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

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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.