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

• 批准号: 9050168
• 负责人: Qin Feng
• 金额: $ 21.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/9050168
• 关键词: Acetylation; Acquired Immunodeficiency Syndrome; Affinity; 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; RNA Virus Infections; Reader; Recruitment Activity; Regulation; Rest; Role; Sampling; Shock; Specificity; Testing; Toxic effect; Viral; Virus; antiretroviral therapy; arginyllysine; 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; small molecular inhibitor; small molecule inhibitor; viral DNA

 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（由申请人提供）：虽然联合抗逆转录病毒疗法 (cART) 非常有效地抑制 HIV 复制并因此延长生命，但它无法根除 HIV 1感染。 HIV 可在长寿命静息记忆 CD4+ T 细胞中持续存在。这种潜伏的 HIV-1 原病毒库是根除 HIV 感染的主要障碍。目前广泛讨论和测试的消除潜在病毒库的方法是所谓的“袜子和杀戮”策略。据推测，在 cART 和基于免疫的治疗存在的情况下重新激活潜在的 HIV（“休克”）将（“杀死”）清除这些储存库。在真核细胞中，基因表达水平受到染色质表观遗传修饰的严格调控，包括组蛋白修饰和 DNA 甲基化。染色质的抑制状态很大程度上导致了艾滋病毒的潜伏期。在这项提议中，我们确定了一种在表观基因组水平上抑制 HIV-LTR 介导的转录的新分子机制。重要的是，我们发现关键表观遗传酶的小分子抑制剂可以在两种 HIV 潜伏细胞模型中重新激活 HIV。在该提案的 R21 阶段，我们将 (1) 进一步剖析 HIV 潜伏期表观遗传调控的分子基础，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，以我们的小分子抑制剂为原型，我们将开发更特异、更有效的小分子抑制剂，并确定这些化合物是否可以重新激活患者样本中潜伏的HIV。我们的化合物与其他已建立的 HIV 潜伏期逆转剂的潜在协同效应也将得到评估。总之，我们提出的研究可能会揭示表观基因组水平上艾滋病毒潜伏期调节的新机制。最重要的是，根据我们的机制研究，我们也许能够开发出一类新型表观遗传化合物，用于重新激活潜在的艾滋病毒。