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Proc Natl Acad Sci USA. Cross-neutralizing human anti-poliovirus antibodies bind the recognition site for cellular receptor
[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
Cross-neutralizing human anti-poliovirus antibodies bind the recognition site for cellular receptor
Zhaochun Chen<SUP>a</SUP>,<SUP>1</SUP>, Elizabeth R. Fischer<SUP>b</SUP>,<SUP>1</SUP>, Diana Kouiavskaia<SUP>c</SUP>,<SUP>1</SUP>, Bryan T. Hansen<SUP>b</SUP>, Steven J. Ludtke<SUP>d</SUP>, Bella Bidzhieva<SUP>c</SUP>, Michelle Makiya<SUP>a</SUP>, Liane Agulto<SUP>a</SUP>, Robert H. Purcell<SUP>a</SUP>,<SUP>2</SUP>, and Konstantin Chumakov<SUP>c</SUP>,<SUP>2</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; <SUP>b</SUP>Electron Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840; <SUP>c</SUP>Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852; and <SUP>d</SUP>National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030
Contributed by Robert H. Purcell, October 26, 2013 (sent for review June 25, 2013)
Significance
This study demonstrated that cross-neutralizing anti-poliovirus antibodies bind the site on poliovirus capsid surface that significantly overlaps the binding site of the cellular receptor. A second antibody with similar specificity was isolated by sequential phage display panning, suggesting that cross-reactive anti-poliovirus antibodies may be more prevalent in primates than previously recognized. Binding to the receptor recognition site explains unusually broad specificity of the antibodies. The antibodies bind type 1 and type 2 polioviruses at a slightly different angle, indicating that molecular details of virus?antibody interaction are different and suggesting that further screening or engineering may produce an antibody neutralizing all three serotypes of poliovirus. These results may be used for developing new antiviral strategies for the polio eradication campaign.
Abstract
Most structural information about poliovirus interaction with neutralizing antibodies was obtained in the 1980s in studies of mouse monoclonal antibodies. Recently we have isolated a number of human/chimpanzee anti-poliovirus antibodies and demonstrated that one of them, MAb A12, could neutralize polioviruses of both serotypes 1 and 2. This communication presents data on isolation of an additional cross-neutralizing antibody (F12) and identification of a previously unknown epitope on the surface of poliovirus virions. Epitope mapping was performed by sequencing of antibody-resistant mutants and by cryo-EM of complexes of virions with Fab fragments. The results have demonstrated that both cross-neutralizing antibodies bind the site located at the bottom of the canyon surrounding the fivefold axis of symmetry that was previously shown to interact with cellular poliovirus receptor CD155. However, the same antibody binds to serotypes 1 and 2 through different specific interactions. It was also shown to interact with type 3 poliovirus, albeit with about 10-fold lower affinity, insufficient for effective neutralization. Antibody interaction with the binding site of the cellular receptor may explain its broad reactivity and suggest that further screening or antibody engineering could lead to a universal antibody capable of neutralizing all three serotypes of poliovirus.
phage display - passive immunization - antiviral therapy - broadly reactive antibodies
Footnotes
<SUP>1</SUP>Z.C., E.R.F., and D.K. contributed equally to this work.
<SUP>2</SUP>To whom correspondence may be addressed. E-mail: robert.purcell@nih.gov or konstantin.chumakov@fda.hhs.gov.
Author contributions: Z.C., E.R.F., R.H.P., and K.C. designed research; Z.C., E.R.F., D.K., B.T.H., S.J.L., B.B., M.M., L.A., and K.C. performed research; Z.C., E.R.F., D.K., B.T.H., S.J.L., B.B., M.M., L.A., R.H.P., and K.C. analyzed data; and Z.C., R.H.P., and K.C. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. KF410673?KF410676).
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Cross-neutralizing human anti-poliovirus antibodies bind the recognition site for cellular receptor
Zhaochun Chen<SUP>a</SUP>,<SUP>1</SUP>, Elizabeth R. Fischer<SUP>b</SUP>,<SUP>1</SUP>, Diana Kouiavskaia<SUP>c</SUP>,<SUP>1</SUP>, Bryan T. Hansen<SUP>b</SUP>, Steven J. Ludtke<SUP>d</SUP>, Bella Bidzhieva<SUP>c</SUP>, Michelle Makiya<SUP>a</SUP>, Liane Agulto<SUP>a</SUP>, Robert H. Purcell<SUP>a</SUP>,<SUP>2</SUP>, and Konstantin Chumakov<SUP>c</SUP>,<SUP>2</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; <SUP>b</SUP>Electron Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840; <SUP>c</SUP>Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852; and <SUP>d</SUP>National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030
Contributed by Robert H. Purcell, October 26, 2013 (sent for review June 25, 2013)
Significance
This study demonstrated that cross-neutralizing anti-poliovirus antibodies bind the site on poliovirus capsid surface that significantly overlaps the binding site of the cellular receptor. A second antibody with similar specificity was isolated by sequential phage display panning, suggesting that cross-reactive anti-poliovirus antibodies may be more prevalent in primates than previously recognized. Binding to the receptor recognition site explains unusually broad specificity of the antibodies. The antibodies bind type 1 and type 2 polioviruses at a slightly different angle, indicating that molecular details of virus?antibody interaction are different and suggesting that further screening or engineering may produce an antibody neutralizing all three serotypes of poliovirus. These results may be used for developing new antiviral strategies for the polio eradication campaign.
Abstract
Most structural information about poliovirus interaction with neutralizing antibodies was obtained in the 1980s in studies of mouse monoclonal antibodies. Recently we have isolated a number of human/chimpanzee anti-poliovirus antibodies and demonstrated that one of them, MAb A12, could neutralize polioviruses of both serotypes 1 and 2. This communication presents data on isolation of an additional cross-neutralizing antibody (F12) and identification of a previously unknown epitope on the surface of poliovirus virions. Epitope mapping was performed by sequencing of antibody-resistant mutants and by cryo-EM of complexes of virions with Fab fragments. The results have demonstrated that both cross-neutralizing antibodies bind the site located at the bottom of the canyon surrounding the fivefold axis of symmetry that was previously shown to interact with cellular poliovirus receptor CD155. However, the same antibody binds to serotypes 1 and 2 through different specific interactions. It was also shown to interact with type 3 poliovirus, albeit with about 10-fold lower affinity, insufficient for effective neutralization. Antibody interaction with the binding site of the cellular receptor may explain its broad reactivity and suggest that further screening or antibody engineering could lead to a universal antibody capable of neutralizing all three serotypes of poliovirus.
phage display - passive immunization - antiviral therapy - broadly reactive antibodies
Footnotes
<SUP>1</SUP>Z.C., E.R.F., and D.K. contributed equally to this work.
<SUP>2</SUP>To whom correspondence may be addressed. E-mail: robert.purcell@nih.gov or konstantin.chumakov@fda.hhs.gov.
Author contributions: Z.C., E.R.F., R.H.P., and K.C. designed research; Z.C., E.R.F., D.K., B.T.H., S.J.L., B.B., M.M., L.A., and K.C. performed research; Z.C., E.R.F., D.K., B.T.H., S.J.L., B.B., M.M., L.A., R.H.P., and K.C. analyzed data; and Z.C., R.H.P., and K.C. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. KF410673?KF410676).
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