Genetic and structural insights into broad neutralization of hepatitis C virus by human V                         H                         1-69 antibodies

Netanel Tzarum; Erick Giang; Leopold Kong; Linling He; Jannick Prentoe; Elias Augestad; Yuanzi Hua; Shaun Castillo; Georg M. Lauer; Jens Bukh; Jiang Zhu; Ian A. Wilson; Mansun Law

doi:10.1126/sciadv.aav1882

Genetic and structural insights into broad neutralization of hepatitis C virus by human V _H 1-69 antibodies

Netanel Tzarum, Erick Giang, Leopold Kong, Linling He, Jannick Prentoe, Elias Augestad, Yuanzi Hua, Shaun Castillo, Georg M. Lauer, Jens Bukh, Jiang Zhu, Ian A. Wilson, Mansun Law^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

Abstract

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.

Original language	American English
Article number	eaav1882
Journal	Science advances
Volume	5
Issue number	1
DOIs	https://doi.org/10.1126/sciadv.aav1882
State	Published - 2019
Externally published	Yes

Bibliographical note

Funding 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).

Publisher Copyright:
Copyright © 2019 The Authors.

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Cite this

Tzarum, N., Giang, E., Kong, L., He, L., Prentoe, J., Augestad, E., Hua, Y., Castillo, S., Lauer, G. M., Bukh, J., Zhu, J., Wilson, I. A., & Law, M. (2019). Genetic and structural insights into broad neutralization of hepatitis C virus by human V _H 1-69 antibodies Science advances, 5(1), Article eaav1882. https://doi.org/10.1126/sciadv.aav1882

@article{d5f877a60326416fb089682251f5f401,

title = " Genetic and structural insights into broad neutralization of hepatitis C virus by human V H 1-69 antibodies ",

abstract = " 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.",

author = "Netanel Tzarum and Erick Giang and Leopold Kong and Linling He and Jannick Prentoe and Elias Augestad and Yuanzi Hua and Shaun Castillo and Lauer, {Georg M.} and Jens Bukh and Jiang Zhu and Wilson, {Ian A.} and Mansun Law",

note = "Funding 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). Publisher Copyright: Copyright {\textcopyright} 2019 The Authors.",

year = "2019",

doi = "10.1126/sciadv.aav1882",

language = "American English",

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journal = "Science advances",

issn = "2375-2548",

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Tzarum, N, Giang, E, Kong, L, He, L, Prentoe, J, Augestad, E, Hua, Y, Castillo, S, Lauer, GM, Bukh, J, Zhu, J, Wilson, IA & Law, M 2019, ' Genetic and structural insights into broad neutralization of hepatitis C virus by human V _H 1-69 antibodies ', Science advances, vol. 5, no. 1, eaav1882. https://doi.org/10.1126/sciadv.aav1882

Genetic and structural insights into broad neutralization of hepatitis C virus by human V _H 1-69 antibodies . / Tzarum, Netanel; Giang, Erick; Kong, Leopold et al.
In: Science advances, Vol. 5, No. 1, eaav1882, 2019.

Research output: Contribution to journal › Article › peer-review

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T1 - Genetic and structural insights into broad neutralization of hepatitis C virus by human V H 1-69 antibodies

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AU - Giang, Erick

AU - Kong, Leopold

AU - He, Linling

AU - Prentoe, Jannick

AU - Augestad, Elias

AU - Hua, Yuanzi

AU - Castillo, Shaun

AU - Lauer, Georg M.

AU - Bukh, Jens

AU - Zhu, Jiang

AU - Wilson, Ian A.

AU - Law, Mansun

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PY - 2019

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N2 - 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.

AB - 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.

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