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.

翻译后摘要：艾滋病毒治愈尚未实现，由于长期潜伏的艾滋病毒水库，在ART 中断重新激活病毒最佳表征的病毒储库是不同的循环 T淋巴细胞的亚群，但已经很明显，大多数病毒水库是本地化的， 包括大脑在内的多个组织然而，对骨髓细胞中的HIV持久性知之甚少， 成为一个有争议的问题。 直到最近，遗传系统发育分析表明，病毒的重新激活不能解释 通过含有病毒的CD 4 T细胞。因此，需要考虑替代储库，例如骨髓细胞。 骨髓组织相关细胞比T细胞具有多个优势，可以考虑持久的病毒感染。 储库包括组织定位、长寿命、缓慢周转和更高的抗凋亡性 与T细胞相比。在脑内，小胶质细胞和巨噬细胞是HIV整合的主要细胞类型。 我们的数据表明，巨噬细胞/小胶质细胞是大脑中关键的病毒储存库，即使在 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，包括甲基苯丙胺，LPS和LRA。潜伏的艾滋病毒感染者 巨噬细胞/小神经胶质细胞通过增加bim来阻断巨噬细胞体的形成， 蛋白表达，防止进一步的凋亡。此外，我们发现潜伏的HIV感染细胞 （小胶质细胞/巨噬细胞）具有独特的代谢特征，依赖于谷氨酸/谷氨酰胺的ATP 生产与生存。更令人惊讶的是，HIV病毒库不能在不同的碳之间转换， 来源，如脂质、葡萄糖或不寻常的碳来源，如未感染的细胞中的氨基酸。 阻断这些代谢途径会导致HIV宿主的显著凋亡，即使在缺乏 重新激活。 我们的研究结果将提供一个更好的了解机制，调节产生 和生存的HIV骨髓储库在中枢神经系统内，并提供必要的信息， 从中枢神经系统中清除这些病毒库。