Sara van den Berg

217 8 General discussion individuals living with a CMV+ partner is CMV-infected themselves [70]. Thus, it might even be that receiving a primary CMV infection in older adults is a reflection of the ageing status of individuals, or their so-called biological age. CONCLUDING REMARKS The research presented in this thesis has generated some important insights into the CMV- enhanced ageing theory. On the one hand it questions the negative effect of CMV on the function of the immune system. Our work suggests that when trying to tackle the aged- impaired immune response to influenza, not much will be gained by interfering with CMV e.g. by vaccination. On the other hand, this thesis again stresses the uniqueness of CMV- specific T-cells and the large impact of CMV infection on the T-cell pool. To what extent non-CMV specific T-cells are also affected by CMV asks for further research. A next step could be to measure expression of senescence markers in multiple non-CMV antigen-specific T-cells in large cohorts, thereby focusing on the known CMV-induced changes in the T-cell pool. Further knowledge on how CMV-specific T-cells in humans become so abundant, while retaining their high quality, would be of great value. This will contribute to our current understanding of fundamental T-cell concepts, including maintaining T-cell quality. Also, this will offer important implications for vaccination strategies that aim to induce long-term and high immunological memory responses, for example using CMV-vector based vaccines to combat infections like HIV [71]. Before potentially extrapolating these high quality T-cell responses into CMV-vector based vaccination strategies, the role of antigen stimulation during CMV infection should be investigated in more detail. A combination of measuring the viral reservoir and viral reactivation itself, and the CMV-specific immune responses is needed. This will help to further understand the rather paradoxical increase of CMV-specific immune responses with age and the complex viral-host balance. In all this, the CD4 + T-cell pool should not be disregarded. As CMV mainly affected CD4 + T-cells in terms of T-cell dynamics, there might be a broader role for cytotoxic CD4+ T-cells in control of CMV infection. Finally, the possibility of high CMV-specific immune responses not as a cause, but merely as a hallmark of ageing, deserves further attention. Rather than solely looking for biomarkers to identify individuals that are most prone to severe CMV-related changes in the immune system and to clinical consequences, we may have to explore the possibility to use the immune response to CMV or the size of the CMV latent reservoir as biomarkers of immunological ageing. Considering this view might shine a whole new light on the association between CMV and ageing of the immune system.