Cytomegalovirus as an immunomodulator across the lifespan

•Human cytomegalovirus (HCMV) infection and HCMV-seropositivity have an age-dependent impact on health and disease.•HCMV is associated with adverse health outcomes at the extremes of age but may boost host immunity in young adulthood.•HCMV infection causes profound immune activation and creates a lifelong imprint on T and NK cell subsets.•More mechanistic studies on how HCMV-mediated immune changes influence health and disease across the life course are needed. Human cytomegalovirus (HCMV) is a nearly ubiquitous β-herpesvirus that establishes latent infection in the majority of the world's population. HCMV infection profoundly influences the host immune system and, perhaps more than any other human pathogen, has been shown to create a lasting imprint on human T and NK cell compartments. HCMV-seropositivity has been associated with both beneficial effects, such as increased vaccine responsiveness or heterologous protection against infections, and deleterious effects, such as pathological neurodevelopmental sequelae from congenital infection in utero and cumulative damage from chronic lifelong latency into old age. The significance of many of these associations is unclear, as studies into the causal mechanisms linking HCMV and these disease outcomes are lacking; however, HCMV-mediated changes to the immune system may play a key role. This review examines how HCMV impacts the host immune system in an age-dependent manner with important implications for human immunophenotypes and long-term disease risk.