The impact of proviral epigenetics on HIV-1 rebound

摘要 尽管抗逆转录病毒疗法(ART)的开发取得了成功，但人们期待已久的艾滋病毒治疗方法仍然没有 被发现了。病毒整合到全身组织的DNA中，并在 艺术学院。接受抗逆转录病毒治疗的人不能停止服药，因为在大多数情况下，病毒会 当艺术停止时，简单地反弹。找到治愈方法的一种方法是通过携带 病毒的潜伏期过长，使被感染的细胞可能被ART或宿主免疫系统杀死。表观遗传 机制被认为在逆转录病毒的持久性和潜伏期中起着重要作用，但人们对此知之甚少 关于与HIV储蓄者相关的表观遗传标记。最近的研究发现， 抑制组蛋白甲基化在原代细胞HIV潜伏期的表观遗传控制中的体外扩增，但 在没有体外操作的情况下，没有临床样本的研究。这项建议的目的是 建立与HIV前病毒相关的两种抑制性表观遗传修饰模式及其 外周血中的整合位点，并确定这些修饰的存在 影响HIV前病毒染色质的可及性及其随后对ART后病毒反弹的影响 中断。使用来自七个抗逆转录病毒治疗中断(ATI)队列的纵向外周血样本 来自艾滋病临床试验小组，我们将检查胞嘧啶甲基化、H3K27me3和开放染色质 在每个前病毒及其周围的整合部位，来自艾滋病病毒携带者ATI前后。使用这些 数据，我们将检验抑制性表观遗传标记对染色质可及性的组合影响。 前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 ATI后冲击反弹。建议的研究结果将提供有关 抗逆转录病毒治疗期间HIV抑制的表观遗传学调节及其对ATI期间病毒反弹的影响。这将是 实现从水库中消除艾滋病毒的假定目标。

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.