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Antibodies directed against HLA can develop through pregnancy, blood transfusions, or organ transplants. Anecdotal evidence suggests that virus-specific antibodies may have the capacity to cross-react with HLA, a phenomenon called heterologous immunity, which is well described for T-cell alloreactivity.To determine whether antibody cross-reactivity between viral antigens and HLA is common, we tested 51 virus-specific human monoclonal antibodies (mAbs) specific for human immunodeficiency virus, varicella zoster virus, cytomegalovirus, and parvovirus, for reactivity against HLA class I and class II in single-antigen bead assays. In addition, we tested the reactivity of 41 HLA-specific human mAbs against common viral antigens of cytomegalovirus, varicella zoster virus, human immunodeficiency virus, Epstein-Barr virus, and BK polyomavirus.No cross-reactivity of any of the virus-specific mAbs with either HLA class I or class II molecules, as well as no cross-reactivity of any of the HLA-specific mAbs with any of the viral antigens was observed.These findings indicate that the frequency of cross-reactivity on the antibody level between viral antigens and HLA, if present at all, is low. The emergence of HLA antibodies upon viral infection or vaccination is therefore probably due to bystander activation of dormant HLA-specific memory B cells.