Epstein-Barr virus gH/gL has multiple sites of vulnerability for virus neutralization and fusion inhibition

Immunity. 2022 Nov 8;55(11):2135-2148.e6. doi: 10.1016/j.immuni.2022.10.003. Epub 2022 Oct 27.

Abstract

Epstein-Barr virus (EBV) is nearly ubiquitous in adults. EBV causes infectious mononucleosis and is associated with B cell lymphomas, epithelial cell malignancies, and multiple sclerosis. The EBV gH/gL glycoprotein complex facilitates fusion of virus membrane with host cells and is a target of neutralizing antibodies. Here, we examined the sites of vulnerability for virus neutralization and fusion inhibition within EBV gH/gL. We developed a panel of human monoclonal antibodies (mAbs) that targeted five distinct antigenic sites on EBV gH/gL and prevented infection of epithelial and B cells. Structural analyses using X-ray crystallography and electron microscopy revealed multiple sites of vulnerability and defined the antigenic landscape of EBV gH/gL. One mAb provided near-complete protection against viremia and lymphoma in a humanized mouse EBV challenge model. Our findings provide structural and antigenic knowledge of the viral fusion machinery, yield a potential therapeutic antibody to prevent EBV disease, and emphasize gH/gL as a target for herpesvirus vaccines and therapeutics.

Keywords: Epstein-Barr virus; antibody therapeutics; fusion machinery; gH/gL; glycoprotein H; herpesvirus; monoclonal antibody; sites of vulnerability; vaccine.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Epstein-Barr Virus Infections*
  • Herpesvirus 4, Human*
  • Humans
  • Membrane Glycoproteins
  • Mice
  • Viral Envelope Proteins

Substances

  • Viral Envelope Proteins
  • Membrane Glycoproteins