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，肠道屏障功能的早期破坏使微生物产物从肠道内流体转化为循环，因此被认为有助于与HIV疾病进展和死亡直接相关的持续性免疫过度激活的发展。这些机制尚未完全理解，缺乏基于科学证据的治疗概念。我们先前已经证明，裂解肠细胞倒置会增加急性HIV感染者上皮屏障的渗透性。我们最近的发现表明，爱泼斯坦 - 巴尔 - 病毒（EBV）特异性CD8+ T细胞在HIV主要反应中协同刺激，参与了这一过程。因此，我们认为对疱疹组病毒的免疫反应在诱导屏障缺陷导致炎症的诱导中起关键作用。在HIV感染的急性期之后，裂解肠肠损伤降低，但肠道屏障的再生在慢性HIV感染的患者中不足。对共生细菌的容忍度丧失可能在这方面发挥作用。在这些人中，我们发现缺乏肠道特异性的CD8+ T细胞，最近已经描述了组织修复中的关键功能。此背景，该项目的重点是分析肠道屏障缺陷的诱导和维持的新方面。 EBV，细胞结血病毒和人类疱疹病毒的相关性将阐明急性HIV感染患者的初始屏障缺陷。在这些患者中，我们还将确定有助于CD8+ T细胞早期作用的结构。此外，将在肠粘膜中定量具有定义的共生肠道细菌特异性的CD8+ T细胞并在功能上进行表征。在合意中，该项目将导致有关粘膜功能障碍的新机械洞察力，以作为开发新治疗方法的基础。