ABSTRACT Immunosuppression required for lifesaving solid organ transplantation is complicated by significant morbidity including increased recurrence of latent viral infection in transplant recipients. Approximately 60-70 percent of adults in the United States are latently infected with Cytomegalovirus (CMV). Control of latent CMV depends on a continuously active immune response. In both healthy individuals and immunocompromised transplant recipients, latent CMV has a profound effect of shaping the T lymphocyte repertoire. We previously showed that the combination of immunosuppression and latent CMV is sufficient to induce “accelerated” aging in the T cell compartment during the first year after kidney transplantation. Immune aging or immunosenescence diminishes the capacity to respond to infection and vaccination. However, whether the acceleration of aging continues to occur after the first year and whether it is confined to the T cell compartment has not been studied. Our preliminary data suggests a rapid aging of the B cell compartment over the first 2 years post-transplant as well as poor antibody responses to vaccination in those with latent CMV. In this renewal, we hypothesize that latent CMV continually shapes and ages the immune system in an accelerated manner after transplantation resulting in diminished heterologous immune responses. Using a network of VA transplant centers and an experienced team of transplant physicians and scientists, we will test this hypothesis with the following specific aims: 1) determine the effect of latent CMV on immune aging in the B cell compartment, 2) determine if accelerated inflation and aging continues after the first-year post- transplantation and 3) determine whether immune changes induced by latent CMV can be used as predictors of successful responses to SARS-CoV-2 booster vaccination responses. Results from these studies will substantially expand our understanding of fundamental changes to the immune system induced by CMV in the setting of solid organ transplantation thus providing critical knowledge that will aid in the care of this at-risk Veteran population.