Controlling HIV latency by manipulating CycT1 turnover

通过操纵 CycT1 更新来控制 HIV 潜伏期

• 批准号: 10548650
• 负责人: Koh Fujinaga
• 金额: $ 41.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548650
• 关键词: AIDS related cancer; Biological Assay; CAR T cell therapy; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Complement Factor B; Complex; Down-Regulation; Equilibrium; Gene Expression; Genes; Genetic Transcription; HIV; Immune; Immune System Diseases; Immune response; Immune system; Individual; Interphase Cell; Kinetics; Maintenance; Mediating; Memory; Methods; Monitor; Pathway interactions; Persons; Pharmacology; Phosphorylation; Phosphotransferases; Physiological; Play; Positive Transcriptional Elongation Factor B; Process; Proliferating; Proteins; Receptor Signaling; Regulation; Rest; Role; Small Nuclear Ribonucleoproteins; System; T cell regulation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; TCF Transcription Factor; Transactivation; Transcription Elongation; Viral; Virus; Virus Diseases; antiretroviral therapy; co-infection; cyclin T1; effector T cell; exhaust; immune function; improved; inhibitor; latent HIV reservoir; mutant; neoplastic cell; new therapeutic target; pathogen; prevent; programs; reactivation from latency; response; tat Protein; transcription factor; tumor; ubiquitin-protein ligase

Abstract Immune dysfunction associated with co-infection and AIDS-related cancers is commonly observed in HIV-infected individuals. In particular, gene expression programs in the immune system are often abnormally regulated in these individuals. We and other groups have recently discovered that the positive transcription factor b (P-TEFb), a critical cellular factor required for productive elongation of transcription, is severely down-regulated in quiescent and aberrant T cells. In resting CD4+ T cells, representing major latent HIV reservoirs, the expression of the cyclin T1 (CycT1) subunit of P-TEFb is diminished post-transcriptionally via currently unknown mechanisms, this being a main cause of HIV latency and tumor-specific T cells' defective response to check-point inhibitors and/or CAR-T cell therapies. Since increasing CycT1 is a prerequisite and mandatory step for optimal HIV reactivation and proper immune response against other pathogens and tumor cells, understanding the mechanism of CycT1 down-regulation is crucial. We have recently demonstrated that P-TEFb assembly regulated by phosphorylation determines the stability of CycT1. Also, we have identified all key players, including E3 ligases, involved in CycT1-degradation. Therefore, we hypothesize that increasing CycT1 proteins in resting and aberrant CD4+ T cells by manipulating cellular pathways to regulate P-TEFb assembly will reverse HIV latency and improve immune functions in HIV-infected individuals. In the proposed study, we will manipulate the cellular pathways regulating P-TEFb assembly and CycT1 stability to control HIV latency and improve immune functions. We will also identify previously uncharacterized "CycT1-degradation complexes", which will serve as new therapeutic targets. Successful completion of the proposed study will result in a new concept of T cell regulation modulated by the protein level of a master transcriptional regulator.

摘要 与合并感染和艾滋病相关癌症相关的免疫功能障碍通常在 艾滋病毒感染者。特别是，免疫系统中的基因表达程序通常是 这些个体中的异常调节。我们和其他团体最近发现， 正转录因子B（P-TEF B），一种重要的细胞因子， 转录，在静止和异常T细胞中严重下调。在静息的CD 4 + T细胞中， P-TEFb代表主要的潜伏HIV储库，P-TEFb的细胞周期蛋白T1（CycT 1）亚基的表达是 通过目前未知的机制在转录后减少，这是HIV的主要原因 潜伏期和肿瘤特异性T细胞对检查点抑制剂和/或CAR-T细胞应答缺陷 治疗由于增加CycT 1是最佳HIV再激活的先决条件和强制性步骤， 以及对其他病原体和肿瘤细胞的适当免疫反应，了解 CycT 1下调的机制至关重要。我们最近证明，P-TEFb 由磷酸化调节的组装决定了CycT 1的稳定性。此外，我们已经确定了所有 关键参与者，包括E3连接酶，参与CycT 1降解。因此，我们假设 通过操纵细胞途径增加静息和异常CD 4 + T细胞中的CycT 1蛋白， 调节P-TEFb组装将逆转HIV潜伏期并改善HIV感染者的免疫功能。 个体在这项研究中，我们将操纵调节P-TEFb的细胞通路， 组装和CycT 1稳定性，以控制HIV潜伏期和改善免疫功能。我们还将 确定以前未表征的“CycT 1-降解复合物”，这将作为新的 治疗目标成功完成拟议的研究将导致T细胞的新概念 由主转录调节因子的蛋白质水平调节的调节。