Structure. 2009 Nov 11; 17(11):1538-46.

PubMed ID: 19913488

Structural basis of the cross-reactivity of genetically related human anti-HIV-1 mAbs: Implications for design of V3-based immunogens

Burke V, Williams C, Sukumaran M, Kim SS, Li H, Wang XH, Gorny MK, Zolla-Pazner S, Kong XP

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.