Metabolic strategies to eliminate CNS Myeloid Viral Reservoirs

消除中枢神经系统骨髓病毒库的代谢策略

• 批准号: 10630131
• 负责人: Eliseo A Eugenin
• 金额: $ 69.05万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630131
• 关键词: Address; Amino Acids; Animal Model; Apoptosis; Autopsy; BIM Bcl-2-binding protein; Blood; Brain; CD4 Positive T Lymphocytes; Carbon; Cell Separation; Cell Survival; Cells; Chronic Disease; DNA Integration; Data; Effectiveness; Energy-Generating Resources; Enzymes; Generations; Genetic; Glucose; Glutamate-Ammonia Ligase; Glutamates; Glutaminase; Glutamine; Goals; HIV; HIV Infections; Human; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Interruption; Life; Lipids; Location; Macrophage; Malignant Neoplasms; Medicine; Messenger RNA; Metabolic; Metabolic Pathway; Methamphetamine; Microbiology; Microglia; Myelogenous; Myeloid Cells; Nature; Neurotransmitters; Persons; Phase II Clinical Trials; Phylogenetic Analysis; Population; Production; Proteins; Proteome; Proteomics; Protocols documentation; Publications; Reporting; Reproducibility; Residual state; Resistance; Sampling; Source; System; T-Lymphocyte; Tissues; Translational Research; Viral; Viral reservoir; Viremia; Virus; Virus Replication; alpha ketoglutarate; antiretroviral therapy; cell type; curative treatments; in vivo; innovation; laser capture microdissection; latent HIV reservoir; metabolic profile; metabolomics; neuroAIDS; novel therapeutics; prevent; protein expression; response; therapeutic target; translational medicine; viral rebound

Abstract: HIV cure has not been achieved due to long-lasting latent HIV reservoirs that, upon ART interruption, reactivate the virus. The best characterized viral reservoirs are different circulating subpopulations of T lymphocytes, but it has become evident that most viral reservoirs are localized in several tissues, including the brain. However, little is known about HIV persistence in myeloid cells, becoming a controversial issue. Only recently, genetic phylogenetic analysis indicates that viral reactivation cannot be explained by CD4 T containing the virus. Thus, alternative reservoirs need to be considered, such as a myeloid cell. Myeloid tissue-associated cells have multiple advantages over T cells to consider long-lasting viral reservoirs including tissue location, long-life, slow turn around, and higher resistance to apoptosis compared to T cells. In the brain, microglia and macrophages are the main cell type with HIV-integrated. Our data identify macrophage/microglia as a key viral reservoir within the brain, even in long-term ART. We developed an in vitro system to generate latent infected microglia or macrophages that can be reactivated by multiple treatments, including Meth, LPS, and LRA. The latently HIV-infected macrophages/microglia cells survive infection by blocking the apoptosome's formation by increasing bim protein expression, preventing further apoptosis. Further, we identified that latently HIV-infected cells (microglia/macrophages) had a unique metabolic signature that relies on glutamate/glutamine for ATP production and survival. More surprising is that HIV reservoirs cannot switch between different carbon sources such as lipids, glucose, or unusual sources of carbon like amino acids like uninfected cells. Blocking these metabolic pathways results in significant apoptosis of HIV reservoirs even in the absence of reactivation. Our results will provide a better understanding of the mechanisms that regulate the generation and survival of HIV myeloid reservoirs within the CNS and provide essential information for eradicating these viral reservoirs from the CNS.

摘要：由于长期潜伏的艾滋病毒蓄积物，根据ART，艾滋病毒的治愈尚未实现 中断，重新激活病毒。最具特点的病毒库是不同的循环 T淋巴细胞亚群，但很明显，大多数病毒库局限于 几种组织，包括大脑。然而，人们对艾滋病毒在髓系细胞中的持久性知之甚少， 成为一个有争议的问题。 直到最近，遗传进化分析表明，病毒的重新激活无法解释。 通过含有病毒的CD4T细胞。因此，需要考虑替代的储存库，例如髓系细胞。 与T细胞相比，髓系组织相关细胞具有多种优势，可以考虑长期病毒 具有组织定位、寿命长、周转慢、抗细胞凋亡能力强等特点 与T细胞相比。在大脑中，小胶质细胞和巨噬细胞是HIV整合的主要细胞类型。 我们的数据发现巨噬细胞/小胶质细胞是大脑中的关键病毒储存库，即使在 长期的艺术。我们开发了一种体外系统来产生潜伏感染的小胶质细胞或巨噬细胞。 可以通过多种治疗方法重新激活，包括蛋氨酸、脂多糖和LRA。潜伏感染艾滋病毒的人 巨噬细胞/小胶质细胞通过增加BIM阻止凋亡体的形成而存活 蛋白质表达，防止进一步的细胞凋亡。此外，我们发现潜伏感染艾滋病毒的细胞 (小胶质细胞/巨噬细胞)有一种独特的代谢特征，依赖于谷氨酸/谷氨酰胺的ATP 生产和生存。更令人惊讶的是，HIV病毒的宿主不能在不同的碳之间切换 脂肪、葡萄糖等来源，或未感染细胞等不寻常的碳源，如氨基酸。 阻断这些代谢途径会导致HIV储存库的显著凋亡，即使在没有这种情况下 重新激活。 我们的结果将提供一个更好的理解机制，调节产生 以及中枢神经系统内艾滋病毒髓系储存库的存活，并为根除 这些来自中枢神经系统的病毒库。