的小T细胞合胞体的多尺度分析

基本信息

批准号：
10762630
负责人：
Markus Thali
金额：
$ 63.73万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762630
关键词：
3-Dimensional Behavior Binding Biochemical Biological Assay Cell Nucleus Cells Computer Analysis Data Endowment Evaluation Exploratory/Developmental Grant for Diagnostic Cancer Imaging Flow Cytometry Fostering Funding Giant Cells Goals Grant HIV HIV-1 HIV/AIDS Heterogeneity Homeostasis Immune Immune response Impairment In Vitro Individual Infection Integration Host Factors Interruption Intervention Investigation Laboratories Lymphoid Tissue Maintenance Maps Mediating Membrane Proteins Minority Natural Killer Cells Pathogenesis Phenotype Physiological Polyploidy Population Procedures Property Proteome Proteomics Public Health Publishing Resistance Resolution Role Secure Surface T-Lymphocyte Testing Therapeutic Universities Viral Virus Work antiretroviral therapy cell motility cellular imaging cytotoxic design differential expression humanized mouse imaging study in vivo inflammatory milieu intravital imaging live cell imaging migration novel particle preservation prevent quantitative imaging recruit resilience tool transmission process viral transmission

项目摘要

HIV-1 dissemination critically depends on migration of infected T cells. Unexpectedly, a fraction of the infected T cells was recently found to exist as small syncytia, containing up to four nuclei. Importantly, these entities differ from larger syncytia which sometimes can be observed in late stages of virus dissemination/pathogenesis. Indeed, and as shown in three independent intravital imaging studies, they are present already at the earliest stages of infection. Our analyses in physiologically relevant in vitro settings further documented that small T cell syncytia can transfer virus to uninfected cells, suggesting that they can contribute to early virus dissemination. With this R01 application, we propose to start exploring whether HIV-1-induced small syncytia can indeed directly contribute to virus spread. We will start our investigations by characterizing motility/migration properties of syncytia and analyzing their role in virus transmission dynamics. Host and viral factors involved in homeostatic maintenance of the syncytial compartment will also be studied. Importantly, we have recruited the support of a leading HIV proteomics lab in order to comprehensively map the expression profiles of syncytia. Should the data resulting from this work support the hypothesis that syncytia contribute significantly to virus dissemination, we will pursue further funding in order to study potential strategies against these entities.

HIV-1传播严重取决于感染T细胞的迁移。出乎意料的是，一小部分被感染最近发现T细胞作为小合胞体存在，最多包含四个核。重要的是，这些实体与较大的合成症不同，有时可以在病毒的后期观察到传播/发病机理。确实，如三个独立的浸润成像研究所示，它们是已经处于感染的最早阶段。我们在生理上相关的体外环境中的分析进一步记录，小型T细胞合成症可以将病毒转移到未感染的细胞中，这表明它们可以有助于早期病毒传播。使用此R01应用程序，我们建议开始探索HIV-1诱导的小型合成症是否确实可以直接有助于病毒扩散。我们将通过表征运动/迁移属性来开始调查合成症并分析其在病毒传播动力学中的作用。宿主和病毒因素涉及还将研究合成室的稳态维护。重要的是，我们招募了支持领先的HIV蛋白质组学实验室，以全面绘制合成曲霉的表达谱。这项工作产生的数据是否支持合成症对病毒产生重大贡献的假设传播，我们将寻求进一步的资金，以研究针对这些实体的潜在策略。