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储存库尚未实现艾滋病毒治愈，在接受抗逆转录病毒疗法（ART）后， 中断，重新激活病毒。最有特征的病毒储存库是不同的循环病毒库 T 淋巴细胞亚群，但很明显，大多数病毒储存库位于 多个组织，包括大脑。然而，人们对艾滋病毒在骨髓细胞中的持续存在知之甚少。 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重新激活无法解释 由含有病毒的 CD4 T 产生。因此，需要考虑替代的储存库，例如骨髓细胞。 骨髓组织相关细胞比 T 细胞具有多种优势，可以考虑持久的病毒 储存库，包括组织定位、长寿命、缓慢周转和更高的细胞凋亡抵抗力 与T细胞相比。在大脑中，小胶质细胞和巨噬细胞是整合艾滋病毒的主要细胞类型。 我们的数据表明巨噬细胞/小胶质细胞是大脑内的关键病毒库，即使在 长期艺术。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 可以通过多种治疗重新激活，包括冰毒、LPS 和 LRA。艾滋病病毒潜伏感染者 巨噬细胞/小胶质细胞通过增加 bim 来阻止凋亡体的形成，从而在感染中存活下来 蛋白表达，防止进一步凋亡。此外，我们还发现潜伏感染 HIV 的细胞 （小胶质细胞/巨噬细胞）具有独特的代谢特征，依赖于谷氨酸/谷氨酰胺提供 ATP 生产和生存。更令人惊讶的是，HIV 储存库无法在不同碳之间切换 脂质、葡萄糖等来源，或不寻常的碳源（如氨基酸，如未感染的细胞）。 即使在不存在的情况下，阻断这些代谢途径也会导致 HIV 病毒库的显着凋亡 的重新激活。 我们的结果将有助于更好地理解调节发电的机制 和中枢神经系统内艾滋病毒骨髓库的存活，并为根除艾滋病毒提供重要信息 这些病毒库来自中枢神经系统。