Characterization and manipulation of control points of virus infection fates

The fate of a virus infection is determined within days after the initial infection event. It is a consequence of the dynamic interplay between an expanding virus and the concomitantly induced immune response. Numerous components of this interplay have been studied extensively however, we still lack a mechanistic link between individual control points within the infection-fate-decision process and require a better knowledge about how to manipulate such a dynamic system for patient benefit. Virus infections, and in particular chronic infections like those caused by HIV or hepatitis B and C viruses remain a major individual burden for the infected person, and a major financial burden for health care systems. Thus, to address fundamental aspects of infection fate regulation and its manipulation is of central interest not only for basic research but also for pharmaceutical industries and societies as a whole. 

Using a systems-based experimental approach in a mouse infection model, we have previously described complex biological processes that are involved in the fate of acute and chronic virus infections. In order to mechanistically link these processes that differentially regulate infection fates and to develop novel therapeutic approaches against chronic infections, our project addresses three aspects of virus-host interactions and their manipulation. First we will analyze the cause and the consequence of the differential type I interferon response in acute and chronic LCMV infection in the mouse model system with the objective to link this early differentiating trait with subsequent outcome-specific innate and adaptive immune responses. Second, we will explore the mechanism of LCMV infection-induced lymphatic tissue fibrosis, its consequences for vaccine responses and its possible therapeutic reversion with the objective to understand and therapeutically maintain lymphatic tissue integrity and function. Third, we will investigate the importance of the previously determined XCL1 chemokine / XCR1+ dendritic cell (DC) crosstalk for HIV control and evaluate the therapeutic potential of XCR1+ DC-targeting immunogens against chronic LCMV infection in mice with the objective to test the relevance of our previous observations in human infections and explore further therapeutic options. 

The project is supported by a grant from the Spanish Ministry of Science and Innovation grant no. PID2019-106323RB-I00 (AEI/MINEICO/FEDER, UE).