Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom

Elderfield, Ruth A. and Watson, Simon J. and Godlee, Alexandra and Adamson, Walt E. and Thompson, Catherine I. and Dunning, Jake and Fernandez-Alonso, Mirian and Blumenkrantz, Deena and Hussell, Tracy and Zambon, Maria and Openshaw, Peter and Kellam, Paul and Barclay, Wendy S. and Nguyen-Van-Tam, Jonathan (2014) Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom. Journal of Virology, 88 (22). pp. 13269-13283. ISSN 1098-5514

[img]
Preview
PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Available under Licence Creative Commons Attribution.
Download (3MB) | Preview

Abstract

The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to alpha-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves. IMPORTANCE: Although most people infected with the 2009 pandemic influenza virus had mild or unapparent symptoms, some suffered severe and devastating disease. The reasons for this variability were unknown, but the numbers of severe cases increased during successive waves of human infection in the United Kingdom. To determine the causes of this variation, we studied genetic changes in virus isolates from individual hospitalized patients. There were no consistent differences between these viruses and those circulating in the community, but we found multiple evolutionary changes that in combination over time increased the virus's ability to infect human cells. These adaptations may explain the remarkable ability of A(H1N1)pdm09 virus to continue to circulate despite widespread immunity and the apparent increase in severity of influenza over successive waves of infection.

Item Type: Article
Keywords: Adaptation, Biological Adolescent Adult Animals Child Child, Preschool Disease Models, Animal Female Genome, Viral Great Britain/epidemiology Humans Infant Infant, Newborn Influenza A Virus, H1N1 Subtype/*genetics/isolation & purification Influenza, Human/epidemiology/*virology Interferons/secretion Lung/immunology/pathology/virology Male Mice, Inbred BALB C *Mutation Orthomyxoviridae Infections/immunology/pathology/virology Phylogeny RNA, Viral Sequence Analysis, DNA Virus Attachment Virus Replication Young Adult
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Medicine > Division of Epidemiology and Public Health
Identification Number: https://doi.org/10.1128/JVI.01636-14
Related URLs:
URLURL Type
http://www.ncbi.nlm.nih.gov/pubmed/25210166UNSPECIFIED
Depositing User: Figgens, Sharon
Date Deposited: 18 Apr 2016 10:39
Last Modified: 14 Sep 2016 08:08
URI: http://eprints.nottingham.ac.uk/id/eprint/32743

Actions (Archive Staff Only)

Edit View Edit View