Signatures of VH1-69-derived hepatitis C virus neutralizing antibody precursors defined by binding to envelope glycoproteins

Abstract

Abstract An effective preventive vaccine for hepatitis C virus (HCV) remains a major unmet need. Antigenic region 3 (AR3) on the E1E2 envelope glycoprotein complex overlaps with the CD81 receptor binding site and represents an important epitope for vaccine design aimed at inducing broadly neutralizing antibodies (bNAbs). Most AR3 bNAbs utilize the VH1-69 gene and share structural features that define the AR3C-class of HCV bNAbs. In this work, we identified E1E2 glycoprotein trimers that bind to the inferred VH1-69 germline precursors of AR3C-class bNAbs, providing candidates for AR3C-class germline-targeting approaches. When presented on nanoparticles these recombinant E1E2 glycoproteins efficiently activated B cells expressing inferred germline AR3C-class bNAb precursors as B cell receptors. Furthermore, we identified critical signatures in two subclasses of the AR3C-class bNAbs that will allow refined protein design. These results provide a framework for germline-targeting vaccine design strategies against HCV.