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.

描述：自 20 世纪 90 年代中期有效的联合抗逆转录病毒疗法出现以来，其安全性和耐受性的改善以及新药物和新类别的出现简化了 HIV 的治疗并提高了治疗成功的可能性。我们对维持长期病毒学抑制所需的治疗依从程度以及与 HIV 感染和治疗相关的一些主要不良事件的病理生理学的了解有所改善。针对艾滋病毒编码酶的抗逆转录病毒药物降低了艾滋病死亡率，但迄今为止尚未开发出有效的疫苗，也没有实际的治疗方法。如今，人们普遍认为 HIV-1 治疗的成功需要靶向其他 HIV 和/或宿主细胞蛋白。 HIV-1转录是最有希望的阶段，目前尚无药物可实现。转录是调节 HIV-1 潜伏期的核心，因此，利用能够靶向该启动子的抑制剂具有重要意义。事实上，如果开发出一种有效的艾滋病毒转录抑制剂，它可以被认为是艾滋病的功能性治愈方法。我们研究的长期目标是了解在活动性和潜伏性感染期间如何抑制 HIV-1 基因组的表达。我们的短期目标将旨在了解 cdk9 抑制剂如何选择性抑制 HIV -1 启动子的机制细节。我们的假设是，了解 Tat 如何与仅存在于 HIV-1 感染细胞中的小形式 P-TEFb 相互作用，将为开发更好的抗病毒药物提供靶点 这将阻止 HIV-1 基因表达。该项目的目的是阐明 cdk9 抑制剂所使用的机制，该抑制剂可以有效维持潜伏感染 T 细胞的静态转录状态。我们进行这些研究的理由是基于越来越多的初步数据，证明受感染细胞中存在独特的 P-TEFb 复合物，并使用潜伏细胞系统和动物模型对其进行抑制。目的包括：使用体外转录测定确定抑制机制，以使用我们的抑制剂确定染色质 HIV DNA 上 Tat 特异性 P-TEFb (cdk9/T1) 复合物的靶标，以及评估任何细胞毒性的体内研究。用于定义任何潜在的副作用；以及CR8#13对HIV-1潜伏模型以及人源化小鼠NSG模型的影响。总的来说，这些研究将确定 CR8#13 如何可能有助于人类持久的转录记忆（即启动子的甲基化）和抑制病毒。

项目成果

HIV-1 Transcription Inhibitors Increase the Synthesis of Viral Non-Coding RNA that Contribute to Latency.

HIV-1 转录抑制剂会增加病毒非编码 RNA 的合成，从而导致潜伏期。

• 发表时间: 2017
• 影响因子: 3.1
• 作者: Akpamagbo, Yao A;DeMarino, Catherine;Pleet, Michelle L;Schwab, Angela;Rodriguez, Myosotys;Barclay, Robert A;Sampey, Gavin;Iordanskiy, Sergey;El;Kashanchi, Fatah
• 通讯作者: Kashanchi, Fatah