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JAC Advance Access published online on March 17, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh155
© 2004 by The British Society for Antimicrobial Chemotherapy
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© 2004 The British Society for Antimicrobial Chemotherapy

Original article

Changes in in vitro susceptibility of influenza A H3N2 viruses to a neuraminidase inhibitor drug during evolution in the human host

Catherine I. Thompson 1 , Wendy S. Barclay 2 *, and Maria C. Zambon 3

1 School of Animal and Microbial Sciences, University of Reading, Whiteknights PO Box 228, Reading RG6 6AJ; Enteric, Respiratory and Neurological Virus Laboratory, Health Protection Agency, Central Public Health Laboratory, London, UK
2 School of Animal and Microbial Sciences, University of Reading, Whiteknights PO Box 228, Reading RG6 6AJ;
3 Enteric, Respiratory and Neurological Virus Laboratory, Health Protection Agency, Central Public Health Laboratory, London, UK

* Corresponding author. E-mail: w.s.barclay{at}reading.ac.uk.

Received 28 November 2003 ; revised 28 January 2004 ; accepted 2 February 2004

Abstract

Objectives: Influenza A H3N2 viruses isolated recently have characteristic receptor binding properties that may decrease susceptibility to neuraminidase inhibitor drugs. A panel of clinical isolates and recombinant viruses generated by reverse genetics were characterized and tested for susceptibility to zanamivir.

Methods: Plaque reduction assays and neuraminidase enzyme inhibition assays were used to assess susceptibility to zanamivir. Receptor binding properties of the viruses were characterized by differential agglutination of red blood cells (RBCs) from different species. Sequence analysis of the haemagglutinin (HA) and neuraminidase (NA) genes was carried out.

Results: Characterization of a panel of H3N2 clinical isolates from 1968 to 2000 showed a gradual decrease in agglutination of chicken and guinea pig RBCs over time, although all isolates could agglutinate turkey RBCs equally. Sequence analysis of the HA and NA genes identified mutations in conserved residues of the HA1 receptor binding site, in particular Leu-226 -> Ile-226/Val-226, and modification of potential glycosylation site motifs. This may be indicative of changes in virus binding to sialic acid (SA) receptors in recent years. Although recent isolates had reduced susceptibility to zanamivir in MDCK cell based plaque reduction assays, no difference was found in an NA enzyme-inhibition assay. Assays with recombinant isogenic viruses showed that the recent HA, but not the NA, conferred reduced susceptibility to zanamivir.

Conclusion: This study demonstrates that recent clinical isolates of influenza A H3N2 virus no longer agglutinate chicken RBCs, but despite significant receptor binding changes as a result of changes in HA, there was little variation in sensitivity of the NA to zanamivir.

Keywords: haemagglutinin, neuraminidase, reverse genetics, sialic acid, zanamivir
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