Sara van den Berg

14 Chapter 1 (1) CMV establishes similar T-cell changes as ageing CMV infection is associated with large changes in the T-cell pool. CMV infection leads to increased numbers of effector memory (T EM ) T-cells and effector memory T-cells reexpressing RA (T EMRA ) [38]. Memory T-cells in CMV-infected individuals also express higher levels of senescence markers, such as CD57 and KLRG-1, as compared to CMV-seronegative individuals [29, 39-43]. These cells are often referred to as terminally differentiated T-cells. The average telomere length in the total circulating T-cell pool was also shown to be reduced in CMV-seropositive individuals, suggesting they have experienced enhanced T-cell proliferation [44]. Furthermore, the number of (oligo)clonal expansions of T-cells is increased in CMV- infected individuals [45], leading to a less diverse T-cell repertoire [10]. Taken together, the effects of CMV on the T-cell pool resemble the general age-associated changes that occur in absence of CMV ( Figure 1 , number 1). Evidence is lacking what explains the CMV-induced changes in the T-cell pool. These changes might – at least in part – be explained by the presence of extremely large numbers of CMV-specific T-cells. Thus, if something more is going on in the CMV-induced changes in the T-cells pool needs more research. (2) First studies suggesting a negative association between CMV and the immune response to influenza The above described CMV-induced T-cell changes are linked to a worse outcome of immune challenge. For example an inverted CD4 + /CD8 + T-cell ratio and the presence of oligoclonal T-cell expansions have been identified as part of the immune risk profile [13, 14, 16] and frequencies of CD8 + CD28 - cells have been found to be inversely correlated with vaccine responses [46]. Therefore, The clinical consequences of CMV-induced changes for the function of the immune system were also investigated. Most of these studies have focused on immune responses against influenza in older adults. The risk for serious complications of influenza infection and hospitalization increase with age [47]. Most western countries recommend seasonal influenza vaccination to reduce disease burden. Several studies reported a negative effect of CMV on the influenza vaccine response [48-51] ( Figure 1 , number 2). However, there is no unequivocal evidence for a negative effect, as another study reported no effect [52] and even beneficial effects of CMV have been reported [53, 54]. Thus, although the current dogma is a negative effect of CMV on the influenza vaccine response, the issue remains debated. (3) Epidemiological evidence links CMV to increased mortality The association between CMV infection and health of older people was further investigated over the last decade. Many studies have reported an association between CMV infection and frailty as well as increased risk for mortality [18, 34-37, 55-59], although again not all studies found such associations [60]. CMV infection was shown to decrease life-expectancy with as much as 3.7 years [59]. Especially individuals with high CMV-specific antibody levels were shown to have lower influenza vaccine responses [32, 48], and more cardiovascular disease [17], frailty and overall mortality [17, 18] ( Figure 1 , number 3). The association between CMV and mortality may be explained by effects on the immune system, or alternatively, by affecting