Sara van den Berg

91 4 CMV on influenza infection Whether CMV infection attenuates the immune response to influenza virus infection in older adults remains unclear. Individuals with high CMV-specific antibody levels, assumed to reflect frequent episodes of viral reactivation, were suggested to experience the largest impact of CMV on the immune system. As CMV might not affect all CMV+ individuals equally, it is crucial to asses not only the effect of CMV-seropositivity, but also the hypothesized underlying mechanism. There are two major hypotheses explaining how CMV infection may affect the immune response to a heterologous virus. First, it has been proposed that large clonal expansions of terminally differentiated CMV-specific CD8+ T-cells, which are a hallmark of CMV infection and can take up to 30%-90% of the CD8+ T-cell memory pool [30-32], may fill the ‘immunological space’ and thereby hamper the induction of other immune responses [10, 13, 33]. Influenza virus-specific T-cells may thus be outcompeted by CMV-specific T-cells in their competition for proliferation and survival factors [13], which may hamper the immune response against influenza. Secondly, it has been suggested that CMV is linked to ’inflammaging’, the lingering low-graded level of inflammation occurring with ageing [34]. The production of pro-inflammatory mediators has been shown to enable CMV reactivation [35, 36]. Upregulation of TNF- α , IL-6 and CRP have been observed in CMV-infected individuals, as well as increased production of IL-10 [11, 37, 38]. Especially the increase of IL-10 combined with a decrease of IFN γ has been associated with reduced cytolytic capacity of CD8+ T-cells responsible for clearing influenza virus from the lungs, which also fits with the observed lower levels of granzyme B [39-41]. Importantly, even though CMV has been suggested to diminish the T-cell response to influenza, there is no clinical evidence of a direct link between CMV infection and the T-cell response against influenza virus infection in humans. We had the unique opportunity to study the effect of CMV infection on influenza virus specific T-cells with age and on the cellular immune response against influenza virus infection in a large group of older adults. We first investigated the effect of CMV infection on the presence of influenza virus-specific memory T-cells in healthy young and older individuals. Next we assessed the effect of latent CMV infection on the influenza virus-specific T-cell response in older adults undergoing an acute influenza virus infection. As CMV might only affect some individuals, we also assessed the association between 1) CMV-specific T-cells and influenza T-cell responses and 2) inflammatory cytokines and influenza T-cell responses in CMV- and CMV+ individuals. Our data show that CMV infection is associated with reduced frequencies of influenza virus-specific T-cells in healthy older adults. Nevertheless, CMV infection does not hamper the T-cell response during acute influenza virus infection. Our data suggest that CMV is unlikely to be detrimental for immune responses to influenza virus infection in older adults.