PROJECT SUMMARY/ABSTRACT Cytomegalovirus (CMV) infection is a frequent and life-threatening complication that significantly limits the successful outcome of allogeneic hematopoietic stem cell or bone marrow transplantation (referred to hereafter at BMT). We have recently developed long-desired preclinical (murine) models of CMV reactivation after BMT and show for the first time, that humoral immunity is critical to prevent viral recrudescence. We now demonstrate that either the transfer of immune T cells or strain-specific sera (containing IgG antibody) prevents viral reactivation, viremia, end-organ viral replication and CMV disease during graft-versus-host disease (GVHD). We plan to utilize our unique, but well-established preclinical models to define the impact of protective antibody on the temporal and spatial characteristics of CMV reactivation, dissemination and antigen presentation. Subsequently we will define the interplay of T cell and humoral responses that are required for the durable control of CMV reactivation after BMT. Finally, we will develop clinically tractable pathways to enhance CMV immunity whilst preventing GVHD and associated inflammation, targeting IL-6 inhibition. Our proposed studies will provide critical insights into the immune requirements for effective and long-term control of CMV in recipients with GVHD and/or clinically relevant immune suppression and inflammation that will allow us to optimize CMV immunity in clinical BMT to improve patient outcomes.