Abstract
Structural studies of the hepatitis C virus (HCV) E2 glycoprotein in complex with broadly neutralizing antibodies (bNAbs) have been instrumental in mapping neutralizing epitopes and guiding the rational design of immunogens. However, robust structural classification of HCV bNAbs is lacking, complicating immunogen design. The majority of HCV bNAbs recognize the E2 front layer (FRLY) supersite. Here, we developed a roadmap for the structural classification of FRLY-specific bNAbs. We discovered three distinct structural classes, each utilizing a unique binding mode to engage the FRLY supersite. HCV strains with multiple FRLY polymorphisms had a profound impact on binding and neutralization of bNAbs from distinct FRLY classes. Our findings establish the FRLY as a major antigenic supersite targeted by three bNAb classes and underscore the intrinsic structural plasticity of V (H) 1-69 -encoded HCV bNAbs.