HIV-1 gp140 epitope recognition is influenced by immunoglobulin DH gene segment sequence.

Journal Article (Journal Article)

Complementarity Determining Region 3 of the immunoglobulin (Ig) H chain (CDR-H3) lies at the center of the antigen-binding site where it often plays a decisive role in antigen recognition and binding. Amino acids encoded by the diversity (DH) gene segment are the main component of CDR-H3. Each DH has the potential to rearrange into one of six DH reading frames (RFs), each of which exhibits a characteristic amino acid hydrophobicity signature that has been conserved among jawed vertebrates by natural selection. A preference for use of RF1 promotes the incorporation of tyrosine into CDR-H3 while suppressing the inclusion of hydrophobic or charged amino acids. To test the hypothesis that these evolutionary constraints on DH sequence influence epitope recognition, we used mice with a single DH that has been altered to preferentially use RF2 or inverted RF1. B cells in these mice produce a CDR-H3 repertoire that is enriched for valine or arginine in place of tyrosine. We serially immunized this panel of mice with gp140 from HIV-1 JR-FL isolate and then used enzyme-linked immunosorbent assay (ELISA) or peptide microarray to assess antibody binding to key or overlapping HIV-1 envelope epitopes. By ELISA, serum reactivity to key epitopes varied by DH sequence. By microarray, sera with Ig CDR-H3s enriched for arginine bound to linear peptides with a greater range of hydrophobicity but had a lower intensity of binding than sera containing Ig CDR-H3s enriched for tyrosine or valine. We conclude that patterns of epitope recognition and binding can be heavily influenced by DH germ line sequence. This may help explain why antibodies in HIV-infected patients must undergo extensive somatic mutation in order to bind to specific viral epitopes and achieve neutralization.

Full Text

Duke Authors

Cited Authors

  • Wang, Y; Kapoor, P; Parks, R; Silva-Sanchez, A; Alam, SM; Verkoczy, L; Liao, H-X; Zhuang, Y; Burrows, P; Levinson, M; Elgavish, A; Cui, X; Haynes, BF; Schroeder, H

Published Date

  • February 2016

Published In

Volume / Issue

  • 68 / 2

Start / End Page

  • 145 - 155

PubMed ID

  • 26687685

Pubmed Central ID

  • PMC4729650

Electronic International Standard Serial Number (EISSN)

  • 1432-1211

Digital Object Identifier (DOI)

  • 10.1007/s00251-015-0890-x


  • eng

Conference Location

  • United States