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.

项目概要 全球艾滋病毒感染率和艾滋病相关死亡人数已大幅下降 扩大联合抗逆转录病毒治疗 (cART) 的可及性 然而，艾滋病毒流行仍然存在。 目前仍无法治愈 HIV 感染，因为 cART 无法根除 HIV，但仍具有复制能力。 病毒整合并沉默原病毒，可以偶尔重新激活以补充病毒 作为艾滋病毒感染和持续/潜伏期的关键解剖学“避难所”，大脑中的储存库。 仍然是艾滋病毒感染的单核细胞导致病毒从外周血液传播的主要障碍。 进入大脑，因为它们可以穿过血脑屏障（BBB）并分化为小胶质细胞 中枢神经系统 (CNS) 是持续性/潜伏性 HIV 的主要且稳定的病毒库。 即使存在 cART，也会导致中枢神经系统感染。此外，感染 HIV 的小胶质细胞会释放神经毒性物质。 促进神经炎症并导致 HIV 相关神经认知障碍 (HAND) 的因素。 因此，调节小胶质细胞中 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来控制和抑制中枢神经系统中的艾滋病毒至关重要。 监管关键决定了 HIV 原病毒的可信度，并对 HIV 潜伏期产生了重大影响。 该项目的重点是研究宿主表观遗传调控在促进持续/潜伏艾滋病毒中的作用 我们已经确定了一组 Jumonji 感染，并针对其预防 HIV 裂解性再激活。 含有组蛋白赖氨酸脱甲基酶 (KDM) 的结构域作为 HIV 潜伏期促进基因 (LPG) 优先靶向组蛋白 H3K4/K36 甲基化 (H3K4/K36me3)，这表明 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 (MCO) 的小胶质细胞中的 HIV 潜伏期。 2、在 KDM 研究的鼓励下，我们希望继续使用我们的功能基因组和蛋白质组学 通过多学科方法确定控制小胶质细胞中艾滋病毒潜伏期的其他复杂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，以便我们能够找到新的宿主靶标。 开发更有效的治疗方案，以增强 HIV 潜伏期并防止其在无 cART 环境下复活 此外，我们还筛选了 FDA 批准的药物库并确定了 HIV 潜伏期 - 促进剂（LPA），包括左西孟旦（LSM）。在目标 3 中，我们提出了转化研究。 调查 FDA 批准的已用于临床治疗和阻断 HIV 药物的重新利用 小胶质细胞的持续/潜伏感染，可能会影响表观遗传过程。