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Journal of Virology, June 2008, p. 6067-6072, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.00252-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Point Mutation Leading to Hepatitis C Virus Escape from Neutralization by a Monoclonal Antibody to a Conserved Conformational Epitope

Zhen-Yong Keck,¹ Oakley Olson,¹ Meital Gal-Tanamy,² Jinming Xia,¹ Arvind H. Patel,³ Marlène Dreux,⁴ Francois-Loïc Cosset,⁴ Stanley M. Lemon,² and Steven K. H. Foung^1*

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305,¹ Center for Hepatitis Research, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555,² MRC Virology Unit, Institute of Virology, University of Glasgow, Church Street, Glasgow G11 5JR, United Kingdom,³ Université de Lyon 1, INSERM, U758, Human Virology Department, Ecole Normale Supérieure de Lyon, and Université Lyon 1, F-69007 Lyon, France⁴

Received 4 February 2008/ Accepted 26 March 2008

A challenge in hepatitis C virus (HCV) vaccine development is defining conserved protective epitopes. A cluster of these epitopes comprises an immunodominant domain on the E2 glycoprotein, designated domain B. CBH-2 is a neutralizing human monoclonal antibody to a domain B epitope that is highly conserved. Alanine scanning demonstrated that the epitope involves residues G523, G530, and D535 that are also contact residues for E2 binding to CD81, a coreceptor required for virus entry into cells. However, another residue, located at position 431 and thus at a considerable distance in the linear sequence of E2, also contributes to the CBH-2 epitope. A single amino acid substitution at this residue results in escape from CBH-2-mediated neutralization in a genotype 1a virus. These results highlight the challenges inherent in developing HCV vaccines and show that an effective vaccine must induce antibodies to both conserved and more invariant epitopes to minimize virus escape.

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* Corresponding author. Mailing address: Stanford Medical School Blood Center, 3373 Hillview Avenue, Palo Alto, CA 94304. Phone: (650) 723-6481. Fax: (650) 725-6610. E-mail: sfoung{at}stanford.edu

Published ahead of print on 2 April 2008.

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Journal of Virology, June 2008, p. 6067-6072, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.00252-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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