Novel aspects in the pathogenesis of HIV infection: Herpesvirus- und gut commensal-specific CD8+ T cells as possible inducers and regulators of gut inflammation in HIV-infected persons

HIV感染发病机制的新方面：疱疹病毒和肠道共生特异性CD8 T细胞作为HIV感染者肠道炎症的可能诱导剂和调节剂

• 批准号: 212373340
• 负责人: Professor Dr. Thomas Schneider
• 金额: --
• 依托单位: Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie (CBF)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/212373340?language=en
• 关键词: Novel; aspects; pathogenesis; HIV; infection

In human immunodeficiency virus (HIV) infection, early disruption of intestinal barrier functions enhances the translocation of microbial products from the gut lumen into circulation, and is thus thought to contribute to the development of persistent immune hyperactivation that is directly linked to HIV disease progression and mortality. The mechanisms are not fully understood and scientific evidence based therapeutic concepts are lacking. We have previously demonstrated that lytic enterocyte desctruction increases permeability of the epithelial barrier in acutely HIV-infected persons. Our recent findings suggest that Epstein-Barr-Virus (EBV)-specific CD8+ T-cells, synergistically stimulated during HIV primary response, are involved in this process. We therefore hyothesize that immune reactions against viruses of the herpes group play a pivotal role in the induction of the barrier defect with resulting inflammation. After the acute phase of HIV infection, lytic enterocyte damage decreases, but regeneration of the intestinal barrier is insufficient in patients with chronic HIV infection. Loss of tolerance against commensal bacteria may play a role in this regard. In these persons we found a lack of gut commensal-specific CD8+ T cells, for which crucial functions in tissue repair has recently been described.Against this background, this project focuses on analyzing novel aspects of the induction and maintenance of the intestinal barrier defect. The relevance of EBV, Cytomemegalovirus and Human herpesvirus type 6 specific CD8+ T cells for the initial barrier defect in acutely HIV-infected patients will be elucidaded. In those patients, we will also identify structures contributing to the early effect of CD8+ T cells. In addition, CD8+ T cells with specificities for defined commensal gut bacteria will be quantified in the intestinal mucosa and functionally characterized. In concusion, this project will lead to novel mechanistic insight concerning the mucosal dysfunction, to serve as a basis for the development of new therapeutic approaches.

在人类免疫缺陷病毒（HIV）感染中，肠屏障功能的早期破坏增强了微生物产物从肠腔到循环中的易位，因此被认为有助于发展与HIV疾病进展和死亡率直接相关的持续免疫超活化。其机制尚未完全了解，缺乏基于科学证据的治疗概念。我们以前已经证明，溶解性肠上皮细胞脱钙蛋白酶增加急性HIV感染者上皮屏障的通透性。我们最近的研究结果表明，EB病毒（EBV）特异性的CD8+ T细胞，在艾滋病毒的主要反应协同刺激，参与了这一过程。因此，我们认为，对疱疹病毒的免疫反应在诱导屏障缺陷并导致炎症中起着关键作用。在HIV感染的急性期之后，溶解性肠细胞损伤减少，但慢性HIV感染患者的肠屏障再生不足。对肠道细菌的耐受性丧失可能在这方面发挥作用。在这些人中，我们发现缺乏肠黏膜特异性CD8+ T细胞，其在组织修复中的关键功能最近已被描述。在此背景下，本项目重点分析诱导和维持肠屏障缺陷的新方面。EB病毒、巨细胞病毒和人类疱疹病毒6型特异性CD8+ T细胞与急性HIV感染患者初始屏障缺陷的相关性将得到阐明。在这些患者中，我们还将确定有助于CD8+ T细胞早期效应的结构。此外，将在肠粘膜中定量对确定的肠道细菌具有特异性的CD8+ T细胞，并对其进行功能表征。结论：本研究将为黏膜功能障碍的机制研究提供新的思路，为开发新的治疗方法提供基础。