title: Structure and accessibility of HA trimers on intact 2009 H1N1 pandemic influenza virus to stem region-specific neutralizing antibodies.
abstract: Rapid antigenic variation of HA, the major virion surface protein of influenza A virus, remains the principal challenge to the development of broader and more effective vaccines. Some regions of HA, such as the stem region proximal to the viral membrane, are nevertheless highly conserved across strains and among most subtypes. A fundamental question in vaccine design is the extent to which HA stem regions on the surface of the virus are accessible to broadly neutralizing antibodies. Here we report 3D structures derived from cryoelectron tomography of HA on intact 2009 H1N1 pandemic virions in the presence and absence of the antibody C179, which neutralizes viruses expressing a broad range of HA subtypes, including H1, H2, H5, H6, and H9. By fitting previously derived crystallographic structures of trimeric HA into the density maps, we deduced the locations of the molecular surfaces of HA involved in interaction with C179. Using computational methods to distinguish individual unliganded HA trimers from those that have bound C179 antibody, we demonstrate that ∼75% of HA trimers on the surface of the virus have C179 bound to the stem domain. Thus, despite their close packing on the viral membrane, the majority of HA trimers on intact virions are available to bind anti-stem antibodies that target conserved HA epitopes, establishing the feasibility of universal influenza vaccines that elicit such antibodies.
authors: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Audray K
authors: AK
authors: Harris
authors: Joel R
authors: JR
authors: Meyerson
authors: Yumiko
authors: Y
authors: Matsuoka
authors: Oleg
authors: O
authors: Kuybeda
authors: Amy
authors: A
authors: Moran
authors: Donald
authors: D
authors: Bliss
authors: Suman R
authors: SR
authors: Das
authors: Jonathan W
authors: JW
authors: Yewdell
authors: Guillermo
authors: G
authors: Sapiro
authors: Kanta
authors: K
authors: Subbarao
authors: Sriram
authors: S
authors: Subramaniam
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology; D000914:Antibodies, Viral / Q000737:chemistry* / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry* / Q000276:immunology; D007251:Influenza, Human / Q000453:epidemiology / Q000276:immunology; D008958:Models, Molecular; D058873:Pandemics; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus