Sara van den Berg

1 15 General introduction the risk of (severe) cardiovascular disease. Indeed, CMV infection has been associated with a higher prevalence and severity of several cardiovascular diseases, for example coronary heart disease and ischemic heart disease [17]. Thus, the increased risk of mortality induced by CMV infection is probably not solely explained by CMV-enhanced immunosenescence. Potential mechanisms of CMV-enhanced immunosenescence Although there is a clear link between CMV infection and several T-cell characteristics, the mechanisms by which CMV-related changes in the T-cells pool worsen the outcome of a heterologous immunological challenge are largely unclear. Two main hypotheses have been proposed. First, the presence of large numbers of CMV-specific T-cells may hamper the induction of other T-cell responses. Both the recruitment as the maintenance of large numbers of CMV-specific T-cells could compete with other memory T-cells, specific for heterologous infections. In this way, CMV-specific T-cells would fill the ‘immunological space’ at the cost of other immunological memories [61]. This is not likely to be competition for a physical space, but rather competition between cells for homeostatic survival factors. This phenomenon has previously more generally been described as ‘memory attrition’ [62]. Secondly, the continual triggering of the immune system by persistent and ‘dynamic latent’ CMV infection may lead to a general low-grade inflammation state, thereby affecting subsequent immune responses. The increase of a more pro-inflammatory immune state with age, which is thought to hamper the function of the immune system, is often summarized as ‘inflammaging’. Both speculated underlying mechanisms of CMV-enhanced immuno-senescence lack solid evidence, especially in humans, and thus remain controversial. SCOPE OF THIS THESIS In this thesis, we aim to address two gaps in the study of CMV-enhanced immunosenescence. PART I: DOES CMV-INFECTION HAMPER THE IMMUNE RESPONSE TO INFLUENZA? Part I of this thesis focuses on the immunological outcome of the CMV-enhanced immunosenescence theory in humans. We investigate if CMV is a threat to the immune response to influenza vaccination and infection. Chapter 2 investigates the effect of age and CMV infection on the antibody response to a novel influenza vaccine strain in humans. We address the hypothesis that CMV causes enhanced immunosenescence in adults, leading to lower antibody responses upon an immune challenge. We hypothesize that the lack of consensus in the literature on the association between CMV infection and antibody responses to influenza vaccination may be due to the fact that pre- existing immunity to influenza can be a disturbing confounder. We therefore focussed on the response to vaccination against the pandemic influenza strain of 2009, thereby aiming to bypass the role of pre-existing immunity. We find no evidence for CMV-induced impairment of the antibody response to this novel influenza strain vaccine in adults. If anything, our data