Novel Epigenetic Marks for HIV Latency Entry and Reversal

HIV潜伏期进入和逆转的新表观遗传标记

基本信息

批准号：
10617943
负责人：
Guochun Jiang
金额：
$ 23.33万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617943
关键词：
Acceleration Acetylation Benzamides Binding CD4 Positive T Lymphocytes Cell model Chemical Structure Chromatin Clinical Research Complex Data Deacetylation EP300 gene Enzymes Epigenetic Process Exposure to Future Genetic Transcription Goals HDAC3 gene HIV HIV Infections HIV-1 Health Histone Deacetylase Histone Deacetylase Inhibitor Histones Infection Lysine MS-275 Mediating Methylation Modernization Modification Molecular Patients Persons Play Post-Translational Protein Processing Proteins Proteomics Proviruses Regulation Role Signal Transduction Signaling Protein Viral Viral reservoir Virus Diseases antiretroviral therapy beta-Transducin Repeat-Containing Proteins chronic infection design epigenetic regulation histone methylation improved in vitro Model inhibitor interest knock-down latent HIV reservoir mutant novel overexpression prevent promoter transcription factor

项目摘要

Novel Epigenetic Marks for HIV Latency Entry and Reversal The latent HIV reservoirs in human immunodeficiency type 1 virus (HIV) infection poses a major challenge to the eradication of HIV. A better understanding of the molecular mechanisms of HIV transcription is essential for developing proper strategies to attack the latent HIV reservoirs. HIV transcription and latency are fundamentally controlled by epigenetic regulations surrounding the chromatin proximal to HIV promoter. However, our understanding of epigenetic regulation of HIV transcription is still incomplete. This is demonstrated by the fact that an effective reduction of the HIV reservoir has not been achieved in HIV+ patients by the inhibition of histone deacetylase alone or in combination with killing strategies. We recently found that HIV was activated from latency when crotonylation is induced. This was associated with enhanced histone crotonylation and acetylation, but reduced histone methylation at the HIV LTR. When histone crotonylation is inhibited, latency reversal was blocked. Crotonylation induction greatly enhanced latency reversal elicited by the activation of noncanonical NF-κB (ncNF-κB) signaling, which was mediated via the enhancing induction of p100 cleavage into p52, one of the essential steps during ncNF-κB activation. Transcription of HIV appears to be regulated by a network of crotonylation interactome which orchestrates an efficient HIV transcription. These preliminary observations indicate that crotonylation- a novel and previously unrecognized protein modification - is directly involved in HIV transcription. Of interest, the opposite may also hold, and when crotonylation is reversed, HIV may be enforced into latency. Importantly, while crotonylation is controlled by the same enzymes stimulating acetylation to activate gene transcription (e.g., p300), crotonylation and its downstream signaling are regulated by distinct mechanisms. Similarly, although crotonylation is reversed by the same enzymes regulating deacetylation to induce latency (e.g., HDACs), the mechanism of decrotonylation signaling is different from deacetylation. The overall objective of this R21 application is to determine the molecular mechanisms of crotonylation that underlie the direct activation of HIV transcription and how the regulation of protein decrotonylation facilitates HIV into latency. We hypothesize that, distinct from acetylation, protein crotonylation plays a direct role in HIV transcription, and this can be applied to our current efforts to eliminate HIV latency, and perhaps to future efforts to enforce HIV into latency. Our goals will be achieved through 2 specific aims, directed at the following premises: Aim 1: Crotonylation is distinct from acetylation and directly induces HIV transcription by effects on epigenetics and signaling. Aim 2: Decrotonylation suppresses HIV transcription to enforce HIV latency by direct effects at the HIV LTR and on the cellular milieu, which is independent of deacetylation,

艾滋病毒潜伏期进入和逆转的新型表观遗传标记人类免疫缺陷1型病毒（HIV）感染中的潜在艾滋病毒储存剂是对根除艾滋病毒。更好地了解HIV转录的分子机制对于制定适当的策略来攻击潜在的艾滋病毒水库。 HIV转录和潜伏期从根本上是由围绕HIV启动子染色质代理的表观遗传法规控制。但是，我们的对HIV转录的表观遗传调节的理解仍然不完整。事实证明了这一点通过抑制组蛋白，在HIV+患者中尚未实现HIV储量有效降低单独或与杀戮策略结合使用脱乙酰基酶。我们最近发现，当诱导共同体时，艾滋病毒是从潜伏期中激活的。这与 HIV LTR处的组蛋白互旋化和乙酰化增强，但组蛋白甲基化降低。当组蛋白时 crotonylation被抑制，延迟逆转被阻塞。共同诱导大大提高了潜伏期通过非规范NF-κB（NCNF-κB）信号的激活引起的逆转，该信号通过增强P100裂解为p52的诱导，这是NCNF-κB激活过程中的基本步骤之一。艾滋病毒的转录似乎是由一个互动的网络调节的，该网络协调了有效的HIV转录。这些初步观察表明，杂种 - 一种小说和以前无法识别的蛋白质修饰 - 直接参与HIV转录。有趣的是，相反保持，当crotonylation逆转时，艾滋病毒可能会延迟到潜伏期中。重要的是，虽然是由相同的酶刺激乙酰化以激活基因转录（例如p300），共旋quonylation。它的下游信号传导受不同的机制调节。同样，虽然互换通过控制脱乙酰化的相同酶诱导潜伏期（例如HDACS），非偏词信号传导不同于脱乙酰基化。该R21应用的总体目的是确定共旋性的分子机制基础HIV转录的直接激活以及蛋白质非偏n的调节如何促进HIV 变成潜伏期。我们假设，与乙酰化不同的是，蛋白质共依依在艾滋病毒转录，这可以应用于我们目前消除艾滋病毒潜伏期的努力，也许是未来将艾滋病毒延长到潜伏期的努力。我们的目标将通过2个特定目标实现，针对以下场所： AIM 1：互氨基化与乙酰化不同，并直接通过影响艾滋病毒转录表观遗传学和信号传导。 AIM 2：非偏肽抑制HIV的直接影响抑制HIV转录以执行HIV潜伏期 LTR和在脱乙酰化的细胞环境中，