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

基本信息

批准号：
10327167
负责人：
Eliseo A Eugenin
金额：
$ 55.94万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
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/10327167
关键词：
Address Amino Acids Animal Model Apoptosis Autopsy BIM Bcl-2-binding protein Blood Brain CD4 Positive T Lymphocytes Carbon Cells Chronic Disease DNA Data Effectiveness Energy-Generating Resources Enzymes Generations Genetic Glucose Glutamate-Ammonia Ligase Glutamates Glutaminase Glutamine Glutarates Goals HIV HIV Infections Human Impaired cognition In Vitro Individual Infection Inflammation Interruption Life Lipids Location Malignant Neoplasms Medicine Messenger RNA Metabolic Metabolic Pathway Microbiology Microglia Myelogenous Myeloid Cells Nature Neurotransmitters 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 antiretroviral therapy base cell type curative treatments in vivo innovation laser capture microdissection latent HIV reservoir macrophage metabolic profile metabolomics neuroAIDS novel therapeutics prevent protein expression response therapeutic target translational medicine viral rebound

项目摘要

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：由于持久的潜在艾滋病毒水库，艾滋病毒治愈尚未实现中断，重新激活病毒。最佳特征的病毒储层是不同的循环 T淋巴细胞的亚群，但已经显而易见的是，大多数病毒储层都位于包括大脑在内的几个组织。但是，关于髓样细胞中的HIV持续性知之甚少，成为一个有争议的问题。直到最近，遗传系统发育分析才表明病毒重新激活无法解释通过含有病毒的CD4 t。因此，需要考虑替代储层，例如髓样细胞。髓样组织相关的细胞比T细胞具有多个优势，以考虑持久的病毒储层包括组织位置，长寿，缓慢的转弯以及对凋亡的抗药性更高与T细胞相比。在大脑中，小胶质细胞和巨噬细胞是艾滋病毒集成的主要细胞类型。我们的数据将巨噬细胞/小胶质细胞识别为大脑中的关键病毒储存库长期艺术。我们开发了一种体外系统来产生潜在的感染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，LP和LRA。受艾滋病毒的潜在感染巨噬细胞/小胶质细胞通过增加BIM来阻止凋亡小体的形成，从而生存感染蛋白质表达，阻止进一步的凋亡。此外，我们确定了潜在的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 生产和生存。更令人惊讶的是，艾滋病毒水库无法在不同的碳之间切换诸如未感染细胞之类的氨基酸之类的碳等碳，葡萄糖或异常来源之类的来源。阻止这些代谢途径会导致HIV储层的明显凋亡重新激活。我们的结果将更好地了解调节世代的机制和中枢神经系统内HIV髓样库的生存来自中枢神经系统的这些病毒储藏。