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. 2024 Mar 12;57(3):559-573.e6.
doi: 10.1016/j.immuni.2024.02.008.

Epstein-Barr virus gp42 antibodies reveal sites of vulnerability for receptor binding and fusion to B cells

Wei Bu  1 , Ashish Kumar  2 , Nathan L Board  1 , JungHyun Kim  1 , Kennichi Dowdell  1 , Shu Zhang  1 , Yona Lei  1 , Anna Hostal  1 , Tammy Krogmann  1 , Yanmei Wang  3 , Stefania Pittaluga  4 , Joseph Marcotrigiano  5 , Jeffrey I Cohen  6
Affiliations

Epstein-Barr virus gp42 antibodies reveal sites of vulnerability for receptor binding and fusion to B cells

Wei Bu et al. Immunity. .

Abstract

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.

Keywords: Epstein-Barr virus; HLA class II; fusion machinery; glycoprotein 42; herpesvirus; monoclonal antibody therapy.

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Conflict of interest statement

Declaration of interests W.B., N.L.B., K.D., and J.I.C. are named as inventors on a patent application describing mAbs A10 and 4C12 in this paper, which has been filed by the National Institutes of Health.

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