Effect of novel cdk9 inhibitor on HIV transcription

新型cdk9抑制剂对HIV转录的影响

• 批准号: 8894397
• 负责人: Fatah Kashanchi
• 金额: $ 22.09万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894397
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Adverse event; Animal Model; Anti-Retroviral Agents; Antiviral Agents; Binding; Biological Assay; Cell Line; Cell model; Cells; Chromatin; Complex; DNA; Data; Death Rate; Drug Targeting; Enzymes; Epigenetic Process; Event; Fibrinogen; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genome; Goals; HIV; HIV Genome; HIV Infections; HIV therapy; HIV-1; Health; Heart; Human; In Vitro; Individual; Intercistronic Region; Memory; Methods; Methylation; Modeling; Mus; New Agents; Pharmaceutical Preparations; Positive Transcriptional Elongation Factor B; Production; Proteins; Relative (related person); Research; Role; SETDB1 gene; Safety; Staging; System; T-Lymphocyte; Toxic effect; Transcription Elongation; Vaccines; Viral; Virus; antiretroviral therapy; base; cyclin T1; improved; in vivo; inhibitor/antagonist; latent infection; mouse model; negative elongation factor; novel; novel strategies; particle; promoter; success; transmission process; treatment adherence

DESCRIPTION: Since the advent of potent combination antiretroviral therapy in the mid-1990s, improvements in its safety and tolerability and the emergence of new agents and classes has simplified treatment of HIV and made treatment success more likely. Our understanding of both the degree of treatment adherence needed to maintain long-term virological suppression and the pathophysiology of some of the major adverse events associated with HIV infection and therapy has improved. Anti-retroviral drugs targeting HIV encoded enzymes have slowed the death rate from AIDS but to date no effective vaccines have been developed and there is no practical cure. Today it is widely believed that the success in HIV-1 treatment will require targeting of other HIV and/or host cellular proteins. HIV-1 transcription is the most promising stage for which no drugs exist. Transcription is at the heart of regulating HIV-1 latency and, therefore, utilizing inhibitors that can target this promoter is significant. In fact, if an effectve inhibitor of HIV transcription was developed it could be considered a functional cure for AIDS. The long-term goal of our research is to understand how expression of the HIV-1 genome can be inhibited during active and latent infection. Our short term goals will be directed toward understanding mechanistic details of how a cdk9 inhibitor is able to selectively inhibit HIV -1 promoter. Our hypothesis is that understanding how Tat interfaces with a small form of P-TEFb, that is present only in HIV-1 infected cells, will provide targets for developing better antivirals that will block HIV-1 gene expression. The objective of this project is to elucidate the mechanisms used by a cdk9 inhibitor that can effectively maintain a quiescent transcriptional state in latently infected T cells. Our rationale for these studies is based on mounting preliminar data demonstrating the presence of unique P-TEFb complex in infected cells and its inhibition using latent cell systems and animal models. The aims include: defining mechanism of inhibition using in vitro transcription assay to define targets of Tat-specific P-TEFb (cdk9/T1) complex on the chromatin HIV DNA with our inhibitor and in vivo studies that will assess any cellular toxicity Assays will be utilized to define any potential side effects; and the effect of CR8#13 on HIV-1 latent models as well as humanized mouse NSG model. Collectively, these studies will define how CR8#13 can potentially contribute to long lasting transcriptional memory (i.e., methylation of the promoter) and suppression of virus in humans.

产品说明：自1990年代中期出现有效的抗逆转录病毒联合疗法以来，其安全性和耐受性的改善以及新药剂和新类别的出现简化了艾滋病毒的治疗，使治疗成功的可能性更大。我们对维持长期病毒学抑制所需的治疗依从性程度以及与HIV感染和治疗相关的一些主要不良事件的病理生理学的理解都有所改善。针对艾滋病毒编码酶的抗逆转录病毒药物已经减缓了艾滋病的死亡率，但迄今为止还没有开发出有效的疫苗，也没有实际的治愈方法。今天，人们普遍认为，HIV-1治疗的成功将需要靶向其他HIV和/或宿主细胞蛋白。HIV-1转录是最有希望的阶段，目前还没有药物可以治疗。转录是调节HIV-1潜伏期的核心，因此，利用可以靶向该启动子的抑制剂是重要的。事实上，如果研制出一种有效的HIV转录抑制剂，它就可以被认为是治疗艾滋病的有效方法。我们研究的长期目标是了解HIV-1基因组的表达如何在活动和潜伏感染期间被抑制。我们的短期目标是了解cdk 9抑制剂如何能够选择性抑制HIV-1启动子的机制细节。我们的假设是，了解达特如何与一种仅存在于HIV-1感染细胞中的小形式的P-TEFb相互作用，将为开发更好的抗病毒药物提供目标 可以阻断HIV-1基因的表达本项目的目的是阐明cdk 9抑制剂在潜伏感染的T细胞中有效维持静止转录状态的机制。我们进行这些研究的基本原理是基于大量的数据，这些数据表明在感染的细胞中存在独特的P-TEFb复合物，并且使用潜伏细胞系统和动物模型对其进行抑制。这些目标包括：使用体外转录测定确定抑制机制，以确定使用我们的抑制剂的染色质HIV DNA上的Tat特异性P-TEFb（cdk 9/T1）复合物的靶点，以及将评估任何细胞毒性的体内研究。总的来说，这些研究将定义CR8#13如何潜在地有助于持久的转录记忆（即，启动子的甲基化）和抑制人类中的病毒。