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      Structural and Functional Bases for Broad-Spectrum Neutralization of Avian and Human Influenza A Viruses

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          Abstract

          Influenza virus remains a constant public health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Monoclonal antibody (mAb)-based immunotherapy is a promising strategy for disease control. Here we use a human Ab phage display library and H5 hemagglutinin (HA) ectodomain to select ten neutralizing mAbs (nAbs) with a remarkably broad range among Group 1 influenza viruses, including the H5N1 “bird flu” and the H1N1 “Spanish flu” strains. Notably, nine of the Abs utilize the same germline gene, VH1-69. The crystal structure of one mAb bound to H5N1 HA reveals that only the heavy chain inserts into a highly conserved pocket in the HA stem, inhibiting the conformational changes required for membrane fusion. Our studies indicate that nAbs targeting this pocket could provide broad protection against both seasonal and pandemic influenza A infections.

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          Most cited references 71

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          Coot: model-building tools for molecular graphics.

          CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as 'Coot'.
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            Refinement of macromolecular structures by the maximum-likelihood method.

            This paper reviews the mathematical basis of maximum likelihood. The likelihood function for macromolecular structures is extended to include prior phase information and experimental standard uncertainties. The assumption that different parts of a structure might have different errors is considered. A method for estimating sigma(A) using 'free' reflections is described and its effects analysed. The derived equations have been implemented in the program REFMAC. This has been tested on several proteins at different stages of refinement (bacterial alpha-amylase, cytochrome c', cross-linked insulin and oligopeptide binding protein). The results derived using the maximum-likelihood residual are consistently better than those obtained from least-squares refinement.
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              [20] Processing of X-ray diffraction data collected in oscillation mode.

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                Author and article information

                Affiliations
                [1 ]Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 44 Binney St. JFB 826, Boston, MA 02115, USA
                [2 ]Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
                [3 ]Influenza Division, Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, 1600 Clifton Road - Mail Stop G-16 Atlanta, GA 30333, USA
                Author notes
                [*]

                Contributed equally to the study.

                Author Contributions DFCI team. J.S. and A.M. constructed H5-TH04 HA. J.S. and D.A. performed phage display Ab library selections and screening for Abs by ELISA, FACS and pseudo-viruses neutralization assays. J.S., M.A. and T.H. carried out epitope mapping using mutagenesis and FACS analysis. J.S., D.A. and M.A. purified antibodies. J.S. and A.Y. analyzed kinetics of Ab binding with HA protein. J.S performed HA subtype cross-binding and neutralization assay, pseudo-virus binding and fusion inhibition assay. J.S. and W.A.M designed the study, analyzed data, and wrote sections about these studies.

                BIMR team R.C.L supervised all of the work done at BIMR. G.W. and G.C. cloned and expressed recombinant H5 for antibody panning and crystallization. W.C.H expressed F10 scFv and crystallized the F10-HA0 complex. W.C.H., E.S. and B.S. collected diffraction data and solved and refined the structure. L.A.B supervised cloning and expression. W.C.H., L.A.B and R.C.L. wrote sections about these studies.

                CDC team. S.P.D., L.C., H.W. and R.O.D designed the study and performed animal study as well as virology study with wild type viruses. R.O.D wrote sections of these studies. J.S., R.O.D., R.C.L and W.A.M. finalized the paper. All authors commented on the manuscript.

                Correspondence should be addressed to J.S. ( jianhua_sui@ 123456dfci.harvard.edu ), R.O.D. ( rvd6@ 123456cdc.gov ), R.C.L ( rlidding@ 123456burnham.org ), and or W.A.M. ( wayne_marasco@ 123456dfci.harvard.edu ).
                Journal
                101186374
                31761
                Nat Struct Mol Biol
                Nature structural & molecular biology
                1545-9993
                1545-9985
                28 April 2009
                22 February 2009
                March 2009
                1 September 2009
                : 16
                : 3
                : 265-273
                2692245
                19234466
                10.1038/nsmb.1566
                nihpa103240
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI055789-040001 ||AI
                Categories
                Article

                Molecular biology

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