A point mutation leading to hepatitis C virus escape from neutralization by a monoclonal antibody to a conserved conformational epitope.
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.
Keck
Zhen-Yong
ZY
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Olson
Oakley
O
Gal-Tanamy
Meital
M
Xia
Jinming
J
Patel
Arvind H
AH
Dreux
Marlène
M
Cosset
Francois-Loïc
FL
Lemon
Stanley M
SM
Foung
Steven K H
SK
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
D000911:Antibodies, Monoclonal; D000939:Epitopes; D018937:Hepatitis C Antibodies