title: Epitope-specific human influenza antibody repertoires diversify by B cell intraclonal sequence divergence and interclonal convergence.
abstract: We generated from a single blood sample five independent human mAbs that recognized the Sa antigenic site on the head of influenza hemagglutinin and exhibited inhibitory activity against a broad panel of H1N1 strains. All five Abs used the V(H)3-7 and J(H)6 gene segments, but at least four independent clones were identified by junctional analysis. High-throughput sequence analysis of circulating B cells revealed that each of the independent clones were members of complex phylogenetic lineages that had diversified widely using a pattern of progressive diversification through somatic mutation. Unexpectedly, B cells encoding multiple diverging lineages of these clones, including many containing very few mutations in the Ab genes, persisted in the circulation. Conversely, we noted frequent instances of amino acid sequence convergence in the Ag combining sites exhibited by members of independent clones, suggesting a strong selection for optimal binding sites. We suggest that maintenance in circulation of a wide diversity of somatic variants of dominant clones may facilitate recognition of drift variant virus epitopes that occur in rapidly mutating virus Ags, such as influenza hemagglutinin. In fact, these Ab clones recognize an epitope that acquired three glycosylation sites mediating escape from previously isolated human Abs.
authors: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Jens C
authors: JC
authors: Krause
authors: Tshidi
authors: T
authors: Tsibane
authors: Terrence M
authors: TM
authors: Tumpey
authors: Chelsey J
authors: CJ
authors: Huffman
authors: Bryan S
authors: BS
authors: Briney
authors: Scott A
authors: SA
authors: Smith
authors: Christopher F
authors: CF
authors: Basler
authors: James E
authors: JE
authors: Crowe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D000918:Antibody Specificity / Q000235:genetics / Q000276:immunology*; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019070:Cell Lineage; D002999:Clone Cells; D018985:Epitopes, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D005803:Genes, Immunoglobulin; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000911:Antibodies, Monoclonal; D000956:Antigens, Viral; D018985:Epitopes, B-Lymphocyte; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C483468:hemagglutinin, human influenza A virus