Identification of an immunodominant antigenic site involving the capsid protein VP3 of hepatitis A virus.
Hepatitis A virus, an hepatotropic picornavirus, is a common cause of acute hepatitis in man for which there is no available vaccine. Competitive binding studies carried out in solid phase suggest that neutralizing monoclonal antibodies to hepatitis A virus recognize a limited number of epitopes on the capsid surface, although the polypeptide locations of these epitopes are not well defined. Neutralization-escape mutants, selected for resistance to monoclonal antibodies, demonstrate broad cross-resistance to other monoclonal antibodies. Sequencing of virion RNA from several of these mutants demonstrated that replacement of aspartic acid residue 70 of capsid protein VP3 (residue 3070) with histidine or alanine confers resistance to neutralization by monoclonal antibody K2-4F2 and prevents binding of this antibody and other antibodies with similar solid-phase competition profiles. These results indicate that residue 3070 contributes to an immunodominant antigenic site. Mutation at residue 102 of VP1 (residue 1102) confers partial resistance against antibody B5-B3 and several other antibodies but does not prevent antibody attachment. Both VP3 and VP1 sites align closely in the linear peptide sequences with sites of neutralization-escape mutations in poliovirus and human rhinovirus, suggesting conservation of structure among these diverse picornaviruses. However, because partial neutralization resistance to several monoclonal antibodies (2D2, 3E1, and B5-B3) was associated with mutation at either residue 3070 or residue 1102, these sites appear more closely related functionally in hepatitis A virus than in these other picornaviruses.
Ping
L H
LH
Department of Medicine, University of North Carolina, Chapel Hill 27599.
Jansen
R W
RW
Stapleton
J T
JT
Cohen
J I
JI
Lemon
S M
SM
D000409:Alanine; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D001667:Binding, Competitive; D002213:Capsid / Q000276:immunology*; D003429:Cross Reactions; D000939:Epitopes / Q000032:analysis*; D006507:Hepatovirus / Q000235:genetics / Q000276:immunology*; D006639:Histidine; D008969:Molecular Sequence Data; D009154:Mutation; D012367:RNA, Viral / Q000032:analysis; D014771:Virion / Q000032:analysis
D000911:Antibodies, Monoclonal; D000939:Epitopes; D012367:RNA, Viral; D006639:Histidine; D000409:Alanine