The Epstein-Barr virus (EBV) is associated with multiple lymphoid malignancies and autoimmune diseases. The glycoprotein gp350, the most abundant envelope protein on the EBV virion surface, has been the primary target for the vaccine design. However, all the attempts have failed to prevent asymptomatic infection in clinical trials. This setback highlights an incomplete understanding of the immune response to gp350 and emphasizes the need for more comprehensive antibody studies. Here, we identified three human-derived anti-gp350 monoclonal antibodies from a nonimmune human scFv library. Of these, the S54 antibody exhibited a potent neutralizing activity against virus infection of Raji B cells. Using cryo-EM, we resolved the structure of the S54-gp350 complex, revealing that the S54 epitope substantially overlaps with the CR2 recognition site. Our findings elucidate the molecular mechanism by which anti-gp350 antibodies block EBV infection of B cells in vitro, providing valuable insights for antibody-based therapy and vaccine development.
Keywords: Epstein-Barr virus; glycoproteins 350; human neutralizing antibody; neutralizing epitope; nonimmune human scFv library.
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