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.

项目总结