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

• 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
• 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

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.

项目摘要 该项目将探索针对表观遗传途径的策略，以实现持续的艾滋病毒缓解 和治疗HIV相关的中枢神经系统（CNS）功能障碍。小泛素的结合- SUMO蛋白质与底物的结合是一种公认的调节蛋白质活性的翻译后修饰， 亚细胞定位和各种下游活性的蛋白质-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 机制等因此，病原体已经进化到利用宿主SUMO化机制来确保病毒 持久性和发病机制。在感染过程中，人类免疫缺陷病毒1型（HIV-1）操纵 宿主SUMO化机制，以确保其在CD 4+中的病毒复制 操纵 小胶质 然而，T细胞是否是HIV-1 SUMO旁系同源物控制其在神经胶质细胞如小神经胶质细胞中的复制和/或潜伏性尚不清楚。 是CNS中主要的HIV-1靶细胞，并构成病毒发病机制的重要储存库。 L 在小胶质细胞中，辅阻遏物COUP-TF相互作用蛋白2（CTIP 2）募集多酶染色质- 修饰复合物，并在HIV-1启动子处建立异染色质环境，导致HIV-1 沉默研究表明，翻译后修饰（PTM），包括磷酸化和 SUMO化介导CTIP 2与其他蛋白质和复合物的相互作用。同样的，三重基序- 含有蛋白质28（TRIM 28），一种已知的SUMO E3连接酶，与异染色质中的CTIP 2缔合 复合物抑制HIV-1病毒复制。而 调节 分别地， 未知 生产性 sumo化 诱导型 SUMO化和磷酸化与 CTIP 2和TRIM 28在T细胞信号传导事件和免疫应答背景下的活性， PTM在小胶质细胞中HIV-1潜伏期的启动和建立中的影响仍然存在， 为此，该建议的中心假设是宿主SUMO化系统在细胞分裂期间被破坏。 HIV-1感染在小胶质细胞中的潜伏期是由于 宿主蛋白质。为了验证这一假设，我们将使用永生化的人类小胶质细胞系， 多能干细胞（iPSC），包括HIV-1潜伏期的新模型。 R 我们还将确定 人类HIV-1感染过程中人类小胶质细胞的SUMO修饰蛋白质组