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 人类免疫缺陷I型病毒(HIV)感染中潜伏的HIV蓄水池对 根除艾滋病毒。更好地了解HIV转录的分子机制对于 制定适当的战略来攻击潜在的艾滋病毒宿主。HIV转录和潜伏期从根本上说是 受HIV启动子近端染色质周围的表观遗传调控。然而，我们的 对HIV转录的表观遗传调控的了解仍然不完全。事实证明了这一点 组蛋白的抑制并没有有效地减少HIV患者体内的HIV蓄积物 脱乙酰酶单独或与杀戮策略结合使用。 我们最近发现，HIV在诱导巴豆化时从潜伏期被激活。这与 促进组蛋白巴豆化和乙酰化，但减少组蛋白甲基化在HIV LTR。当组蛋白 巴豆化受到抑制，潜伏期逆转被阻断。巴豆化诱导显著延长潜伏期 非规范核转录因子-κB(NcNF-κB)信号的激活引起的逆转，这是通过 增强p100裂解为p52的诱导，这是ncNF-κB激活过程中的重要步骤之一。 HIV的转录似乎受到一个巴豆化相互作用体网络的调控，该网络协调 高效的艾滋病毒转录。这些初步观察表明，巴豆化是一种新的和以前的 未被识别的蛋白质修饰--直接参与HIV转录。有趣的是，相反的情况也可能 保持，当巴豆化反转时，HIV可能被强制进入潜伏期。重要的是，虽然巴豆化是 由相同的酶控制，刺激乙酰化以激活基因转录(例如，p300)，巴豆化 其下游信号受不同机制的调节。类似地，尽管巴豆化作用被逆转 通过相同的酶调节脱乙酰基以诱导潜伏期(例如，HDAC)，其机制 脱酮信号不同于脱乙酰基。 此R21应用的总体目标是确定巴豆化的分子机制 HIV转录的直接激活和蛋白质去内酯调节如何促进HIV 进入延迟时间。我们假设，与乙酰化不同，蛋白质巴豆化在 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，或许还可以 未来努力强制艾滋病毒进入潜伏期。我们的目标将通过两个具体的目标来实现，针对 以下是前提： 目的1：巴豆化不同于乙酰化，它通过作用于 表观遗传学和信号传递。 目的2：通过直接作用于HIV来抑制HIV转录以增强HIV潜伏期 Ltr和细胞环境上，这与脱乙酰基无关，

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,