Control of HIV-1 Transcription by CPSF6 and PP2A

CPSF6 和 PP2A 对 HIV-1 转录的控制

• 批准号: 10693519
• 负责人: VICENTE PLANELLES
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693519
• 关键词: Biology; CDK9 Protein Kinase; Cells; Cleavage And Polyadenylation Specificity Factor; Complex; DNA Polymerase II; Effectiveness; FDA approved; Gene Expression; Genetic Transcription; HIV; HIV-1; Immune; In Vitro; Infection; Investigation; Mediating; Methods; Minority; Molecular; Output; Persons; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Dephosphorylation; Protein Phosphatase Inhibitor; Protein phosphatase; Proteins; Proteolysis; Proteomics; Proviruses; RNA; Regulation; T-Lymphocyte; Testing; Therapeutic Agents; Transcriptional Regulation; Viral; Virus Latency; cancer type; design; experimental study; in vivo; innovation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; promoter; reactivation from latency; tool; ubiquitin ligase; ubiquitin-protein ligase

PROJECT SUMMARY The major barrier toward the eradication of HIV-1 infection is the presence of a small reservoir of latently infected cells that escape immune-mediated clearance. Due to the lack of transcriptional activity, latent proviruses in vivo are not easily detectable and cannot be targeted by either natural immune mechanisms or molecular therapies. Therefore, understanding how HIV-1 transcription is regulated will open doors to novel therapeutic strategies targeting the latent reservoir. Pharmacological approaches to reactivate the latent reservoir in vivo have been considered as potential eradication therapies for more than a decade. However, the effectiveness of these approaches has been disappointing as only a minority of latently infected cells appear to be responsive to latency-reversing agents. A deeper understanding of the transcriptional regulation of the HIV-1 promoter is necessary before we can design novel and effective LRAs. Cleavage and polyadenylation specificity factor 6 (CPSF6) is a cellular protein with multiple functions both in cellular and viral biology. Our recent finding that CPSF6 controls the stability and activity of PP2A, a phosphatase directly implicated in the de-phosphorylation and inactivation of CDK9 and RNA Pol II, reveals an exciting new line of investigation into potential cure strategies. This proposal will focus on the following innovative directions: (a) to further understand the factors regulating HIV-1 transcription, with a focus on CPSF6 and PP2A; (b) to explore the possibility of using PP2A inhibition as a method to reactivate latent viruses; and (3) to further explore the unknown functions of CPSF6 based on a recent proteomics experiment from our group yielding several exciting hits.

项目摘要 消除HIV-1感染的主要障碍是存在一个小储层 逃脱免疫介导的清除率的感染细胞。由于缺乏转录活性，潜在 体内病毒病毒不容易检测到，不能由自然免疫机制或 分子疗法。因此，了解如何调节HIV-1转录将为新颖 针对潜在储层的治疗策略。 在体内重新激活潜在储层的药理方法已被认为是潜在的 根除十多年来。但是，这些方法的有效性已经 令人失望的是，只有少数受感染的细胞似乎对延迟逆转剂有反应。一个 在我们设计之前，有必要更深入了解HIV-1启动子的转录调节 新颖有效的LRA。裂解和聚腺苷酸化特异性因子6（CPSF6）是一种细胞蛋白，具有 细胞和病毒生物学中的多个功能。我们最近的发现CPSF6控制着稳定性和活动 PP2A的磷酸酶直接与CDK9和RNA POL II的磷酸化和失活有关的磷酸酶 揭示了对潜在治疗策略的激动人心的调查。该建议将重点介绍以下 创新方向：（a）进一步了解调节HIV-1转录的因素，重点是CPSF6 和pp2a; （b）探索使用PP2A抑制作用作为重新激活潜在病毒的方法的可能性； （3） 为了进一步探索CPSF6的未知功能，基于我们小组的最新蛋白质组学实验 产生了几次激动人心的热门歌曲。