P-TEFb and HIV Latency

P-TEFb 和 HIV 潜伏期

• 批准号: 8685494
• 负责人: Andrew P Rice
• 金额: $ 36.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-17 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685494
• 关键词: AIDS/HIV problem; CD4 Positive T Lymphocytes; Catalytic Domain; Cells; Chromatin; Down-Regulation; Event; Genes; Goals; HIV; HIV Infections; HIV-1; Individual; Infection; Jurkat Cells; Latent Virus; Life; Maintenance; Messenger RNA; MicroRNAs; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Positive Transcriptional Elongation Factor B; Protein Dephosphorylation; Protein phosphatase; Proteins; Proviruses; Publishing; Regulation; Repression; Research; Resistance; Rest; Role; Site; System; T-Cell Activation; Testing; Transcriptional Elongation Factors; Translations; Up-Regulation; Variant; Viral; Virus Replication; Vorinostat; cyclin T1; improved; memory CD4 T lymphocyte; prostratin; protein function; purge; success; tat Protein; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Combinations of current anti-HIV-1 drugs suppress virus replication to undetectable levels in many patients. However, these patients possess a reservoir of cells harboring latent HIV-1 proviruses that spontaneously reactivate upon cessation of anti-viral drugs, thereby precluding a cure of infection. The best described latent reservoir is that of long-lived memory CD4+ T lymphocytes which contain a transcriptionally silent but replication competent provirus. Although mechanisms involved in latency in CD4+ T lymphocytes are incompletely understood, it is believed that multiple mechanisms act in concert to establish and maintain latency. Transcriptional interference by cellular genes at the site of integration can contribute to latency. Repressive chromatin is established for latent proviruses. Limiting levels of cellular transcription factors also make important contributions to latency, especially P-TEFb, a transcriptional elongation factor involved in the viral Tat protein's function Core P-TEFb is composed of Cyclin T1 (CCNT1) and CDK9. Recent results in a primary CD4+ T lymphocyte system of HIV-1 latency have shown that CCNT1 protein and CDK9 T-loop phosphorylation levels are down-regulated as latency is established. Conversely, CCNT1 and T-loop phosphorylation are up- regulated in this system when latent viruses are induced by T cell activation. These findings suggest that down-regulation of CCNT1 is an important and perhaps essential event in the establishment of latency. The research proposed here will test the hypothesis that down-regulation of P-TEFb can drive HIV-1 latency in CD4+ T lymphocytes. The research will also investigate mechanisms involved in the down-regulation of CCNT1 and mechanisms that regulate CDK9 T-loop phosphorylation in resting and activated CD4+ T lymphocytes. Finally, the research will determine if selective up-regulation of P-TEFb can contribute to reactivation of latent HIV-1 in a primary cell system of latency. Completion of the research will determine if P- TEFb is a key cellular factor for establishment and maintenance of HIV-1 latency. The research has the potential to establish P-TEFb as an important therapeutic target to reactivate latent viruses and thereby cure HIV-1 infection.

描述（由申请人提供）：目前抗HIV-1药物的组合在许多患者中将病毒复制抑制到无法检测的水平。然而，这些患者拥有一个储存潜伏的HIV-1前病毒的细胞库，这些前病毒在停止抗病毒药物后自发地重新激活，从而排除了感染的治愈。最好描述的潜在储层是 长寿命记忆性CD 4 + T淋巴细胞，其含有转录沉默但有复制能力的前病毒。虽然参与CD 4 + T淋巴细胞潜伏期的机制尚未完全了解，但据信多种机制共同作用以建立和维持潜伏期。在整合位点的细胞基因的转录干扰可以促成潜伏期。抑制性染色质是为潜伏的前病毒建立的。细胞转录因子的限制水平也对潜伏期做出重要贡献，特别是P-TEFb，一种参与病毒达特蛋白功能的转录延伸因子核心P-TEFb由细胞周期蛋白T1（CCNT 1）和CDK 9组成。HIV-1潜伏期的原代CD 4 + T淋巴细胞系统的最新结果表明，随着潜伏期的建立，CCNT 1蛋白和CDK 9 T环磷酸化水平下调。相反，当潜伏病毒被T细胞活化诱导时，CCNT 1和T环磷酸化在该系统中上调。这些发现表明，CCNT 1的下调是潜伏期建立中的一个重要且可能是必不可少的事件。本文提出的研究将检验P-TEFb下调可以驱动HIV-1在CD 4 + T淋巴细胞中潜伏的假设。该研究还将研究参与CCNT 1下调的机制以及调节静息和活化的CD 4 + T淋巴细胞中CDK 9 T环磷酸化的机制。最后，该研究将确定P-TEFb的选择性上调是否有助于在潜伏的原代细胞系统中重新激活潜伏的HIV-1。这项研究的完成将确定P-TEFb是否是建立和维持HIV-1潜伏期的关键细胞因子。这项研究有可能将P-TEFb作为一个重要的治疗靶点，重新激活潜伏病毒，从而治愈HIV-1感染。