Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with hepatitis C virus envelope glycoproteins

Human IGHV1-69 -encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36 , is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here we studied the genetic, structural and functional properties of VH1.36 -encoded bnAbs generated by vaccination, in comparison to IGHV1-69 -encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36 -derived B cells in immunized animals. Most E2-specific, VH1.36 -encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36 -encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications to vaccination in humans. The human IGHV1-69 gene is preferentially utilized in broadly neutralizing antibody (bnAb) responses against HCV infection. Chen et al. discovered that HCV Env immunization of macaques elicited analogous VH1.36 bnAbs on the functional and molecular level. Functional convergence of a corresponding germline-encoded bnAb response within primates has implications for HCV rational vaccine design and testing.