Background: Immune senescence, defined as the age-related loss of function of the immune system, is one of the major causes for the increased susceptibility of aging individuals to infectious diseases and for poor protective immunity after vaccination. A variety of age-associated problems contribute to immune senescence and affect both innate and adaptive immunity. The quantity and quality of T and B cell responses in aging hosts is particularly limited against 'new' antigens by the reduced availability of naïve cells and the compensatory proliferation of memory cells leading to a restriction of the antigenic repertoire. Recent studies indicate that persistent viral infections particularly with Cytomegalovirus (CMV) constantly promote CMV-specific memory cell proliferation and thus increase the imbalance between naïve and memory cells and diminish the diversity of remaining memory cells. Persistent infections might therefore contribute substantially to premature immune senescence. However, direct experimental evidence to support this hypothesis is currently lacking.Aim: This project directly addresses the question, whether and how persistent viral infections propagate immune senescence. We will also develop an animal model for the study of infection enhanced immune senescence (IEIS). This will help to elucidate underlying mechanisms, to evaluate preventive measures and to devise successful vaccination strategies in the setting of IEIS. Methods: We propose two experimental strategies in humans and in mice to tackle these questions:1) We will perform a vaccination trial in healthy elderly individuals using the currently licensed vaccine against tick-borne encephalitis virus (TBEV). Participants will be subdivided in two groups according to their CMV-serology (CMV-seropositive vs seronegative). Comprehensive analyses of overall immune reactivity, CMV-specific immune responses and TBEV-specific immunity will be performed with current technology before and after immunization. We will then compare the TBEV-specific vaccine response between the two groups and correlate immune responsiveness with the quantity and quality of the pre-existing CMV-specific immunity. 2) We will develop a mouse model of IEIS. To generate a large pool of memory cells with defined specificities in aging mice, we will use three different viruses which establish persistent infection in their natural host, i.e. mouse CMV (MCMV), lymphocytic choriomeningitis virus (LCMV) and mouse -herpesvirus-68 (MHV-68). We will analyse immune responses against these persistent viruses and against 'new' heterologous antigens in detail. We will compare immune reactivity of aged mice with and without persistent infections and elucidate molecular and cellular mechanisms, how immune senescence is propagated by persistent infections. Intervention strategies to prevent IEIS or to allow successful vaccination despite IEIS will be developed and tested in this model.Outlook:The proposed project will provide solid evidence for several important questions in the context of immune senescence and persistent infections: 1) What is the impact of persistent infections on the development of immune senescence. 2) What are the mechanisms propagating immune senescence by persistent infections.3) Which strategies have the potential to prevent or attenuate IEIS and/or its consequences.