Genetic and structural insights into broad neutralization of hepatitis C virus by human VH1-69 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_H1-69 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

37 Citations (Scopus)

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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_H1-69. 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_H1-69 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_H1-69 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	English
Article number	eaav1882
Journal	Science Advances
Volume	5
Issue number	1
Number of pages	12
ISSN	2375-2548
DOIs	https://doi.org/10.1126/sciadv.aav1882
Publication status	Published - 2019

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Genetic and structural insights into broad neutralization of hepatitis C virus by human VH1-69 antibodiesFinal published version, 5.68 MBLicence: CC BY-NC

Cite this

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title = "Genetic and structural insights into broad neutralization of hepatitis C virus by human VH1-69 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 VH1-69. 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 VH1-69 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 VH1-69 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",

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doi = "10.1126/sciadv.aav1882",

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T1 - Genetic and structural insights into broad neutralization of hepatitis C virus by human VH1-69 antibodies

AU - Tzarum, Netanel

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

PY - 2019

Y1 - 2019

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 VH1-69. 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 VH1-69 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 VH1-69 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 VH1-69. 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 VH1-69 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 VH1-69 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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