Effect of novel cdk9 inhibitor on HIV transcription

描述：自20世纪90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物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有所改善。针对艾滋病毒编码酶的抗逆转录病毒药物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，也没有切实可行的治疗方法。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。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是重要的。事实上，如果一种有效的HIV转录抑制剂被开发出来，它可能被认为是一种功能性治愈艾滋病的方法。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。我们的短期目标是了解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结合，将为开发更好的抗病毒药物提供靶点

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.