Human herpesvirus 6B glycoprotein B postfusion structure, vulnerability mapping, and receptor recognition

Abstract

Human herpesvirus 6B (HHV-6B), a β-herpesvirus that significantly threatens immunocompromised individuals, currently lacks targeted antiviral therapies or vaccines. Glycoprotein B (gB), the primary mediator of membrane fusion during viral entry, is a key target for neutralizing antibody (nAb) and vaccine development. In this study, we determined a 2.8 Å cryo-EM structure of the HHV-6B gB ectodomain in its postfusion conformation, unveiling unique N-terminal features and resolving the furin site for the first time in herpesviruses. Comparative analyses highlighted similarities between HHV-6B gB and gB from human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), mapping conserved residues across herpesviruses. Cross-binding assays indicated minimal cross-epitope recognition by nAbs from other herpesviruses, while several potential vulnerable sites on HHV-6B gB were identified. These insights advance our understanding of HHV-6B infection mechanisms and support future development of antibodies or vaccines targeting gB.