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

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
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-08-05 至 2025-07-31

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中文摘要
翻译
项目总结 该项目将探索针对表观遗传途径的策略,以实现艾滋病毒的持续缓解。 以及艾滋病毒相关中枢神经系统(CNS)功能障碍的治疗。小泛素的偶联作用- 相扑蛋白质到底物是一种众所周知的翻译后修饰,它调节蛋白质的活性, 亚细胞定位,以及各种下游活动的蛋白质-蛋白质相互作用。相扑蛋白质是 在抗病毒免疫、反对病毒复制和介导干扰素依赖的抗病毒方面也很重要 机械装置。因此,病原体已经进化到利用宿主的SUMO化机制来确保病毒 持久力与病机。在感染期间,人类免疫缺陷病毒1型(HIV-1)操纵 宿主SUMO化机制确保其在CD4+中的病毒复制 操控 小胶质细胞 然而,T细胞是否会感染HIV-1 相扑在小胶质细胞等神经胶质细胞中控制其复制和/或功能的类似物尚不清楚。 是中枢神经系统中HIV-1的主要靶细胞,是病毒致病的重要蓄水池。 L 在小胶质细胞中,共抑制因子COUP-TF相互作用蛋白2(CTIP2)招募了一种多酶染色质- 修饰复合体并在HIV-1启动子上建立异色环境,导致HIV-1 沉默。研究表明,翻译后修饰(PTM),包括磷酸化和 苏莫化,介导CTIP2‘S与其他蛋白质和复合体的相互作用。同样,三方主题- 包含蛋白28(TRIM28)是一种已知的相扑E3连接酶,它与异染色质中的CTIP2结合 抑制HIV-1病毒复制的复合体。而当 监管 分别, 未知。 多产 相思甲基化 可感应的 相思甲基化和磷酸化已被认为与 CTIP2和TRIM28在T细胞信号事件和免疫反应背景下的活性, PTMS在小胶质细胞中HIV-1潜伏期的启动和建立中的作用 为此,这一建议的中心假设是,宿主SUMO化系统在 HIV-1在小胶质细胞中感染和潜伏期的建立是由于 宿主蛋白。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和 多能干细胞(IPSCs),包括一种新的HIV-1潜伏期模型。 R 我们还将确定 人类HIV-1感染过程中人小胶质细胞的相扑修饰蛋白质组。
英文摘要
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.
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  • 项目类别:
  • 资助金额:
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  • 财政年份:
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  • 负责人:
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  • 依托单位:
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海外基金