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An epigenomic approach to reactivate latent HIV

重新激活潜伏艾滋病毒的表观基因组方法

基本信息

批准号：
9190360
负责人：
Qin Feng
金额：
$ 22.19万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-08 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9190360
关键词：
Acetylation Acquired Immunodeficiency Syndrome Affinity Arginine Biological Assay CCL19 gene CD4 Positive T Lymphocytes Cell model Cells Chromatin Complex DNA Methylation Enzymes Epigenetic Process Eukaryotic Cell Gene Activation Gene Expression Genetic Transcription Genome HIV HIV Infections HIV-1 Histone H3 Immune Individual Infection Life Link Lysine Mediating Methods Methylation Modeling Modification Molecular Patients Phase Positive Transcriptional Elongation Factor B Production Protein Inhibition Provirus Integration Proviruses Reader Recruitment Activity Regulation Rest Role Sampling Shock Specificity Testing Toxic effect Viral Virus antiretroviral therapy base coactivator-associated arginine methyltransferase 1 ds-DNA epigenetic regulation epigenomics histone modification inhibitor/antagonist integration site killings memory CD4 T lymphocyte novel novel strategies prototype public health relevance purge reactivation from latency small molecular inhibitor small molecule inhibitor viral DNA viral RNA

项目摘要

DESCRIPTION (provided by applicant): Although Combination Antiretroviral Therapy (cART) is very potent in suppressing HIV replication and therefore life-prolonging, it can't eradicate HIV 1 infection. HIV can persist in long-lived resting memory CD4+ T cells. This reservoir of latent HIV-1 proviruses is the principal impediment to eradication of HIV infection. The current widely discussed and tested approach to eliminate the latent reservoirs is the so-called "sock and kill" strategy. It is hypothesized that reactivating latent HIV ('shock') in the presence of cART and immune-based therapy would ('kill') purge these reservoirs. In eukaryotic cells, the level of gene expression is strictly regulated by epigenetic modifications on chromatin including histone modifications and DNA methylation. The repressive status of chromatin largely contributes to HIV latency. In this proposal, we have identified a novel molecular mechanism of repressing HIV-LTR mediated transcription at epigenomic level. Importantly, we found that a small molecule inhibitor of a key epigenetic enzyme could reactivate HIV in two HIV latency cell models. In the R21 phase of this proposal, we will (1) further dissect the molecular basis of epigenetic regulation of HIV latency, and (2) evaluate our small molecular inhibitor in a primary CD4+ T cells model. In the R33 phase, using our small molecular inhibitor as a prototype, we will develop more specific and potent small molecule inhibitors, and determine whether these compounds can reactivate latent HIV in patients' samples. The potential synergistic effect of our compounds with other established HIV latency- reversing agents will also be evaluated. In summary, our proposed studies will likely uncover new mechanisms of regulation of HIV latency at the epigenomic level. Most importantly, based on our mechanistic studies, we might be able to develop a novel class of epigenetic compounds for reactivation of the latent HIV.

描述(申请人提供)：尽管联合抗逆转录病毒疗法(CART)在抑制艾滋病毒复制从而延长生命方面非常有效，但它不能根除艾滋病毒感染1例。HIV可以在长寿的静止记忆中存活的CD4+T细胞。这种潜伏的艾滋病毒-1前病毒是根除艾滋病毒感染的主要障碍。目前被广泛讨论和试验的消除潜在油气藏的方法是所谓的“袜子和压井”战略。据推测，在CART和基于免疫的疗法存在的情况下，重新激活潜伏的HIV(‘休克’)将(‘杀死’)清除这些蓄水池。在真核细胞中，基因的表达水平受到染色质的表观遗传修饰的严格调控，包括组蛋白修饰和DNA甲基化。染色质的抑制状态在很大程度上导致了HIV的潜伏期。在这一建议中，我们发现了一种在表观基因组水平上抑制HIV-LTR介导的转录的新的分子机制。重要的是，我们发现一种关键表观遗传酶的小分子抑制剂可以在两个HIV潜伏细胞模型中重新激活HIV。在这项提案的R21阶段，我们将(1)进一步剖析HIV潜伏期的表观遗传调节的分子基础，以及(2)在原代CD4+T细胞模型中评估我们的小分子抑制剂。在R33阶段，我们将以我们的小分子抑制剂为原型，开发更特异、更有效的小分子抑制剂，并确定这些化合物是否能重新激活患者样本中的潜伏HIV。我们还将评估我们的化合物与其他已建立的HIV潜伏期逆转药物的潜在协同效应。总而言之，我们提议的研究可能会揭示在表观基因组水平上调节HIV潜伏期的新机制。最重要的是，基于我们的机制研究，我们可能能够开发出一类新的表观遗传化合物来重新激活潜伏的艾滋病毒。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency.

DOI：
10.1093/nar/gkx550
发表时间：
2017-09-19
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Zhang Z;Nikolai BC;Gates LA;Jung SY;Siwak EB;He B;Rice AP;O'Malley BW;Feng Q
通讯作者：
Feng Q

HIV Latency Gets a New Histone Mark.

艾滋病毒潜伏期获得了新的组蛋白标记。