The impact of proviral epigenetics on HIV-1 rebound

摘要 尽管抗逆转录病毒疗法（ART）的成功发展，人们期待已久的艾滋病毒治愈方法仍然没有实现。 被发现病毒整合到全身组织的DNA中， 接受抗逆转录病毒治疗的人不能停止用药，因为在大多数情况下，病毒会 只是在停止抗逆转录病毒疗法后反弹找到治疗方法的一种方法是通过将 病毒的潜伏期，使受感染的细胞可能被杀死的艺术或宿主免疫系统。后生 据信，机制在逆转录病毒的持久性和潜伏期中起重要作用，但知之甚少 关于HIV宿主的表观遗传标记最近的研究发现， 在体外扩增的原代细胞中，抑制性组蛋白甲基化在HIV潜伏期的表观遗传控制中起作用， 没有在没有体外操作的情况下对临床样品进行研究。这项建议的目的是 建立了与HIV前病毒相关的两种抑制性表观遗传修饰的模式， 周围的整合位点在外周血中，并确定如何存在这些修饰 影响HIV前病毒的染色质可及性及其对ART后病毒反弹的后续影响 中断.使用来自七个ART治疗中断（ATI）队列的纵向外周血样本 来自艾滋病临床试验组，我们将检查胞嘧啶甲基化，H3K27me3，和开放染色质 在每个前病毒和其周围的整合网站从艾滋病毒感染者前和后ATI。使用这些 数据，我们将研究抑制性表观遗传标记对染色质可及性的组合效应， 原病毒及其周围的基因组环境，然后进一步评估这些表观遗传标记如何 ATI后冲击回弹。拟议研究的结果将提供有关 ART期间HIV抑制的表观遗传调节及其对ATI期间病毒反弹的影响。这将 产生从宿主中消除HIV的假定目标。

Abstract Despite the successful development of antiretroviral therapies (ART), the long-awaited cure for HIV has still not been discovered. The virus integrates into DNA of tissues throughout the body and becomes latent after institution of ART. Persons receiving ART cannot discontinue their medications, as in most cases the virus will simply rebound upon ART cessation. One approach to finding a cure is to eliminate the reservoir by bringing the virus out of latency so that infected cells might be killed by ART or the host immune system. Epigenetic mechanisms are believed to play an important role in retroviral persistence and latency, yet little is known about the epigenetic markers associated with the HIV reservoir. Recent studies have found a role for repressive histone methylation in the epigenetic control of HIV latency in primary cells expanded in vitro, but there are no studies in clinical samples without in vitro manipulation. The objective of this proposal is to establish patterns of two repressive epigenetic modifications associated with HIV proviruses and their surrounding integration sites in peripheral blood, and to determine how the presence of these modifications affects chromatin accessibility of the HIV provirus and its subsequent impact on viral rebound following ART interruption. Using longitudinal peripheral blood samples from seven ART Treatment Interruption (ATI) cohorts from the AIDS Clinical Trials Group, we will examine cytosine methylation, H3K27me3, and open chromatin across each provirus and its surrounding integration sites from people with HIV pre- and post- ATI. Using these data, we will examine the combinatorial effects of repressive epigenetic marks upon chromatin accessibility of the provirus and its surrounding genomic environment, and then further evaluate how these epigenetic marks impact rebound post-ATI. The results of the proposed studies will provide crucial information about the epigenetic regulation of HIV suppression during ART and its effect upon viral rebound during ATI. This will yield putative targets to eliminate HIV from the reservoir.