ANTIBODY-MEDIATED NEUTRALIZATION OF HUMAN-RHINOVIRUS-14 EXPLORED BY MEANS OF CRYOELECTRON MICROSCOPY AND X-RAY CRYSTALLOGRAPHY OF VIRUS-FABCOMPLEXES

The structures of three different human rhinovirus 14 (HRV14)-Fab comp lexes have been explored with X-ray crystallography and cryoelectron m icroscopy procedures.;UI three antibodies bind to the NIm-IA site of H RV14, which is the beta-B-beta-C loop of the viral capsid protein VP1. Two antibodies, Fab17-IA (Fab17) and Fab12-IA (Fab12), bind bivalentl y to the virion surface and strongly neutralize viral infectivity wher eas Fab1-IA (Fab1) strongly aggregates and weakly neutralizes virions. The structures of the two classes of virion-Fab complexes clearly dif fer and correlate with observed binding neutralization differences. Fa b17 and Fab12 bind in essentially identical, tangential orientations t o the viral surface, which favors bidentate binding ol er icosahedral twofold axes. Fab1 binds in a more radial orientation that makes biden tate binding unlikely. Although the binding orientations of these two antibody groups differ, nearly identical charge interactions occur at all paratope-epitope interfaces, Nucleotide sequence comparisons sugge st that Fab17 and Fab12 are from the same progenitor cell and that som e of the differing residues contact the south wall of the receptor bin ding canyon that encircles each of the icosahedral fivefold vertices, All of the antibodies contact a significant proportion of the canyon r egion and directly overlap much of the receptor (intercellular adhesio n molecule 1 [ICAM-1]) binding site, Fab1, however, does not contact t he same residues on the upper south wall (the side facing away from fi vefold axes) at the receptor binding region as do Fab12 and Fab17. All three antibodies cause some stabilization of HRV14 against pH-induced inactivation; thus, stabilization may be mediated by invariant contac ts with the canyon.