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; 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1990年代中期有效组合抗逆转录病毒疗法的出现以来，其安全性和耐受性的提高以及新药物和类别的出现已经简化了对HIV的治疗，并使治疗成功更可能。我们对维持长期病毒学抑制所需的治疗程度以及与HIV感染和治疗相关的一些主要不良事件所需的治疗程度的理解已得到改善。靶向HIV编码酶的抗逆转录病毒药物已减缓艾滋病的死亡率，但迄今为止尚未开发出有效的疫苗，并且没有实际治愈方法。如今，人们普遍认为，HIV-1治疗的成功将需要针对其他HIV和/或宿主细胞蛋白。 HIV-1转录是不存在药物的最有希望的阶段。转录是调节HIV-1潜伏期的核心，因此，使用可以靶向该启动子的抑制剂很重要。实际上，如果开发了HIV转录的效应抑制剂，则可以将其视为艾滋病的功能治疗。我们研究的长期目标是了解如何在活性和潜在感染过程中抑制HIV-1基因组的表达。我们的短期目标将针对理解CDK9抑制剂如何有选择性抑制HIV -1启动子的机理细节。我们的假设是，了解TAT如何与仅在HIV-1感染细胞中存在的小型P-TEFB接口，将为开发更好的抗病毒药物提供目标 这将阻止HIV-1基因表达。该项目的目的是阐明CDK9抑制剂使用的机制，该机制可以有效地维持潜在感染的T细胞中静止的转录状态。我们对这些研究的理由是基于安装前数据，证明了使用潜在细胞系统和动物模型在感染细胞中存在独特的P-TEFB复合物及其抑制作用。目的包括：使用体外转录测定法定义抑制机制，以定义与我们的抑制剂和体内研究的TAT特异性P-TEFB（CDK9/T1）复合物在染色质HIV DNA上进行评估的任何潜在副作用；以及CR8＃13对HIV-1潜在模型以及人源化小鼠NSG模型的影响。总的来说，这些研究将定义CR8＃13如何有可能导致持久的转录记忆（即启动子的甲基化）和人类病毒的抑制。