Manipulating Epigenetic Control Mechanisms to Control HIV Transcription

操纵表观遗传控制机制来控制 HIV 转录

• 批准号: 8258069
• 负责人: JONATHAN KARN
• 金额: $ 15.39万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258069
• 关键词: Antiviral Agents; Brain; Cells; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Development; Double-Stranded RNA; Epigenetic Process; Gene Silencing; Genes; Genetic Transcription; HIV; Highly Active Antiretroviral Therapy; Histone Acetylation; Individual; Lead; Life; Mediator of activation protein; Microglia; Patients; Population; Proteins; Repressor Proteins; Retroviridae; Site; Small Interfering RNA; Therapeutic; Toxic effect; Viral; Virus; analog; cell type; cost; drug development; drug of abuse; latent infection; macrophage; memory CD4 T lymphocyte; new technology; novel therapeutics; promoter; small molecule; tool

DESCRIPTION (provided by applicant): Lifelong highly active antiretroviral therapy (HAART) not only presents formidable problems in terms of patient management, cost and long-term toxicities but also fails to eradicate the virus from infected individuals. HIV persists in the face of HAART due to constitutive low-level replication in sites that are poorly accessible to drugs and the development of latent infections in a variety of types including the long-lived memory CD4+ T cell population, macrophages, and microglial cells in the brain. The need to develop novel therapeutic tools to attack the latently infected population has been widely recognized, but there has been little progress using conventional drug development approaches. Here we propose to develop novel technologies allowing exploitation a natural epigenetic silencing mechanism, DNA methylation, to block HIV transcription. As a prelude to developing therapeutic silencing agents, a much better understanding of the natural silencing mechanisms used by cells to control retroviruses and retrotranspons is needed. Key questions about HIV silencing that remain to be answered include: What are the primary sequence triggers and mechanisms that induce silencing (i.e. protein repressors and/or viral-derived siRNA)? What conditions lead to proviral DNA methylation? Do similar silencing mechanisms operate in each of the cell types infected by HIV? Do drugs of abuse block HIV silencing by inducing histone acetylation? Therapeutic approaches to exploit silencing include development of small molecules that enhance DNA methylation, gene-specific induction of silencing by short double-stranded RNA (or it analogues) and silencing by direction of DNA methyltransferases to promoters through protein mediators. In contrast to traditional antivirals, which require continuous administration, therapeutic epigenetic gene silencing has the potential to produce stable inheritable blocks to viral replication after only a single exposure of an infec

描述（由申请人提供）：终身高效抗逆转录病毒疗法（HAART）不仅在患者管理、成本和长期毒性方面存在巨大问题，而且未能从感染个体中根除病毒。HIV在HAART中持续存在，这是由于在药物难以到达的部位的组成性低水平复制以及在各种类型中潜伏感染的发展，包括脑中的长寿命记忆性CD 4 + T细胞群、巨噬细胞和小胶质细胞。人们已经广泛认识到需要开发新的治疗工具来攻击潜伏感染人群，但使用常规药物开发方法的进展甚微。在这里，我们建议开发新的技术，允许利用自然的表观遗传沉默机制，DNA甲基化，以阻止艾滋病毒的转录。作为开发治疗性沉默剂的前奏，需要更好地理解细胞用于控制逆转录病毒和逆转录转座子的天然沉默机制。关于HIV沉默的关键问题仍然有待回答，包括：诱导沉默的主要序列触发因素和机制是什么（即蛋白质阻遏物和/或病毒衍生的siRNA）？什么情况下会导致前病毒DNA甲基化？在感染HIV的每种细胞类型中是否都有类似的沉默机制？滥用药物是否通过诱导组蛋白乙酰化阻断HIV沉默？利用沉默的治疗方法包括开发增强DNA甲基化的小分子，通过短双链RNA（或其类似物）的基因特异性诱导沉默，以及通过蛋白质介体将DNA甲基转移酶引导至启动子来沉默。与需要连续给药的传统抗病毒药物相反，治疗性表观遗传基因沉默有可能在感染的单次暴露后产生稳定的可遗传的病毒复制阻断剂。