POLYCOMB REPRESSIVE COMLEXE AS KEY REGULATORS OF HIV LATENCY AND TARGETS FOR LATENCY REVERSAL

多梳抑制复合体作为 HIV 潜伏期的关键调节因子和潜伏期逆转的目标

• 批准号: 10620063
• 负责人: Lindsey Ingerman James
• 金额: $ 87.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620063
• 关键词: ATAC-seq; Adverse effects; Automobile Driving; Biochemical; Biological; Biological Models; Biology; CD4 Positive T Lymphocytes; Cell model; ChIP-seq; Chemicals; Chromatin; Chronic; Clinic; Clinical; Cocaine; Communities; Complex; DNA; Data; Development; Effectiveness; Ensure; Environmental Risk Factor; Epigenetic Process; Equilibrium; Evaluation; Exhibits; Exposure to; Financial Hardship; Future; Gene Expression; Gene Silencing; Genetic; Genetic Transcription; Genome; Goals; HIV; HIV Infections; Individual; Ligands; Maintenance; Mediating; Modeling; Modification; PRC1 Protein; Pathway interactions; Patients; Phase; Polycomb; Population; Post-Translational Protein Processing; Process; Proteins; Proviruses; Recording of previous events; Regulation; Regulator Genes; Reporter; Rest; Risk; Role; Sampling; Substance abuse problem; Validation; Viral; Viral reservoir; Virus; Virus Latency; antiretroviral therapy; drug abuser; drug of abuse; epigenetic regulation; experimental study; genetic approach; genetic regulatory protein; histone methylation; immune activation; inhibitor; interest; knock-down; latent HIV reservoir; member; multidisciplinary; novel; novel therapeutic intervention; protein degradation; response; small hairpin RNA; small molecule inhibitor; substance use; tool

ABSTRACT: POLYCOMB REPRESSIVE COMPLEXES AS KEY REGULATORS OF HIV LATENCY AND TARGETS FOR LATENCY REVERSAL In an effort to achieve a cure for HIV, approaches to eliminate the persistent reservoir of latent HIV infection are needed. Enforced by a delicate balance of regulators of viral and cellular gene expression, the persistence of the quiescent retroviral genome is a remarkable way by which the virus ensures its stability within the host. Manipulation of viral latency to allow renewed viral expression and the potential for viral clearance is a leading strategy for HIV cure in chronically infected patients. Chemical strategies that promote reversal of viral latency by disrupting repressive epigenetic processes represent a groundbreaking step towards a clinical strategy to cure HIV. Fortuitously, the effort to epigenetically reactivate HIV proviruses has intersected with the scientific community’s interest in chromatin regulation and an increased appreciation for the role of epigenetic chemical probes in driving biological understanding of their targets. Proof of concept studies in reactivating HIV transcription via inhibition of epigenetic regulatory proteins have yielded promising results. However, many of these compounds exhibit only modest latency reversing activity, and only a limited number of chemical tools to achieve this goal are currently available. A better understanding of the landscape of epigenetic pathways that influence proviral latency, as well as novel chemical tools, are clearly needed to develop fully effective latency reversing agents (LRAs) for use alone or in combination towards an HIV cure. The overarching objectives of this proposal are to apply genetic, biochemical, and chemical biology approaches to cellular models of latency and HIV+ donor-derived samples to i) define the role of the Polycomb Repressive Complexes, PRC1 and PRC2, in HIV latency and ii) understand the effect of substance use on Polycomb- mediated HIV latency. PRC1 and PRC2 are critical regulators of gene silencing through the installation and recognition of the repressive H3K27me3 post-translational modification (PTM), and hence, are well poised to make a significant contribution to HIV latency. Our preliminary data suggests that components of both PRC1 and PRC2 that have not yet been implicated in the maintenance of HIV latency, as well as Polycomb-associated proteins, are key regulators of latency and novel targets for latency reversal. Additionally, drugs of abuse have been shown to induce changes in epigenetic modifications, including histone methylation, and in turn could significantly impact the epigenetic profiles of resting CD4+ T-cells from HIV-infected drug abusers. Therefore, we also aim to explore the effect of substance abuse on Polycomb function in resting CD4+ T-cells, and the influence of such environmental factors on the establishment and maintenance of HIV latency.

摘要：作为HIV潜伏期关键调节因子的多梳抑制复合物， 延迟反转的目标 在努力实现治愈HIV的过程中，消除潜伏HIV感染的持续储存库的方法是 needed.由于病毒和细胞基因表达调节因子的微妙平衡， 静止的逆转录病毒基因组是病毒确保其在宿主内稳定性的一种显著方式。 操纵病毒潜伏期以允许更新的病毒表达和病毒清除的潜力是一种领先的方法。 慢性感染者HIV治疗策略促进逆转病毒潜伏期的化学策略 通过破坏抑制性的表观遗传过程，代表了朝着临床策略迈出的开创性一步， 治愈艾滋病幸运的是，在表观遗传学上重新激活艾滋病毒前病毒的努力与科学界的共识一致。 社区对染色质调控的兴趣和对表观遗传化学物质作用的日益重视， 探针在推动生物学对其目标的理解。重新激活艾滋病毒的概念验证研究 通过抑制表观遗传调节蛋白的转录产生了有希望的结果。但许多 这些化合物仅表现出适度的潜伏期逆转活性，并且只有有限数量的化学工具， 实现这一目标，目前已有。更好地理解表观遗传途径的景观， 显然需要影响前病毒潜伏期以及新化学工具来开发完全有效的潜伏期 逆转剂（LRA）单独或组合用于HIV治愈。 该提案的总体目标是应用遗传学、生物化学和化学生物学方法 用于潜伏期的细胞模型和HIV+供体来源的样品，以i）定义Polycomb抑制剂的作用 PRC1和PRC2复合物在HIV潜伏期中的作用，以及ii）了解物质使用对Polycomb的影响， 介导的HIV潜伏期。PRC1和PRC2是基因沉默的关键调节因子， 抑制性H3K27me3翻译后修饰（PTM）的识别，因此， 对艾滋病毒潜伏期有很大影响。我们的初步数据表明，PRC1和 PRC2尚未涉及HIV潜伏期的维持，以及Polycomb相关的 蛋白质是潜伏期的关键调节因子和潜伏期逆转的新靶点。此外，滥用药物 已被证明可以诱导表观遗传修饰的变化，包括组蛋白甲基化，反过来， 显著影响HIV感染药物滥用者静息CD4+ T细胞的表观遗传特征。因此，我们认为， 我们还旨在探索药物滥用对静息CD4+ T细胞中Polycomb功能的影响，以及药物滥用对CD4+ T细胞中Polycomb功能的影响。 这些环境因素对HIV潜伏期的建立和维持的影响。