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Title: Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1

Abstract

Hepatitis C virus (HCV) infects more than 2% of the global population and is a leading cause of liver cirrhosis, hepatocellular carcinoma, and end-stage liver diseases. Circulating HCV is genetically diverse, and therefore a broadly effective vaccine must target conserved T- and B-cell epitopes of the virus. Human mAb HCV1 has broad neutralizing activity against HCV isolates from at least four major genotypes and protects in the chimpanzee model from primary HCV challenge. The antibody targets a conserved antigenic site (residues 412-423) on the virus E2 envelope glycoprotein. Two crystal structures of HCV1 Fab in complex with an epitope peptide at 1.8-{angstrom} resolution reveal that the epitope is a {beta}-hairpin displaying a hydrophilic face and a hydrophobic face on opposing sides of the hairpin. The antibody predominantly interacts with E2 residues Leu{sup 413} and Trp{sup 420} on the hydrophobic face of the epitope, thus providing an explanation for how HCV isolates bearing mutations at Asn{sup 415} on the same binding face escape neutralization by this antibody. The results provide structural information for a neutralizing epitope on the HCV E2 glycoprotein and should help guide rational design of HCV immunogens to elicit similar broadly neutralizing antibodies through vaccination.

Authors:
; ; ; ; ; ;  [1]
  1. (Scripps)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERNIH
OSTI Identifier:
1046254
Resource Type:
Journal Article
Journal Name:
Proc. Natl. Acad. Sci. USA
Additional Journal Information:
Journal Volume: 109; Journal Issue: (24) ; 06, 2012; Journal ID: ISSN 0027-8424
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; ANTIBODIES; CARCINOMAS; CRYSTAL STRUCTURE; HEPATITIS; LIVER; LIVER CIRRHOSIS; VACCINES; VIRUSES

Citation Formats

Kong, Leopold, Giang, Erick, Robbins, Justin B., Stanfield, Robyn L., Burton, Dennis R., Wilson, Ian A., and Law, Mansun. Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1. United States: N. p., 2012. Web. doi:10.1073/pnas.1202924109.
Kong, Leopold, Giang, Erick, Robbins, Justin B., Stanfield, Robyn L., Burton, Dennis R., Wilson, Ian A., & Law, Mansun. Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1. United States. doi:10.1073/pnas.1202924109.
Kong, Leopold, Giang, Erick, Robbins, Justin B., Stanfield, Robyn L., Burton, Dennis R., Wilson, Ian A., and Law, Mansun. Mon . "Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1". United States. doi:10.1073/pnas.1202924109.
@article{osti_1046254,
title = {Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1},
author = {Kong, Leopold and Giang, Erick and Robbins, Justin B. and Stanfield, Robyn L. and Burton, Dennis R. and Wilson, Ian A. and Law, Mansun},
abstractNote = {Hepatitis C virus (HCV) infects more than 2% of the global population and is a leading cause of liver cirrhosis, hepatocellular carcinoma, and end-stage liver diseases. Circulating HCV is genetically diverse, and therefore a broadly effective vaccine must target conserved T- and B-cell epitopes of the virus. Human mAb HCV1 has broad neutralizing activity against HCV isolates from at least four major genotypes and protects in the chimpanzee model from primary HCV challenge. The antibody targets a conserved antigenic site (residues 412-423) on the virus E2 envelope glycoprotein. Two crystal structures of HCV1 Fab in complex with an epitope peptide at 1.8-{angstrom} resolution reveal that the epitope is a {beta}-hairpin displaying a hydrophilic face and a hydrophobic face on opposing sides of the hairpin. The antibody predominantly interacts with E2 residues Leu{sup 413} and Trp{sup 420} on the hydrophobic face of the epitope, thus providing an explanation for how HCV isolates bearing mutations at Asn{sup 415} on the same binding face escape neutralization by this antibody. The results provide structural information for a neutralizing epitope on the HCV E2 glycoprotein and should help guide rational design of HCV immunogens to elicit similar broadly neutralizing antibodies through vaccination.},
doi = {10.1073/pnas.1202924109},
journal = {Proc. Natl. Acad. Sci. USA},
issn = {0027-8424},
number = (24) ; 06, 2012,
volume = 109,
place = {United States},
year = {2012},
month = {10}
}