The impact of proviral epigenetics on HIV-1 rebound

前病毒表观遗传学对 HIV-1 反弹的影响

• 批准号: 10258541
• 负责人: Sarah Adrianne LaMere
• 金额: $ 23.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-19 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258541
• 关键词: AIDS clinical trial group; ATAC-seq; Address; Affect; Area; Attention; Biological Assay; Blood specimen; Cells; ChIP-seq; Characteristics; Chromatin; Clinical; Cytosine; DNA; DNA Methylation; DNA methylation profiling; Data; Development; Environment; Epigenetic Process; Future; Genomic Segment; Genomics; Goals; HIV; HIV Infections; HIV-1; Histone Deacetylase Inhibitor; Immune system; In Vitro; Individual; Institution; Interruption; Measurement; Methods; Methylation; Modeling; Modification; Molecular Conformation; Monitor; Pattern; Persons; Pharmaceutical Preparations; Play; Provirus Integration; Proviruses; Repression; Research; Role; Sampling; Site; System; Techniques; Time; Tissues; Transcriptional Regulation; Transposase; Virus; antiretroviral therapy; base; cohort; combinatorial; effective therapy; epigenetic marker; epigenetic regulation; experimental study; histone methylation; histone modification; in vivo; integration site; peripheral blood; viral RNA; viral rebound; virtual

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.

抽象的 尽管抗逆转录病毒疗法成功发展（ART），但期待已久的艾滋病毒治疗仍然没有 被发现。该病毒整合到整个身体的组织DNA中，并在 艺术制度。接受艺术的人无法停止使用药物，因为在大多数情况下，病毒都会 只需反弹艺术停止即可。找到治愈方法的一种方法是通过带来消除储层 该病毒从潜伏期中脱离，因此被感染的细胞可能被ART或宿主免疫系统杀死。表观遗传学 据信机制在逆转录病毒持久性和潜伏期中起着重要作用，但知之甚少 关于与HIV储层相关的表观遗传标记。最近的研究发现了 抑制性组蛋白甲基化在原代细胞中艾滋病毒潜伏期的表观遗传控制中，体外膨胀，但 没有体外操作，没有研究临床样本的研究。该提议的目的是 建立与HIV病毒及其相关的两种抑制性表观遗传修饰的模式 周围周围的外围血液中的整合位点，并确定这些修饰的存在如何 影响HIV病毒的染色质可及性及其随后对ART后病毒反弹的影响 中断。使用来自七个ART治疗中断（ATI）队列的纵向外周血样本 从艾滋病临床试验组中，我们将检查胞嘧啶甲基化，H3K27me3和开放染色质 跨每个病毒病毒及其周围的整合地点，来自艾滋病毒前后的人。使用这些 数据，我们将检查抑制性表观遗传标记对染色质可及性的组合效应 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后影响反弹。拟议研究的结果将提供有关有关的关键信息 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。这会 产生推定的目标，以消除储层中的艾滋病毒。