Protective anti-gB neutralizing antibodies targeting two vulnerable sites for EBV-cell membrane fusion

Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2202371119. doi: 10.1073/pnas.2202371119. Epub 2022 Aug 2.


Epstein-Barr virus (EBV) infects more than 90% of the world's adult population and accounts for a significant cancer burden of epithelial and B cell origins. Glycoprotein B (gB) is the primary fusogen essential for EBV entry into host cells. Here, we isolated two EBV gB-specific neutralizing antibodies, 3A3 and 3A5; both effectively neutralized the dual-tropic EBV infection of B and epithelial cells. In humanized mice, both antibodies showed effective protection from EBV-induced lymphoproliferative disorders. Cryoelectron microscopy analyses identified that 3A3 and 3A5 bind to nonoverlapping sites on domains D-II and D-IV, respectively. Structure-based mutagenesis revealed that 3A3 and 3A5 inhibit membrane fusion through different mechanisms involving the interference with gB-cell interaction and gB activation. Importantly, the 3A3 and 3A5 epitopes are major targets of protective gB-specific neutralizing antibodies elicited by natural EBV infection in humans, providing potential targets for antiviral therapies and vaccines.

Keywords: Epstein–Barr virus; glycoprotein B; lymphoproliferative disorder; neutralizing antibody; viral membrane fusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing* / chemistry
  • Antibodies, Neutralizing* / isolation & purification
  • Antibodies, Neutralizing* / therapeutic use
  • Antibodies, Viral* / chemistry
  • Antibodies, Viral* / isolation & purification
  • Antibodies, Viral* / therapeutic use
  • Cryoelectron Microscopy
  • Epstein-Barr Virus Infections* / prevention & control
  • Epstein-Barr Virus Infections* / therapy
  • Herpesvirus 4, Human* / immunology
  • Humans
  • Membrane Fusion
  • Mice
  • Viral Proteins* / immunology


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epstein-Barr virus glycoprotein gp110
  • Viral Proteins