CMV reactivation in seropositive recipients after stem cell transplantation. (A) Strain-specific humoral immunity (ie, IgG) variably persists after SCT, reflecting the eradication of recipient plasma cells by conditioning, GVHD, and antibody sequestration and loss in tissues. (B) Donor grafts from seropositive donors include CMV-specific memory T and B cells and NK cells, including memory-like NK cells. NK cell expansion is affected by GVHD because of the competition for survival cytokines (IL-15) with alloreactive T cells. (C) After transplant, T and B cells differentiate from donor stem/progenitor cells and are primed de novo. The presence of GVHD and immune suppression profoundly impairs innate and adaptive immune responses, including humoral immunity (arrows). Concurrent absence of these responses, together with loss of preexisting immunoglobulins (as shown in panel A) is permissive of CMV reactivation. (D) Prevention of CMV reactivation and disease may require multiple interventions. The protection conferred by CMV-specific memory B cells or immunoglobulins is ambiguous in clinical settings, but preclinical studies suggest that matching humoral responses to specific CMV strains will be effective. Monoclonal antibodies may be an alternative intervention if they provide multistrain protection. HLA-compatible, CMV-specific T cells can control CMV dissemination and disease. NK cells and IL-15 mimetics may provide additional antiviral activities.