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

在人类免疫缺陷病毒(HIV)感染中，肠道屏障功能的早期破坏加强了微生物产物从肠腔到血液循环的转移，因此被认为促进了与HIV疾病进展和死亡率直接相关的持续性免疫过度激活的发展。其机制尚不完全清楚，缺乏以科学证据为基础的治疗概念。我们先前已经证明，在急性HIV感染者中，肠上皮细胞裂解可增加上皮屏障的通透性。我们最近的发现表明，EB病毒(EBV)特异的CD8+T细胞在HIV初始应答过程中协同刺激，参与了这一过程。因此，我们认为针对疱疹病毒的免疫反应在导致炎症的屏障缺陷的诱导中起着关键作用。HIV感染急性期后，溶解的肠道细胞损伤减少，但慢性HIV感染患者的肠道屏障再生不足。丧失对共生细菌的耐受性可能在这方面起到作用。在这些患者中，我们发现缺乏肠道共系膜特异性CD8+T细胞，最近描述了CD8+T细胞在组织修复中的关键功能。在这种背景下，本项目专注于分析诱导和维持肠道屏障缺陷的新方面。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被阐明。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，具有特定共生肠道细菌特异性的CD8+T细胞将在肠粘膜中进行量化和功能表征。综上所述，该项目将带来有关粘膜功能障碍的新的机制洞察力，为开发新的治疗方法奠定基础。

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.