Consequences for Health and Vaccination

People aged 60 and older represent over 11 % of the world population, with the proportion expected to increase to 22 % by 2050. Ageing is obviously associated with an increased frequency of age-related diseases including higher susceptibility to infections, cancer, cardiovascular and neurodegenerative diseases [58]. The role of CMV in the etiology of these age-associated diseases is currently under intensive investigation. It has been reported that CMV infection markedly increases mortality in the elderly and has been associated with frailty and impaired survival [59-61]. As discussed above, it is associated with the “Immune Risk Profile” in the Swedish OCTO/NONA studies but not in BELFRAIL. Functional decline of older individuals has been associated with immune parameters and the intensity of the response to CMV [62]. Thus, for example, in one powerful study, the impact of CMV infection on mortality was investigated in a cohort of 511 individuals aged at least 65 years at entry, who were then followed up for 18 years. Infection with CMV was associated with an increased mortality rate in healthy older individuals due to an excess of vascular deaths. It was estimated that those elderly who were CMV-seropositive at the beginning of the study had a near 4-year reduction in lifespan compared to those who were CMV-seronegative, a striking result with major implications for public health [59]. Other data, such as those from the large US NHANES-III survey, have shown that CMV seropositivity together with higher than median levels of the inflammatory marker CRP correlate with a significantly lower 10-year survival rate of individuals who were mostly middle-aged at the start of the study [63]. Further evidence comes from a recently published Newcastle 85+ study of the immune parameters of 751 octogenarians investigated for their power to predict survival during a 65-month follow-up. It was documented that CMV-seropositivity was associated with increased 6-year cardiovascular mortality or death from stroke and myocardial infarction. It was therefore concluded that CMV-seropositivity is linked to a higher incidence of coronary heart disease in octogenarians and that senescence in both the CD4+ and CD8+ T-cell compartments is a predictor of overall cardiovascular mortality [61t. Another study demonstrated that resting blood pressure is associated with the magnitude of CMV-specific CD8+ T-cell responses and with a novel regulatory type CD4+ T-cell subpopulation expressing CD25, CD39 and CD134 upon activation with CMV-antigen [64]. These investigators speculated that CMV infection might directly target vascular endothelium and smooth muscle and might be related to accelerated vascular pathology and mortality in the aged, and/or that CMV-specific T-cell immunity itself might directly contribute to this pathological process. The mechanism whereby CMV infection is associated with increased cardiovascular risk may relate to findings of increased arterial stiffness in patients with chronic kidney disease associated with CMV infection, which could contribute to the cardiovascular complications seen in these patients and possibly also reflect a more general CMV effect [65].

The issue concerning the role of CMV infection on mental health and cognitive state in the old remains even more controversial [14]. In a study of 1061 participants of the Lothian Birth Cohort a small but significant decrease in cognitive function was seen in the CMV-seropositive group. The likelihood of contracting CMV infection by age 70 is predicted by a number of demographic and environmental factors. After accounting for these, CMV infection (considered as serostatus) was not cognitively detrimental. Within CMV-seropositive individuals, however, higher CMV antibody levels were associated with lower general cognitive ability of old people [66].

In cancer, available evidence indicates that CMV is present in several solid tumors with a high prevalence, approaching 100 % in malignant glioblastoma [14]. The longer survival in patients whose tumors had low-grade CMV infection suggests that the level of CMV infection in malignant glioblastoma may be considered as a prognostic factor. Furthermore, it is possible that CMV may contribute to the pathogenesis of glioblastoma itself [67]. In a similar way, invasiveness and relapses of neuroblastoma may also be linked to the presence of human cytomegalovirus. The CMV-specific drug valganciclovir significantly reduced viral protein expression and tumor cell growth both in vitro and in vivo. Therefore, it was speculated that CMV infection may contribute to the pathogenesis of neuroblastoma and antiviral therapy may provide a novel treatment option for children with neuroblastoma [68]. Following these results, a randomized, double-blind, placebo-controlled, hypothesis-generating study was initiated to examine the safety and potential efficacy of valganciclovir as an add-on therapy for glioblastoma [69]. However, the involvement of immunity, if any, in these effects is not known.

CMV-seropositivity has been shown in some but not all studies to be linked to diminished humoral responsiveness of the old to influenza vaccination [70-74]. It was suggested that infection with CMV, accompanied by elevated pro-inflammatory potential, could contribute to the poor responsiveness to influenza vaccine in older individuals [73]. In two independent cohorts it was demonstrated that CD4+ T-cell responses to influenza core proteins are absent in almost half of CMV-seropositive older adults, whereas older people not infected with CMV respond as well as the young. It was concluded that advanced chronological age plays a role in compromised responses to influenza but only in concert with CMV infection [71]. Intriguing results from the recent study of Furman et al., indicated that CMV-seropositive young adults exhibited enhanced antibody responses to influenza vaccination, increased CD8+ T-cell sensitivity, and elevated levels of circulating interferon- gamma compared to seronegative individuals [45]. The overall decreased responses to vaccination in aged individuals commonly observed by others were also seen in this study, regardless of CMV status of the subjects. Results consistent with these findings were also reported in a murine model, where young mice infected with murine CMV also showed significant protection against influenza compared with uninfected mice. These data further show that CMV can have a beneficial effect on the immune response of young individuals—a finding that may go some way to explaining the ubiquity of CMV infection in human (and animal) populations [45]. These and other findings [43, 71] show that the CMV-associated impact on immune features phenotyped as immunosenescence is not necessarily detrimental to the host, and suggest that the term “senescence” should be avoided because this by definition means something detrimental. Rather, data suggest that the remodeling of the T-cell compartment in the presence of a latent infection with CMV represents a crucial adaptation of the immune system towards the chronic challenge of lifelong CMV. Thus, continued immunosurveillance against persistent CMV appears to be more important for host survival than reserving immune resources for responses to other viruses [71]. These data add to the accumulating evidence that infection with CMV has important but apparently very heterogeneous effects on responses to other viruses and this may influence on the design of influenza (and other) vaccines, especially for the elderly population.

Acknowledgments This work was supported by the European Commission under Grant Agreement FP7 259679, Integrated research on developmental determinants of ageing and longevity, “IDEAL” and by an unrestricted educational grant from the Croeni Foundation (to GP).

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