Productive and latent HIV infection of microglia: virus and host wrestle for SUMOylation system control

小胶质细胞的生产性和潜伏性 HIV 感染：病毒和宿主为控制 SUMO 化系统而斗争

基本信息

批准号：
10748561
负责人：
Dianne Teresa LANGFORD
金额：
$ 23.78万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
2023-08-05 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748561
关键词：
Address Biological Assay Brain Cell Line Cells Central Nervous System Chromatin Chromatin Remodeling Factor Co-Immunoprecipitations Complex Data Development Disease remission Ensure Environment Enzymes Epigenetic Process Event Exhibits Functional disorder Future HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder Health Heterochromatin Histone Deacetylase Human Immune response Impairment In Vitro Infection Innate Immune Response Interferons Longevity Lysine Mediating Methyltransferase Microglia Modeling Neuroglia Pathogenesis Pathway interactions Pattern Peptide Hydrolases Persons Phosphorylation Pluripotent Stem Cells Post-Translational Protein Processing Process Productivity Proteins Proteome Proteomics Regulation Research Role SUMO1 gene Shock Signal Transduction Site Small Ubiquitin-Related Modifier Proteins Source Sumoylation Pathway System T-Lymphocyte TRIM Motif Testing Time Ubiquitin Ubiquitination Viral Viral Load result Viral Pathogenesis Viral reservoir Virus Virus Diseases Virus Latency Virus Replication Work Wrestling adduct antiretroviral therapy antiviral immunity cell type chicken ovalbumin upstream promoter-transcription factor genetic corepressor human model insight mutant novel paralogous gene particle pathogen prevent promoter protein protein interaction recruit restoration success therapeutic development transcription factor ubiquitin ligase ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY This project will explore strategies to target epigenetic pathways for achieving sustained HIV remission and treatment of HIV associated-central nervous system (CNS) dysfunction. The conjugation of small ubiquitin- SUMO proteins to substrates is a well-described post-translational modification that regulates protein activity, subcellular localization, and protein-protein interactions for various downstream activities. SUMO proteins are also important in anti-viral immunity, opposing viral replication and mediating interferon-dependent anti-viral mechanisms. Thus, pathogens have evolved to exploit the host SUMOylation machinery to ensure viral persistence and pathogenesis. During infection, the human immunodeficiency virus type 1 (HIV-1) manipulates the host SUMOylation machinery to ensure its viral replication in CD4+ manipulates Microglia T cells, however, whether HIV-1 the SUMO paralogs to control its replication and/or atency in glial cells like microglia is unclear. are the main HIV-1 target cells in the CNS and constitute an important reservoir for viral pathogenesis. l In microglial cells, the co-repressor COUP-TF interacting protein 2 (CTIP2) recruits a multi-enzymatic chromatin- modifying complex and establishes a heterochromatic environment at the HIV-1 promoter, leading to HIV-1 silencing. Studies have shown that post-translational modifications (PTMs), including phosphorylation and SUMOylation, mediate CTIP2's interactions with other proteins and complexes. Similarly, tripartite motif- containing protein 28 (TRIM28), a known SUMO E3 ligase, associates with CTIP2 in the heterochromatin complex to inhibit HIV-1 viral replication. While regulating respectively, unknown. productive SUMOylation inducible SUMOylation and phosphorylation have been implicated in the activity of CTIP2 and TRIM28 in the context of T-cell signaling events and immune responses, the impact of PTMs in the initiation and establishment of HIV-1 latency in microglia remains To this end, this proposal's central hypothesis is that the host SUMOylation system is i mpaired during HIV-1 infection in microglia and that latency is established as a result of the estoration of of host proteins. To test this hypothesis , we will use immortalized human microglial cell lines and pluripotent stem cells (iPSCs), including a novel model of HIV-1 latency. r We will also identify the SUMO-modified proteome of human microglial cells during human HIV-1 infection.

项目概要该项目将探索针对表观遗传途径的策略，以实现艾滋病毒持续缓解以及治疗艾滋病毒相关的中枢神经系统（CNS）功能障碍。小泛素的缀合 SUMO 蛋白质与底物是一种众所周知的翻译后修饰，可调节蛋白质活性，亚细胞定位以及各种下游活动的蛋白质-蛋白质相互作用。 SUMO 蛋白是在抗病毒免疫、对抗病毒复制和介导干扰素依赖性抗病毒方面也很重要机制。因此，病原体已经进化到利用宿主 SUMO 化机制来确保病毒持续性和发病机制。在感染过程中，1 型人类免疫缺陷病毒 (HIV-1) 会操纵宿主 SUMO 化机制确保其病毒在 CD4+ 中复制操纵小胶质细胞然而，T 细胞是否 HIV-1 SUMO 旁系同源物在小胶质细胞等神经胶质细胞中控制其复制和/或活性的机制尚不清楚。是中枢神经系统中主要的 HIV-1 靶细胞，构成病毒发病机制的重要储存库。我在小胶质细胞中，共阻遏物 COUP-TF 相互作用蛋白 2 (CTIP2) 招募多酶染色质修饰复合体并在 HIV-1 启动子处建立异色环境，从而导致 HIV-1 沉默。研究表明，翻译后修饰（PTM），包括磷酸化和 SUMOylation，介导 CTIP2 与其他蛋白质和复合物的相互作用。同样，三重主题—— 含有蛋白 28 (TRIM28)，一种已知的 SUMO E3 连接酶，与异染色质中的 CTIP2 结合复合物抑制 HIV-1 病毒复制。尽管调节分别，未知。富有成效的 SUMO化诱导型 SUMO 化和磷酸化与 CTIP2 和 TRIM28 在 T 细胞信号事件和免疫反应中的活性， PTM 对小胶质细胞中 HIV-1 潜伏期的启动和建立的影响仍然存在为此，该提案的中心假设是宿主 SUMOylation 系统在小胶质细胞中的 HIV-1 感染以及潜伏期的建立是由于宿主蛋白。为了检验这个假设，我们将使用永生化的人类小胶质细胞系和多能干细胞 (iPSC)，包括新型 HIV-1 潜伏期模型。 r 我们还将确定人类 HIV-1 感染期间人类小胶质细胞的 SUMO 修饰蛋白质组。