Comparative Retroviral Epigenomics

比较逆转录病毒表观基因组学

• 批准号: 10836287
• 负责人: Sarah Adrianne LaMere
• 金额: $ 12.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10836287
• 关键词: Animal Disease Models; Animal Model; Blood; Brain; COVID-19 pandemic; Clinical; DNA; DNA Methylation; Development; Epigenetic Process; Grant; HIV; HIV Infections; Immune system; Impaired cognition; Macaca mulatta; Modification; Parents; Patients; Persons; Play; Proviruses; Research; Research Personnel; Role; SIV; Sampling; Site; Testing; Tissues; Virus; Virus Integration; Work; antiretroviral therapy; comparative; effective therapy; epigenetic regulation; epigenetic silencing; epigenomics; experimental study; pandemic disease; pandemic impact

Abstract Although effective antiretroviral therapies (ART) have been developed for HIV, a cure has remained elusive even after more than three decades. Because the virus integrates into host DNA and can silence itself with or without ART through harnessing host epigenetic mechanisms, it is highly effective at masking its presence from the immune system, making its clearance difficult. Two strategies have been proposed to attempt to cure the virus once and for all, both dependent upon epigenetic modulation. The first proposes to 'kick and kill' the virus by reversing silencing modifications in order to make the virus visible to the immune system. The second strategy proposes to 'block and lock' the virus by introducing permanent epigenetic silencing, resulting in a functional clinical cure. Both strategies require a far more exhaustive understanding of the epigenetic silencing modifications exploited by the HIV provirus. The parent K01 proposal sought to characterize more specifically the role of two known modifications (DNA methylation and H3K27me3) from clinical samples of patients with HIV, and to compare them to rhesus macaques with SIV, which are considered to be the best animal model for HIV infection, as any and all epigenetic targets will likely be tested on them first. The COVID-19 pandemic hindered scientific research across the globe and impacted new investigators heavily. This original K01 proposal was no exception, as the primary investigator on this grant was substantially impacted by the pandemic. Therefore, this supplement seeks to overcome the barriers introduced by the pandemic in order to finish this important work examining proviral silencing in the brain. The brain is a particularly important reservoir tissue, as the virus is known to sequester itself at this site and appears to play a role in the development of cognitive impairment in people with HIV (PWH). Therefore, we are evaluating whether the same mechanisms are at play for SIV in the brains of rhesus macaques.

摘要 尽管已经开发出有效的抗逆转录病毒疗法（ART）来治疗艾滋病毒，但即使在治疗过程中， 在三十多年之后。因为病毒会整合到宿主DNA中， ART通过利用宿主的表观遗传机制，它非常有效地掩盖了它的存在， 免疫系统，使其清除困难。已经提出了两种策略来试图治愈这种病毒 一劳永逸，都依赖于表观遗传调节。第一种建议是通过以下方式“踢死”病毒： 逆转沉默修饰以使病毒对免疫系统可见。第二种策略 提出通过引入永久的表观遗传沉默来“阻止和锁定”病毒，从而导致功能性 临床治愈这两种策略都需要对表观遗传沉默有更详尽的了解， HIV前病毒利用的修饰。母K 01提案试图更具体地描述 两种已知的修饰（DNA甲基化和H3 K27 me 3）的作用，从患者的临床样本， HIV，并将它们与SIV恒河猴进行比较，SIV被认为是最好的动物模型。 艾滋病毒感染，因为任何和所有的表观遗传目标可能会首先在他们身上进行测试。 COVID-19疫情阻碍了地球仪的科学研究，并严重影响了新的研究人员。 最初的K 01提案也不例外，因为该资助的主要研究者受到了实质性的影响 大流行病。因此，本补编旨在克服疫情带来的障碍， 为了完成这项重要的研究大脑中前病毒沉默的工作。大脑是一个特别重要的 储库组织，因为已知病毒在该部位隔离自身，并且似乎在发育中发挥作用 艾滋病病毒感染者的认知障碍（PWH）。因此，我们正在评估是否相同的机制， 在恒河猴的大脑中扮演SIV的角色。