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Research Article

Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate

Erin E. H. Tran, Kira A. Podolsky, Alberto Bartesaghi, Oleg Kuybeda, Giovanna Grandinetti, Teddy John Wohlbold, Gene S. Tan, Raffael Nachbagauer, Peter Palese, Florian Krammer, Sriram Subramaniam
Yasuko Rikihisa, Editor
Erin E. H. Tran
aCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Kira A. Podolsky
aCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Alberto Bartesaghi
aCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Oleg Kuybeda
aCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Giovanna Grandinetti
aCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Teddy John Wohlbold
bDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
cGraduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Gene S. Tan
bDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Raffael Nachbagauer
bDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
dFaculty of Life Sciences, University of Vienna, Vienna, Austria
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Peter Palese
bDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
eDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Florian Krammer
bDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Sriram Subramaniam
aCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Yasuko Rikihisa
Ohio State University
Roles: Editor
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Michael Farzan
The Scripps Research Institute
Roles: Solicited external reviewer
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Richard J. Kuhn
Purdue University
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DOI: 10.1128/mBio.00257-16
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ABSTRACT

Influenza viruses expressing chimeric hemagglutinins (HAs) are important tools in the quest for a universal vaccine. Using cryo-electron tomography, we have determined the structures of a chimeric HA variant that comprises an H1 stalk and an H5 globular head domain (cH5/1 HA) in native and antibody-bound states. We show that cH5/1 HA is structurally different from native HA, displaying a 60° rotation between the stalk and head groups, leading to a novel and unexpected “open” arrangement of HA trimers. cH5/1N1 viruses also display higher glycoprotein density than pH1N1 or H5N1 viruses, but despite these differences, antibodies that target either the stalk or head domains of hemagglutinins still bind to cH5/1 HA with the same consequences as those observed with native H1 or H5 HA. Our results show that a large range of structural plasticity can be tolerated in the chimeric spike scaffold without disrupting structural and geometric aspects of antibody binding.

IMPORTANCE Chimeric hemagglutinin proteins are set to undergo human clinical trials as a universal influenza vaccine candidate, yet no structural information for these proteins is available. Using cryo-electron tomography, we report the first three-dimensional (3D) visualization of chimeric hemagglutinin proteins displayed on the surface of the influenza virus. We show that, unexpectedly, the chimeric hemagglutinin structure differs from those of naturally occurring hemagglutinins by displaying a more open head domain and a dramatically twisted head/stalk arrangement. Despite this unusual spatial relationship between head and stalk regions, virus preparations expressing the chimeric hemagglutinin are fully infectious and display a high glycoprotein density, which likely helps induction of a broadly protective immune response.

FOOTNOTES

    • Received 16 February 2016
    • Accepted 17 February 2016
    • Published 22 March 2016
  • Copyright © 2016 Tran et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate
Erin E. H. Tran, Kira A. Podolsky, Alberto Bartesaghi, Oleg Kuybeda, Giovanna Grandinetti, Teddy John Wohlbold, Gene S. Tan, Raffael Nachbagauer, Peter Palese, Florian Krammer, Sriram Subramaniam
mBio Mar 2016, 7 (2) e00257-16; DOI: 10.1128/mBio.00257-16

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Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate
Erin E. H. Tran, Kira A. Podolsky, Alberto Bartesaghi, Oleg Kuybeda, Giovanna Grandinetti, Teddy John Wohlbold, Gene S. Tan, Raffael Nachbagauer, Peter Palese, Florian Krammer, Sriram Subramaniam
mBio Mar 2016, 7 (2) e00257-16; DOI: 10.1128/mBio.00257-16
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