tetano
Editor, Senior Moderator
Published online before print October 1, 2012, doi: 10.1073/pnas.1212371109 PNAS October 1, 2012
Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity
Peter S. Leea,
Reiko Yoshidab,
Damian C. Ekierta,1,
Naoki Sakaic,
Yasuhiko Suzukib,
Ayato Takadab,2, and
Ian A. Wilsona,2
+ Author Affiliations
aDepartment of Molecular Biology and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
bDivision of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan; and
cInstitute of Biochemistry, Center for Structural and Cell Biology in Medicine and German Center for Infection Research, University of L?beck, L?beck 23538, Germany
Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved August 31, 2012 (received for review July 18, 2012)
Abstract
Continual and rapid mutation of seasonal influenza viruses by antigenic drift necessitates the almost annual reformulation of flu vaccines, which may offer little protection if the match to the dominant circulating strain is poor. S139/1 is a cross-reactive antibody that neutralizes multiple HA strains and subtypes, including those from H1N1 and H3N2 viruses that currently infect humans. The crystal structure of the S139/1 Fab in complex with the HA from the A/Victoria/3/1975 (H3N2) virus reveals that the antibody targets highly conserved residues in the receptor binding site and contacts antigenic sites A, B, and D. Binding and plaque reduction assays show that the monovalent Fab alone can protect against H3 strains, but the enhanced avidity from binding of bivalent IgG increases the breadth of neutralization to additional strains from the H1, H2, H13, and H16 subtypes. Thus, antibodies making relatively low affinity Fab interactions with the receptor binding site can have significant antiviral activity when enhanced by avidity through bivalent interactions of the IgG, thereby extending the breadth of binding and neutralization to highly divergent influenza virus strains and subtypes.
http://intl.pnas.org/content/early/2012/09/28/1212371109.abstract
Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity
Peter S. Leea,
Reiko Yoshidab,
Damian C. Ekierta,1,
Naoki Sakaic,
Yasuhiko Suzukib,
Ayato Takadab,2, and
Ian A. Wilsona,2
+ Author Affiliations
aDepartment of Molecular Biology and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
bDivision of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan; and
cInstitute of Biochemistry, Center for Structural and Cell Biology in Medicine and German Center for Infection Research, University of L?beck, L?beck 23538, Germany
Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved August 31, 2012 (received for review July 18, 2012)
Abstract
Continual and rapid mutation of seasonal influenza viruses by antigenic drift necessitates the almost annual reformulation of flu vaccines, which may offer little protection if the match to the dominant circulating strain is poor. S139/1 is a cross-reactive antibody that neutralizes multiple HA strains and subtypes, including those from H1N1 and H3N2 viruses that currently infect humans. The crystal structure of the S139/1 Fab in complex with the HA from the A/Victoria/3/1975 (H3N2) virus reveals that the antibody targets highly conserved residues in the receptor binding site and contacts antigenic sites A, B, and D. Binding and plaque reduction assays show that the monovalent Fab alone can protect against H3 strains, but the enhanced avidity from binding of bivalent IgG increases the breadth of neutralization to additional strains from the H1, H2, H13, and H16 subtypes. Thus, antibodies making relatively low affinity Fab interactions with the receptor binding site can have significant antiviral activity when enhanced by avidity through bivalent interactions of the IgG, thereby extending the breadth of binding and neutralization to highly divergent influenza virus strains and subtypes.
http://intl.pnas.org/content/early/2012/09/28/1212371109.abstract