[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]
Open Access / Peer-reviewed / Research Article
Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses
William T. Harvey, Donald J. Benton, Victoria Gregory, James P. J. Hall, Rodney S. Daniels, Trevor Bedford, Daniel T. Haydon, Alan J. Hay, John W. McCauley, Richard Reeve
PLOS / Published: April 8, 2016 / http://dx.doi.org/10.1371/journal.ppat.1005526
Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997–2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens.
Influenza A viruses are characterized by rapid antigenic drift: structural changes in B-cell epitopes that facilitate escape from pre-existing immunity. Consequently, seasonal influenza continues to impose a major burden on human health. Accurate quantification of the antigenic impact of specific amino acid substitutions is a pre-requisite for predicting the fitness and evolutionary outcome of variant viruses. Using assays to attribute antigenic variation to amino acid sequence changes we identify substitutions that contribute to antigenic drift and quantify their impact. We show that substitutions identified as low-impact are a critical component of virus antigenic evolution and by including these, as well as the high-impact substitutions often focused on, the accuracy of predicting antigenic phenotypes of emerging viruses from genotype is doubled.
Citation: Harvey WT, Benton DJ, Gregory V, Hall JPJ, Daniels RS, Bedford T, et al. (2016) Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses. PLoS Pathog 12(4): e1005526. doi:10.1371/journal.ppat.1005526
Editor: Scott E. Hensley, The Wistar Institute, UNITED STATES
Received: August 19, 2015; Accepted: March 4, 2016; Published: April 8, 2016
Copyright: © 2016 Harvey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Sequences are available from GISAID—http://platform.gisaid.org—and the assay data underpinning this publication (and the GISAID accession numbers of the viruses used) are available from the associated data deposition at doi:10.5525/gla.researchdata.289.
Funding: This research was supported by the Medical Research Council under programme number U117512723 (WTH, VG, DJB, RSD, AJH, JWM) and grant MR/J50032X/1 (WTH), the Wellcome Trust grant number 083224 (JPJH), NIH grant U54GM111274 (TB), and by the Biotechnology and Biological Sciences Research Council Institute Strategic Programme on Livestock Viral Diseases at The Pirbright Institute (RR), grant BB/H009175/1 (RR), and grant BB/E010326/1 (DTH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Research; Abstracts; Seasonal Influenza; H1N1.