Search

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with B cell lymphomas. EBV glycoprotein 42 (gp42) binds HLA class II and activates membrane fusion with B cells. We isolated gp42-specific monoclonal antibodies (mAbs), A10 and 4C12, which use distinct mechanisms to neutralize virus infection. mAb A10 was more potent than the only known neutralizing gp42 mAb, F-2-1, in neutralizing EBV infection and blocking binding to HLA class II. mAb 4C12 was similar to mAb A10 in inhibiting glycoprotein-mediated B cell fusion but did not block receptor binding, and it was less effective in neutralizing infection. Crystallographic structures of gH/gL/gp42/A10 and gp42/4C12 complexes revealed two distinct sites of vulnerability on gp42 for receptor binding and B cell fusion. Passive transfer of mAb A10 into humanized mice conferred nearly 100% protection from viremia and EBV lymphomas after EBV challenge. These findings identify vulnerable sites on EBV that may facilitate therapeutics and vaccines. [Display omitted] • Isolated mAbs to EBV gp42, which is required for the fusion of the virus to B cells • gp42 mAbs A10 and 4C12 use different mechanisms to inhibit EBV fusion to B cells • Two distinct sites were identified on gp42 for receptor binding and for fusion to B cells • gp42 mAb A10 prevented viremia and EBV lymphoma in humanized mice challenged with virus EBV glycoprotein gp42 is essential for B cell entry, and identifying sites of vulnerability is important for rational vaccine design. Bu et al. isolated two gp42 mAbs that neutralize EBV infection and block fusion with B cells by distinct mechanisms, defining unique sites of vulnerability. Passive transfer of one mAb prevented viremia and EBV lymphoma in EBV-challenged humanized mice. [ABSTRACT FROM AUTHOR]