Controlling HIV latency by manipulating CycT1 turnover

通过操纵 CycT1 更新来控制 HIV 潜伏期

基本信息

批准号：
10680481
负责人：
Koh Fujinaga
金额：
$ 39.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10680481
关键词：
AIDS related cancer Biological Assay CAR T cell therapy CD4 Positive T Lymphocytes Cell physiology Cells Chronic Complement Factor B Complex Cyclins Down-Regulation Equilibrium Gene Expression Genes Genetic Transcription HIV Immune Immune System Diseases Immune checkpoint inhibitor Immune response Immune system Individual Interphase Cell Kinetics Maintenance Mediating Memory Methods Monitor NF-kappa B Pathway interactions Persons Phosphorylation Phosphotransferases Physiological Play Positive Transcriptional Elongation Factor B Process Productivity Protein Dephosphorylation Proteins Receptor Signaling Regulation Rest Role Small Nuclear Ribonucleoproteins Stimulation of Cell Proliferation 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 latent HIV reservoir mimetics mutant neoplastic cell new therapeutic target nuclear factors of activated T-cells pathogen pharmacologic posttranscriptional prevent programs reactivation from latency response tat Protein transcription factor tumor ubiquitin-protein ligase

项目摘要

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.

抽象的与共同感染和艾滋病相关癌症相关的免疫功能障碍常见于艾滋病毒感染者。特别是，免疫系统中的基因表达程序通常是这些个体的调节异常。我们和其他团体最近发现正转录因子 b (P-TEFb)，是生产性伸长所需的关键细胞因子转录在静止和异常 T 细胞中严重下调。在静息 CD4+ T 细胞中，代表主要的潜在 HIV 储存库，P-TEFb 的细胞周期蛋白 T1 (CycT1) 亚基的表达为通过目前未知的机制转录后减少，这是艾滋病毒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 细胞的缺陷反应疗法。由于增加 CycT1 是最佳 HIV 重新激活的先决条件和强制性步骤以及针对其他病原体和肿瘤细胞的适当免疫反应，了解 CycT1下调机制至关重要。我们最近证明了 P-TEFb 磷酸化调节的组装决定了 CycT1 的稳定性。此外，我们还确定了所有参与 CycT1 降解的关键参与者，包括 E3 连接酶。因此，我们假设通过操纵细胞通路来增加静息和异常 CD4+ T 细胞中的 CycT1 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人。在拟议的研究中，我们将操纵调节 P-TEFb 的细胞途径组装和 CycT1 稳定性可控制 HIV 潜伏期并改善免疫功能。我们还将鉴定出以前未表征的“CycT1 降解复合物”，这将作为新的治疗目标。拟议研究的成功完成将带来 T 细胞的新概念由主转录调节因子的蛋白质水平调节。