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增强了微生物产物从肠腔进入循环的易位，因此被认为有助于持续免疫过度激活的发展，这与HIV疾病的进展和死亡率直接相关。其机制尚不完全清楚，缺乏基于科学证据的治疗概念。我们以前已经证明，溶解性肠细胞破坏增加急性hiv感染者上皮屏障的通透性。我们最近的研究结果表明，eb病毒特异性CD8+ t细胞在HIV初次应答期间协同刺激，参与了这一过程。因此，我们假设针对疱疹病毒群的免疫反应在诱导屏障缺陷和由此产生的炎症中起关键作用。HIV感染急性期后，溶性肠细胞损伤减少，但慢性HIV感染患者肠屏障再生不足。失去对共生菌的耐受性可能在这方面起作用。在这些人中，我们发现缺乏肠道评论特异性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，本项目重点分析肠屏障缺陷诱导和维持的新方面。EBV、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细胞早期作用的结构。此外，将对肠道黏膜中具有特定肠道共生细菌特异性的CD8+ T细胞进行量化并进行功能表征。总之，该项目将导致有关粘膜功能障碍的新的机制见解，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.