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 全球艾滋病毒感染率和与艾滋病有关的死亡人数急剧下降， 扩大获得组合抗逆转录病毒疗法的机会。然而，艾滋病毒的流行仍然存在， 艾滋病毒感染仍然没有治愈的方法。因为cART不能根除艾滋病毒，而复制能力 病毒成为整合的和沉默的前病毒，其可以零星地重新激活以补充病毒， 水库作为HIV感染和持续/潜伏的关键解剖学“避难所”，脑中的储库 仍然是艾滋病治愈的主要障碍。HIV感染的单核细胞有助于病毒从外周血传播 因为它们可以迁移穿过血脑屏障（BBB）并在脑内分化成小胶质细胞。 中枢神经系统（CNS）。小胶质细胞是持续性/潜伏性HIV的主要和稳定的病毒库 CNS感染，即使在cART存在的情况下。此外，HIV感染的小胶质细胞释放神经毒素， 促进神经炎症并导致HIV相关神经认知障碍（HAND）的因素。 因此，在小胶质细胞中调节HIV持续/潜伏感染的分子特征的表征是 对于制定有效的干预策略以控制和抑制CNS中的HIV至关重要。后生 调控决定了艾滋病毒前病毒的信念，并大大有助于艾滋病毒的潜伏期。的 本项目的重点是研究宿主表观遗传调节在促进持续/潜伏HIV中的作用 感染小胶质细胞并靶向其以防止HIV裂解再激活。我们发现了一套Jumonji 作为HIV潜伏期促进基因（LPGs）的含结构域的组蛋白赖氨酸脱甲基酶（KDM）， 优先靶向组蛋白H3 K4/K36甲基化（H3 K4/K36 me 3），这表明了 组蛋白去甲基化在HIV潜伏期调节中作用在目标1中，我们将研究这些KDM的贡献 促进人类小胶质细胞和iPSC衍生的含有类器官的小胶质细胞（MCO）中的HIV潜伏期。在Aim中 2、受KDM研究的鼓舞，我们希望继续利用我们的功能基因组和蛋白质组学 通过多学科方法确定控制小胶质细胞中HIV潜伏期的其他ovel宿主因素的专业知识， 包括单细胞CRISPR筛选。这是一个需要解决的重要问题，这样我们就可以找到新的宿主靶点， 开发更有效的方案，以加强艾滋病毒的潜伏期，并防止其在无cART环境中复活 在小胶质细胞中。此外，我们还筛选了FDA批准的药物库并识别艾滋病毒潜伏期- 促进剂（LPAs），包括左西孟旦（LSM）。在目标3中，我们提出了翻译研究， 调查FDA批准的已用于临床治疗和阻断HIV的药物的再利用 小胶质细胞中的持续/潜伏感染，这可能影响表观遗传过程。