An effective vaccine to the antigenically diverse hepatitis C virus (HCV) must target conserved immune epitopes. Here, we investigate cross-neutralization of HCV genotypes by broadly neutralizing antibodies (bNAbs) encoded by the relatively abundant human gene family V H 1-69. We have deciphered the molecular requirements for cross-neutralization by this unique class of human antibodies from crystal structures of HCV E2 in complex with bNAbs. An unusually high binding affinity is found for germ line-reverted versions of V H 1-69 precursor antibodies, and neutralization breadth is acquired during affinity maturation. Deep sequencing analysis of an HCV-immune B cell repertoire further demonstrates the importance of the V H 1-69 gene family in the generation of HCV bNAbs. This study therefore provides critical insights into immune recognition of HCV with important implications for rational vaccine design.
Bibliographical noteFunding Information:
We thank R. Stanfield, X. Dai, and M. Elsliger for crystallographic and computational support; H. Tien in the Wilson lab for automated crystal screening; K. Cogburn, A. Honda, and K. Jackson for HCV donor sample analysis; and J. Ball for the UKN HCV constructs. This work was funded in part by NIH grants R01AI079031 (to M.L.), R01AI123365 and R01AI106005 (to M.L. and I.A.W.), U19AI123861 (to M.L. and J.Z.), U01AI131314 (to G.M.L.), and R01AI129698 (to J.Z.); the HIV Vaccine Research and Design (HIVRAD) program P01AI124337 (to J.Z.); the Danish Council for Independent Research DFF-4004-00598 (to J.B.); the Novo Nordisk Foundation NNF14OC001253 (to J.B.); and the Candys Foundation (to J.P., E.A., and J.B.). NBDS at TSRI was supported by the Clinical Translational Science Award (CTSA) grant UL1 TR001114. X-ray datasets were collected at the APS beamline 23ID-B (GM/CA CAT) and SSRL beamline 12-2. The use of the APS was supported by the U.S. Department of Energy (DOE), Basic Energy Sciences, Office of Science, under contract DE-AC02-06CH11357. The use of the SSRL Structural Molecular Biology Program was supported by the DOE Office of Biological and Environmental Research and by the NIH NIGMS (including P41GM103393) and the National Center for Research Resources (P41RR001209).
Copyright © 2019 The Authors.