Dysfunction and Metabolic Reprogramming of Gut Regulatory T Cells in HIV-Infected Immunological Non-Responders

作者：Minrui Yu, Mengmeng Qu, Zerui Wang, Cheng Zhen, Baopeng Yang, Yi Zhang, Huihuang Huang, Chao Zhang, Jin‐Wen Song, Xing Fan, Ruonan Xu, Yan‐Mei Jiao, Fu‐Sheng Wang · 发表于：Cells · 年份：2025 · DOI：10.3390/cells14151164 · 被引用次数：5 · 研究领域：HIV Research and Treatment、Immune Cell Function and Interaction、Gut microbiota and health

Disruption of the gut microenvironment is a hallmark of HIV infection, where regulatory T cells (Tregs) play a critical role in maintaining gut homeostasis. However, the mechanisms by which gut Tregs contribute to immune reconstitution failure in HIV-infected individuals remain poorly understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to analyze gut Treg populations across three cohorts: eight immunological responders (IRs), three immunological non-responders (INRs), and four HIV-negative controls (NCs). Our findings revealed that INRs exhibit an increased proportion of gut Tregs but with significant functional impairments, including reduced suppressive capacity and heightened apoptotic activity. Notably, these Tregs underwent metabolic reprogramming in INRs, marked by an upregulation of glycolysis-related genes and a downregulation of the oxidative phosphorylation (OXPHOS) pathway. Additionally, both the abundance of short-chain fatty acid (SCFA)-producing bacteria and SCFA concentrations were reduced in INRs. In vitro SCFA supplementation restored Treg function by enhancing suppressive capacity, reducing early apoptosis, and rebalancing cellular energy metabolism from glycolysis to OXPHOS. These findings provide a comprehensive characterization of gut Treg dysfunction in INRs and underscore the therapeutic potential of targeting gut Tregs through microbiota and metabolite supplementation to improve immune reconstitution in HIV-infected individuals...