title: Preferential selection of receptor-binding variants of influenza virus hemagglutinin by the neutralizing antibody repertoire of transgenic mice expressing a human immunoglobulin mu minigene.
abstract: An analysis was made of the neutralizing antibody repertoire, for influenza virus hemagglutinin (HA) of transgenic mice expressing a human immunoglobulin mu (IgH) minigene, by monoclonal antibody (MAb) selection and sequencing of the HA genes of X31 (H3N2 subtype) laboratory variants. Whereas previously reported laboratory variants, selected in ovo with high-affinity murine MAbs of the IgG class, differed from wild-type virus by a single amino acid residue change in one of the major antigenic sites, neutralizing MAbs from transgenic donors selected novel variant viruses with altered receptor-binding specificity and contained residue changes in both the receptor-binding pocket (HA1 225 or HA1 226) and an antigenic site (HA1 135, HA1 145, or HA1 158). Changes in receptor-binding specificities of the variant viruses were confirmed by their resistance to inhibition by horse serum glycoproteins and altered binding to neoglycoproteins. The residue changes in variant virus V-21.2 (HA1 135 G-->R, 225 G-->D) abrogated neutralization by each of the MAbs; nevertheless V-21.2 was recognized by its own selecting MAb in enzyme-linked immunosorbent assay and therefore qualified as an adsorptive mutant rather than an antigenic variant. We consider that a low-affinity neutralizing antibody response may preferentially select for receptor-binding variants of influenza virus HA.
authors.affiliation: National Institute for Medical Research, London, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Laeeq
authors.forename: C A
authors.initials: CA
authors.lastname: Smith
authors.forename: S D
authors.initials: SD
authors.lastname: Wagner
authors.forename: D B
authors.initials: DB
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology*; D000918:Antibody Specificity; D002642:Chick Embryo; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D014644:Genetic Variation; D006001:Glycoconjugates / Q000276:immunology; D006385:Hemagglutination Inhibition Tests; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000235:genetics / Q000276:immunology*; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D015394:Molecular Structure; D019158:N-Acetylneuraminic Acid / Q000276:immunology; D010641:Phenotype; D011991:Receptors, Virus / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D006001:Glycoconjugates; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007148:Immunoglobulin mu-Chains; D011991:Receptors, Virus; D019158:N-Acetylneuraminic Acid