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.

摘要