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

• 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
• 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

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,

HIV潜伏期进入和阻断的新型表观遗传学标记 人类免疫缺陷1型病毒（HIV）感染中的潜伏HIV储库对人类免疫缺陷病毒（HIV）的治疗构成了重大挑战。 根除艾滋病毒。更好地理解HIV转录的分子机制对于 制定适当的策略来攻击潜伏的艾滋病毒宿主。艾滋病毒的转录和潜伏期从根本上 由HIV启动子附近染色质周围的表观遗传调控控制。但我们的 对HIV转录的表观遗传调控的理解仍然不完全。事实证明了这一点 在HIV+患者中，通过抑制组蛋白， 脱乙酰酶单独或与杀伤策略组合。 我们最近发现，当巴豆酰化被诱导时，HIV从潜伏期被激活。这是与 增强组蛋白巴豆酰化和乙酰化，但降低HIV LTR的组蛋白甲基化。当组蛋白 巴豆酰化被抑制，潜伏期逆转被阻断。巴豆酰化诱导大大增加潜伏期 逆转由非经典NF-κB（ncNF-κB）信号转导激活引起，该信号转导通过 增强p100裂解为p52的诱导，这是ncNF-κB活化过程中的重要步骤之一。 HIV的转录似乎受到巴豆酰化相互作用组网络的调节， 高效的HIV转录。这些初步观察表明，巴豆酰化-一种新的和以前的 未识别的蛋白质修饰-直接参与HIV转录。的利益，相反也可能 保持，当巴豆酰化被逆转时，HIV可能会被迫进入潜伏期。重要的是，虽然巴豆酰化是 由刺激乙酰化以激活基因转录的相同酶控制（例如，p300），巴豆酰化 并且其下游信号传导由不同的机制调节。类似地，尽管巴豆酰化被逆转， 通过调节脱乙酰化以诱导潜伏期的相同酶（例如，HDACs）， 去巴豆基化信号传导不同于去乙酰化。 该R21应用的总体目标是确定巴豆酰化的分子机制， HIV转录的直接激活以及蛋白质去巴豆基化的调节如何促进HIV 变成了潜伏期我们假设，与乙酰化不同，蛋白质巴豆酰化在蛋白质的合成中起着直接的作用。 HIV转录，这可以应用于我们目前消除HIV潜伏期的努力， 未来的努力，迫使艾滋病毒进入潜伏期。我们的目标将通过两个具体目标来实现， 以下前提： 目的1：巴豆酰化与乙酰化不同，它通过影响乙酰化直接诱导HIV转录。 表观遗传学和信号传导。 目的2：去巴豆酰化抑制HIV转录，通过直接作用于HIV LTR和细胞环境，这是独立的脱乙酰化，