Rhinovirus-Antibody Structures. Thomas J. Smith*, Elaine S. Chase, Timothy J. Schmidt, Norman H. Olson, Timothy S. Baker, Department of Biological Sciences, Purdue University, West Lafayette, IN 47907

The three-dimensional structure of intact human rhinovirus 14 (HRV14) complexed with Fab fragments (Fab17-IA) from a strongly neutralizing antibody that binds bivalently to the virion has been determined to 4.0 Å resolution using both X-ray crystallography and cryo-electron microscopy. In contradiction to the most commonly held model of antibody-mediated neutralization, this strongly neutralizing antibody does not induce conformational changes in the capsid. Instead, the antibody undergoes a large conformational change in the paratope to accommodate the epitope. Unlike any previously described antibody-antigen structure, the conserved framework region makes extensive contact with the viral surface. In addition, we have sequenced another antibody (Fab12) and have determined the cryo-EM structure of the Fab12/HRV14 complex. This antibody is most likely from the same progenitor B cell as Fab17 and differs in only a few amino acids and binds in an identical orientation as Fab17. Three of these differences lie at and near the framework/canyon interface. This suggests that framework residues may also be involved in the positive selection process subsequent to somatic hypermutations. Fab17 antibody penetrates the deep canyon to which the receptor binds. Since such a deep recess on the viral surface is accessible to antibody recognition, it seems unlikely that evasion of immune recognition drives the evolution of viral quaternary structure. Instead, the shape and position of the receptor binding region on a virus is probably more related to receptor binding and subsequent uncoating events than for concealment from the immune system. Finally, we determined the atomic structure of another Fab (Fab1) that binds to the same antigenic site but with a different orientation according to the cryo-EM image reconstruction. In spite of a very different binding orientation and CDR structure to Fab17, charge interactions at the paratope/epitope interface are highly conserved.