title: Structural basis of the cross-reactivity of genetically related human anti-HIV-1 mAbs: implications for design of V3-based immunogens.
abstract: Human monoclonal antibodies 447-52D and 537-10D, both coded by the VH3 gene and specific for the third variable region (V3) of the HIV-1 gp120, were found to share antigen-binding structural elements including an elongated CDR H3 forming main-chain interactions with the N terminus of the V3 crown. However, water-mediated hydrogen bonds and a unique cation-pi sandwich stacking allow 447-52D to be broadly reactive with V3 containing both the GPGR and GPGQ crown motifs, while the deeper binding pocket and a buried Glu in the binding site of 537-10D limit its reactivity to only V3 containing the GPGR motif. Our results suggest that the design of immunogens for anti-V3 antibodies should avoid the Arg at the V3 crown, as GPGR-containing epitopes appear to select for B cells making antibodies of narrower specificity than V3 that carry Gln at this position.
authors.affiliation: Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Valicia
authors.initials: V
authors.lastname: Burke
authors.forename: Constance
authors.initials: C
authors.lastname: Williams
authors.forename: Madhav
authors.initials: M
authors.lastname: Sukumaran
authors.forename: Seung-Sup
authors.initials: SS
authors.lastname: Kim
authors.forename: Huiguang
authors.initials: H
authors.lastname: Li
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wang
authors.forename: Miroslaw K
authors.initials: MK
authors.lastname: Gorny
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.forename: Xiang-Peng
authors.initials: XP
authors.lastname: Kong
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D003429:Cross Reactions; D003460:Crystallization; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014614:Vaccines, Synthetic / Q000737:chemistry* / Q000276:immunology; D014961:X-Ray Diffraction
chemical_list: D000911:Antibodies, Monoclonal; D017931:DNA Primers; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D007140:Immunoglobulin Fab Fragments; D010446:Peptide Fragments; D014614:Vaccines, Synthetic