Identification of novel co-factors for HIV Tat and Rev as therapeutic targets

鉴定 HIV Tat 和 Rev 的新辅助因子作为治疗靶点

• 批准号: 8401302
• 负责人: Andrew P Rice
• 金额: $ 23.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401302
• 关键词: Achievement; Binding; Biological Assay; CD4 Positive T Lymphocytes; Catalytic Domain; Cell Nucleus; Cells; Co-Immunoprecipitations; Complex; Data Analyses; Data Set; Funding; Goals; HIV; HIV-1; Human; Immunoprecipitation; Individual; Infection; Latent Virus; Mining; Multiprotein Complexes; Nuclear; Patients; Pharmaceutical Preparations; Positioning Attribute; Positive Transcriptional Elongation Factor B; Process; Protein Kinase; Proteins; Proviruses; Publications; Publishing; Reporting; Research; Research Proposals; Role; Set protein; Testing; Therapeutic; Viral; Work; cyclin T1; data mining; improved; new therapeutic target; novel; protein complex; protein function; purge; research study; rev Protein; tat Protein; therapeutic target

DESCRIPTION (provided by applicant): The goal of this project is to identify novel therapeutic targets for HIV-1 infection, focusing on cellular co- factors involved in the viral Tat protein or Rev protein function. Although it is not known how many cellular factors are involved in Tat and Rev function, recent studies and data mining have revealed that on the order of 50 cellular proteins are likely involved in these processes. The best understood cellular co-factor for Tat is a protein kinase complex termed P-TEFb. P-TEFb is composed of Cyclin T1 (CCNT1) as a regulatory subunit and CDK9 as the catalytic subunit; Tat binds directly to CCNT1. The best understood cellular co-factor for Rev is termed XPO1 (CRM1); Rev binds directly to XPO1. Nearly all processes in cells are carried out by multiprotein complexes which are thought to be the minimal functional unit. It is therefore likely that both CCNT1/CDK9 and XPO1 exist is several higher order multiprotein complexes and these complexes may be involved in Tat and Rev function. We have mined a recently published dataset that described the human nuclear complexome - the set of multiprotein complexes defined by a high-throughput co-immunoprecipitation/mass spec analysis. We have identified a number of novel cellular complexes that contain CCN1/CDK9 or XPO1. We will test the hypothesis that several of these complexes are involved in either Tat or Rev function. In our preliminary studies, we have obtained strong experimental support for this hypothesis. Importantly, our initial results also indicate that we will identify cellular factors that negatively regulate Tat activation of the HIV- LTR. Such negative acting factors have therapeutic potential in strategies to purge the latent HIV-1 reservoir in patients taking anti-viral drugs. Completion of the proposed work will reveal a number of potential therapeutic targets, especially some that may be useful for strategies to purge the reservoir of latent viruses in HIV-infected individuals. PUBLIC HEALTH RELEVANCE: We will identify cellular proteins that regulate HIV-1 replication. Some of these proteins might be useful as therapeutic targets to treat infection. Our research may improve patient treatment.

描述（由申请人提供）：该项目的目标是确定HIV-1感染的新治疗靶点，重点是参与病毒达特的细胞辅因子。 蛋白或Rev蛋白功能。虽然不知道有多少细胞因子参与了达特和Rev的功能，但最近的研究和数据挖掘表明，大约50种细胞蛋白可能参与了这些过程。最好理解的达特的细胞辅因子是称为P-TEFb的蛋白激酶复合物。P-TEFb由作为调节亚基的细胞周期蛋白T1（CCNT 1）和作为催化亚基的CDK 9组成;达特直接与CCNT 1结合。最好理解的Rev细胞辅因子称为XPO 1（CRM 1）; Rev直接与XPO 1结合。 细胞中几乎所有的过程都是由多蛋白复合物进行的，多蛋白复合物被认为是最小的功能单位。因此，CCNT 1/CDK 9和XPO 1可能都存在于几种更高级的多蛋白复合物中，并且这些复合物可能参与达特和Rev功能。我们已经挖掘了最近发表的数据集，描述了人类核复合物-一组多蛋白复合物定义的高通量共免疫沉淀/质谱分析。我们已经鉴定了许多含有CCN 1/CDK 9或XPO 1的新型细胞复合物。我们将检验这一假设，即这些复合物中的几个参与达特或Rev功能。在我们的初步研究中，我们已经获得了强有力的实验支持这一假设。重要的是，我们的初步结果还表明，我们将鉴定出负调节HIV- LTR的达特激活的细胞因子。这些负作用因子在清除服用抗病毒药物患者体内潜伏的HIV-1储库的策略中具有治疗潜力。完成拟议的工作将揭示一些潜在的治疗靶点，特别是一些可能有助于清除HIV感染者体内潜伏病毒的策略。 公共卫生相关性：我们将确定调节HIV-1复制的细胞蛋白。这些蛋白质中的一些可能用作治疗感染的治疗靶点。我们的研究可能会改善患者的治疗。