Solid organ transplantation (SOT) is the treatment of choice for end-stage organ failure but the immunosuppressive drugs used to prevent graft rejection expose to an increased risk of opportunistic infections among which CMV disease leads to the most frequent morbidity and even mortality. HORUS project gathers solid-organ transplantation experts, computational data scientists, virologists and immunologists in a fully operating European network including 25 partners. HORUS ambitious but realistic goals is to improve our understanding of CMV/host interactions in the context of immunosuppression, with a particular focus on i) the characterization of signatures associated with the control of CMV replication after transplantation, ii) the characterization of signatures associated with the evolution toward a difficult-to-treat CMV disease and poor outcome during CMV replication, iii) the discovery of new specific immunomodulatory molecules promoting CMV control while maintaining prevention of acute rejection. HORUS includes the constitution of the first European SOT recipient longitudinal cohort. In a sub- “HORUS-exploratory cohort”, we will perform a deep investigation of viral, clinical and immunological characteristics. Combining those parameters will provide a signature early after transplantation to predict the risk of developing CMV infection and a signature at day 0 of infection to predict the risk of CMV disease severity. This signature will next be validated retrospectively on the whole cohort and prospectively in a “proof-of-concept" study. Moreover, HORUS will include functional in vitro and mice models to understand the mechanisms of lymphocyte response to CMV and provide innovative methods to increase CMV-specific immunity. Altogether, HORUS will lead to personalized clinical prevention and treatment of CMV disease and to improvement of patient outcomes.