Pandemic H1N1 2009 influenza virus with the H275Y oseltamivir resistance neuraminidase mutation shows a small compromise in enzyme activity and viral fitness

Daniel W. Brookes, Shahjahan Miah, Angie Lackenby, Lorian Hartgroves, Wendy S. Barclay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

Abstract

Background: Resistance to the neuraminidase inhibitor oseltamivir can be conferred by a well-characterized mutation in the neuraminidase gene, H275Y. In human H1N1 viruses that circulated in the first years of the 21st century, this mutation carried a fitness cost and resistant viruses were rare. During the 2007-08 influenza season, oseltamivir-resistant viruses of H1N1 phenotype emerged and predominated. March 2009 saw the emergence of a novel H1N1 influenza pandemic. We examined whether the H275Y mutation affected neuraminidase enzyme activity or replication of the pandemic influenza virus. Methods: Using reverse genetics we engineered the H275Y mutation into the neuraminidase of a 2009 pandemic H1N1 virus and assessed the ability of this enzyme to desialylate mono- and multivalent substrates. The growth kinetics of wild-type and mutant viruses were assessed in Madin-Darby canine kidney (MDCK) and fully differentiated human airway epithelial (HAE) cells. Results: The presence of H275Y was associated with a 1.3-fold decrease in the affinity of the neuraminidase for a monovalent substrate and a 4-fold compromise in desialylation of multivalent substrate. This was associated with a fitness cost to viral replication in vitro, which only became apparent during competitive replication in the mucus-rich HAE culture system. Conclusions: The neuraminidase protein of pandemic influenza isolates tolerates the H275Y mutation and this mutation confers resistance to oseltamivir. However, unlike seasonal H1N1 viruses isolated since 2007, the mutation is not associated with any fitness advantage and thus is unlikely to predominate without further antigenic drift, compensating mutations or intense selection pressure.

Original languageEnglish
Article numberdkq486
Pages (from-to)466-470
Number of pages5
JournalJournal of Antimicrobial Chemotherapy
Volume66
Issue number3
DOIs
Publication statusPublished - Mar 2011

Bibliographical note

Funding Information:
This work was supported by a Biotechnology and Biological Sciences Research Council studentship awarded to D. B. and a project grant from the Wellcome Trust (090028/Z/09/Z) that allowed the generation of the reverse genetics system for A/England/195/09.

Keywords

  • Neuraminidase inhibitor
  • Pandemic influenza
  • nvH1N1

Fingerprint

Dive into the research topics of 'Pandemic H1N1 2009 influenza virus with the H275Y oseltamivir resistance neuraminidase mutation shows a small compromise in enzyme activity and viral fitness'. Together they form a unique fingerprint.

Cite this