Viral factors in influenza pandemic risk assessment

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Abstract

The threat of an influenza A virus pandemic stems from continual virus spillovers from reservoir species, a tiny fraction of which spark sustained transmission in humans. To date, no pandemic emergence of a new influenza strain has been preceded by detection of a closely related precursor in an animal or human. Nonetheless, influenza surveillance efforts are expanding, prompting a need for tools to assess the pandemic risk posed by a detected virus. The goal would be to use genetic sequence and/or biological assays of viral traits to identify those non-human influenza viruses with the greatest risk of evolving into pandemic threats, and/or to understand drivers of such evolution, to prioritize pandemic prevention or response measures. We describe such efforts, identify progress and ongoing challenges, and discuss three specific traits of influenza viruses (hemagglutinin receptor binding specificity, hemagglutinin pH of activation, and polymerase complex efficiency) that contribute to pandemic risk.

DOI: http://dx.doi.org/10.7554/eLife.18491.001

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Most cited references 183

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Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. The structures of three conformations of the ectodomain of the 1968 Hong Kong influenza virus HA have been determined by X-ray crystallography: the single-chain precursor, HA0; the metastable neutral-pH conformation found on virus, and the fusion pH-induced conformation. These structures provide a framework for designing and interpreting the results of experiments on the activity of HA in receptor binding, the generation of emerging and reemerging epidemics, and membrane fusion during viral entry. Structures of HA in complex with sialic acid receptor analogs, together with binding experiments, provide details of these low-affinity interactions in terms of the sialic acid substituents recognized and the HA residues involved in recognition. Neutralizing antibody-binding sites surround the receptor-binding pocket on the membrane-distal surface of HA, and the structures of the complexes between neutralizing monoclonal Fabs and HA indicate possible neutralization mechanisms. Cleavage of the biosynthetic precursor HA0 at a prominent loop in its structure primes HA for subsequent activation of membrane fusion at endosomal pH (Figure 1). Priming involves insertion of the fusion peptide into a charged pocket in the precursor; activation requires its extrusion towards the fusion target membrane, as the N terminus of a newly formed trimeric coiled coil, and repositioning of the C-terminal membrane anchor near the fusion peptide at the same end of a rod-shaped molecule. Comparison of this new HA conformation, which has been formed for membrane fusion, with the structures determined for other virus fusion glycoproteins suggests that these molecules are all in the fusion-activated conformation and that the juxtaposition of the membrane anchor and fusion peptide, a recurring feature, is involved in the fusion mechanism. Extension of these comparisons to the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) protein complex of vesicle fusion allows a similar conclusion.

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Author and article information

Contributors

Yi Guan

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 11 November 2016

Publication date Collection: 2016

Volume: 5

Electronic Location Identifier: e18491

Affiliations

[1 ]deptCenter for Communicable Disease Dynamics , Harvard T. H Chan School of Public Health , Boston, United States

[2 ]deptDepartment of Epidemiology , Harvard T. H. Chan School of Public Health , Boston, United States

[3 ]deptDepartment of Immunology and Infectious Diseases , Harvard T. H. Chan School of Public Health , Boston, United States

[4 ]deptDivision of Infectious Disease, Faculty of Medicine , Imperial College , London, United Kingdom

[5 ]deptDepartment of Biological Engineering, Koch Institute for Integrative Cancer Research , Massachusetts Institute of Technology , Cambridge, United States

[6 ]deptDepartment of Infectious Diseases , St. Jude Children’s Research Hospital , Memphis, United States

[7 ]Centers for Disease Control and Prevention , Atlanta, United States

[8 ]deptDepartment of Ecology and Evolutionary Biology , University of Chicago , Chicago, United States

[9 ]deptDepartment of Biomedical Engineering , University of Virginia , Charlottesville, United States

[10 ]deptDepartment of Molecular Physiology and Biological Physics , University of Virginia , Charlottesville, United States

[11 ]deptDepartment of Ecology and Evolutionary Biology , University of California, Los Angeles , Los Angeles, United States

[12 ]deptFogarty International Center , National Institutes of Health , Bethesda, United States

[13 ]deptBioinformatics Institute , Agency for Science Technology and Research , Singapore, Singapore

[14 ]deptNational Public Health Laboratory, Communicable Diseases Division , Ministry of Health , Singapore, Singapore

[15 ]deptSchool of Biological Sciences , Nanyang Technological University , Singapore, Singapore

[16 ]deptMRC Centre for Outbreak Analysis and Modelling , School of Public Health, Imperial College London , London, United Kingdom

[17 ]deptDepartment of Infectious Disease Epidemiology , School of Public Health, Imperial College London , London, United Kingdom

[18 ]deptDepartment of Physics , Ryerson University , Toronto, Canada

[19 ]deptVaccine and Infectious Disease Division , Fred Hutchinson Cancer Research Center , Seattle, United States

[20 ]deptDepartment of Pathobiological Sciences , University of Wisconsin School of Veterinary Medicine , Madison, United States

[21 ]deptDepartment of Epidemiology and Biostatistics, College of Public Health , University of Georgia , Athens, United States

[22 ]deptDepartment of Viroscience , Erasmus Medical Center , Rotterdam, Netherlands

[23 ]MRC-University of Glasgow Centre For Virus Research , Glasgow, United Kingdom

[24 ]IRD/UPMC UMMISCO , Montpellier, France

[25 ]deptCenter for Computational Biology and Bioinformatics , Institute for Cellular and Molecular Biology, The University of Texas at Austin , Austin, United States

[26 ]deptDepartment of Integrative Biology , The University of Texas at Austin , Austin, United States

[27 ]deptDepartment of Veterinary Medicine , University of Cambridge , Cambridge, United Kingdom

[28]University of Hong Kong , Hong Kong

Author notes

mlipsitc@ 123456hsph.harvard.edu

Author information

Marc Lipsitch http://orcid.org/0000-0003-1504-9213

James O Lloyd-Smith http://orcid.org/0000-0001-7941-502X

Catherine AA Beauchemin http://orcid.org/0000-0003-0599-0069

Andreas Handel http://orcid.org/0000-0002-4622-1146

Pablo R Murcia http://orcid.org/0000-0002-4352-394X

Claus O Wilke http://orcid.org/0000-0002-7470-9261

Colin A Russell http://orcid.org/0000-0002-2113-162X

Article

Publisher ID: 18491

DOI: 10.7554/eLife.18491

PMC ID: 5156527

PubMed ID: 27834632

SO-VID: b20b4dcb-28c8-4a4e-a511-8620c33495e3

License:

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

History

Date received : 09 June 2016

Date accepted : 03 November 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: U54 GM088558

Award Recipient : Marc Lipsitch

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: RAPIDD program, Science and Technology Directorate, U.S Department of Homeland Security, and the Fogarty International Center

Award Recipient : Marc Lipsitch

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: Centers of Excellence for Influenza Research and Surveillance (Contract HHSN272201400006C)

Award Recipient : Charles J Russell

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R01 GM098304

Award Recipient : Peter M Kasson

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: 12/1/06/24/5793

Award Recipient : Sebastian Maurer-Stroh

Funded by: FundRef http://dx.doi.org/10.13039/501100001348, Agency for Science, Technology and Research;

Award ID: 12/1/06/24/5793

Award Recipient : Sebastian Maurer-Stroh

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Award ID: Project 093488/Z/10/Z