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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：
10458785
负责人：
Eliseo A Eugenin
金额：
$ 70.55万
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/10458785
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 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 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：由于长期潜伏的艾滋病毒库在抗逆转录病毒治疗后无法治愈艾滋病毒