title: A point mutation leading to hepatitis C virus escape from neutralization by a monoclonal antibody to a conserved conformational epitope.
abstract: 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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Zhen-Yong
authors.initials: ZY
authors.lastname: Keck
authors.forename: Oakley
authors.initials: O
authors.lastname: Olson
authors.forename: Meital
authors.initials: M
authors.lastname: Gal-Tanamy
authors.forename: Jinming
authors.initials: J
authors.lastname: Xia
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.forename: Marlène
authors.initials: M
authors.lastname: Dreux
authors.forename: Francois-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.forename: Steven K H
authors.initials: SK
authors.lastname: Foung
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D000939:Epitopes / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000276:immunology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D017354:Point Mutation; D011487:Protein Conformation
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D018937:Hepatitis C Antibodies