biostudies-literatureChen WHCCR NIH HHSIntramural NIH HHSNCRR NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHS2135-2148.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC9815946biostudies-literatureUnknown55(11)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.ImmunityEpstein-Barr virus gH/gL has multiple sites of vulnerability for virus neutralization and fusion inhibition.PMC9815946HHSN261200800001ES10 RR028976ZIA AI000978HHSN261200800001CP30 GM124165S10 OD027000S10 OD021527Peterson CETsybovsky YHostal AJoyce MGBoard NLYang ESCohen JIPegu AFisher BEAndrews SFChoe MKim JKanekiyo MPittaluga SMcDermott ABBu WMascola JRGillespie RAChen WHWang YStephens TfalseEpstein-Barr virus gH/gL has multiple sites of vulnerability for virus neutralization and fusion inhibition.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.2022-01-01T00:00:00Z2022 Nov2026-05-28T02:06:28.225Z2025-04-19T20:16:02.724ZS-EPMC98159463630678410.1016/j.immuni.2022.10.003