Structural basis of the cross-reactivity of genetically related human anti-HIV-1 mAbs: implications for design of V3-based immunogens.
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.
Burke
Valicia
V
Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA.
Williams
Constance
C
Sukumaran
Madhav
M
Kim
Seung-Sup
SS
Li
Huiguang
H
Wang
Xiao-Hong
XH
Gorny
Miroslaw K
MK
Zolla-Pazner
Susan
S
Kong
Xiang-Peng
XP
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
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