Target Host Epigenetic Regulation of HIV Proviruses to Reinforce Viral Deep Latency in Microglia

HIV原病毒的靶宿主表观遗传调控可增强小胶质细胞中病毒的深潜伏期

• 批准号: 10748760
• 负责人: WENZHE HO
• 金额: $ 78.87万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748760
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Anatomy; Blood; Blood - brain barrier anatomy; Brain; CRISPR screen; Cells; Central Nervous System; Cessation of life; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Epidemic; Epigenetic Process; FDA approved; Faith; Gene Expression; Genes; Genetic Transcription; HIV; HIV Infections; HIV-associated neurocognitive disorder; Histones; Human; Integration Host Factors; Intervention; Knock-out; Levosimendan; Libraries; Link; Lysine; Lytic; Mediating; Methylation; Microglia; Molecular; Nuclear Proteins; Organoids; Pharmaceutical Preparations; Preclinical Testing; Protein Dynamics; Proteomics; Proviruses; Reagent; Regimen; Regulation; Reporting; Role; Site; Therapeutic; Viral; Viral reservoir; Virus; Withdrawal; antiretroviral therapy; brain tissue; chromatin remodeling; combinatorial; demethylation; effective intervention; epigenetic regulation; functional genomics; induced pluripotent stem cell; interdisciplinary approach; latent infection; migration; monocyte; neuroinflammation; neurotoxic; novel; prevent; research clinical testing; therapeutically effective; translational study

PROJECT SUMMARY The global rate of HIV infection and the number of AIDS related deaths have dramatically declined due to the expanding access to combinatorial anti-retroviral therapy (cART). However, the HIV epidemic remains and there is still no cure for HIV infection. Because cART does not eradicate HIV, while replication-competent viruses become integrated and silenced proviruses, which can be sporadically reactivated to replenish viral reservoirs. As a key anatomical “sanctuary site” for HIV infection and persistence/latency, reservoirs in brain remains a main hurdle for HIV cure. HIV-infected monocytes contribute to viral spread from the periphery blood to the brain as they can migrate across the blood brain barrier (BBB) and differentiate into microglia in the central nervous system (CNS). Microglia are a major and stable viral reservoir for persistent/latent HIV infection in the CNS, even in the presence of cART. Furthermore, HIV-infected microglia release neurotoxic factors that promote neuroinflammation and contribute to HIV-associated neurocognitive disorders (HAND). Therefore, characterization of molecular features regulating HIV persistent/latent infection in microglia is essential for developing effective intervention strategies to control and inhibit HIV in the CNS. Epigenetic regulation critically determines the faith of HIV proviruses and contributes significantly to HIV latency. The focus of this project is to investigate the role of host epigenetic regulation in promoting persistent/latent HIV infection in microglia and target it for preventing HIV lytic reactivation. We have identified a set of Jumonji domain-containing histone lysine demethylases (KDMs) as HIV latency-promoting genes (LPGs) that preferentially target histone H3K4/K36 methylation (H3K4/K36me3), which indicates the potential role of histone demethylation in regulation of HIV latency. In Aim 1, we will investigate the contribution of these KDMs to promoting HIV latency in human microglia and iPSC-derived microglia containing organoids (MCOs). In Aim 2, encouraged by the KDM studies, we would like to continue the use of our functional genomic and proteomic expertise to identify other ovel host factors governing HIV latency in microglia by multidisciplinary approaches, including single-cell CRISPR screen. This is an important issue to address so that we can novel host targets to develop more potent regimen for reinforcing HIV latency and preventing its resurrection at a cART-free setting in microglia. Furthermore, we also screened a library of FDA-approved drugs and identify HIV latency- promoting agents (LPAs), including levosimendan (LSM). In Aim 3, we propose the translational studies to investigate the repurposing of FDA-approved drugs already used in clinic for treating and blocking HIV persistent/latent infection in microglia, which likely affect epigenetic processes.

项目摘要 由于艾滋病毒感染的全球感染率和与艾滋病相关的死亡人数急剧下降 扩大了对组合抗逆转录病毒疗法（CART）的访问。但是，艾滋病毒流行仍然存在， 仍然无法治愈艾滋病毒感染。因为购物车不放射艾滋病毒，而复制能力 病毒成为整合和沉默的病毒，可以偶尔重新激活以复制病毒 作为艾滋病毒感染和持久性/潜伏期的关键解剖学“庇护所”，大脑中的水库 仍然是艾滋病毒治愈的主要障碍。 HIV感染的单核细胞导致外周血传播 向大脑迁移到大脑，可以在血脑屏障（BBB）上迁移并分化为小胶质细胞 中枢神经系统（CNS）。小胶质细胞是持续/潜在艾滋病毒的主要且稳定的病毒库 中枢神经系统的感染，即使在马车的存在下也是如此。此外，HIV感染的小胶质细胞释放神经毒性 促进神经炎症并导致与HIV相关的神经认知障碍（手）的因素。 因此，在小胶质细胞中调节HIV持续/潜在感染的分子特征的表征是 制定有效的干预策略以控制和抑制中枢神经系统的HIV至关重要。表观遗传学 监管批判性地决定了艾滋病毒病毒的信仰，并为艾滋病毒潜伏期做出了重大贡献。这 该项目的重点是调查宿主表观遗传调节在促进持续/潜在艾滋病毒中的作用 小胶质细胞感染并靶向以防止HIV裂解活化。我们已经确定了一组Jumonji 含域的组蛋白赖氨酸脱甲基酶（KDMS）作为HIV潜伏期促进基因（LPGS） 优先靶向组蛋白H3K4/K36甲基化（H3K4/K36me3），这表明 Hisstone脱甲基在调节艾滋病毒潜伏期中。在AIM 1中，我们将研究这些KDM的贡献 促进人类小胶质细胞和IPSC衍生的小胶质细胞（MCO）的HIV潜伏期。目标 2在KDM研究的鼓励下，我们想继续使用我们的功能基因组和蛋白质组学 通过多学科方法来识别有关小胶质细胞中艾滋病毒潜伏期的其他宿主因素的专业知识， 包括单细胞CRISPR屏幕。这是要解决的重要问题，以便我们可以新颖的主机目标 开发更多的潜在方案，以增强艾滋病毒潜伏期并防止其在无推车环境中复活 在小胶质细胞中。此外，我们还筛选了FDA批准的药物库，并确定HIV潜伏期 - 促进剂（LPA），包括Levosimendan（LSM）。在AIM 3中，我们将翻译研究提出 研究已经在诊所中用于治疗和阻断艾滋病毒的FDA批准药物的再利用 小胶质细胞中持续/潜在感染，这可能会影响表观遗传过程。