Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of latedifferentiated CD4 ₊ and CD8 ₊ T-cells in humans

Human cytomegalovirus (CMV) establishes persistent, usually asymptomatic, infection in healthy people. Because CMV infection is associated with the presence of lower proportions of peripheral naïve CD8 ⁺ T-cells and a higher fraction of late-differentiated CD8 ⁺ cells, commonly taken as biomarkers of age-associated compromised adaptive immunity ('immunosenescence'), we asked whether chronic exposure to any persistent virus mediates these effects. Herpes simplex virus (HSV) is also a widespread herpesvirus that establishes lifelong persistence, but, unlike CMV, its impact on the distribution of T-cell subsets has not been established. Here, we analysed T-cell subsets in 93 healthy people aged 42-81 years infected or not infected with CMV and/or HSV. Individuals harbouring CMV were confirmed to possess lower frequencies of nai{dotless}̈ve CD8 ⁺ T-cells (defined as CD45RA ⁺CCR7 ⁺CD27 ⁺CD28 ⁺) and greater proportions of late-differentiated effector memory (CD45RA-CCR7-CD27-CD28-) and so-called TEMRA (CD45RA ⁺CCR7 _-CD27 _-CD28 _-) CD4 and CD8 subsets, independent of HSV seropositivity. In CMV _-seronegative donors, HSV did not affect T-cell subset distribution significantly. We conclude that these hallmarks of age-associated alterations to immune signatures are indeed observed in the general population in people infected with CMV and not those infected with a different persistent herpesvirus.