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Journal of Virology, October 2007, p. 11170-11178, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01217-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Alterations in Receptor Binding Properties of Recent Human Influenza H3N2 Viruses Are Associated with Reduced Natural Killer Cell Lysis of Infected Cells

Rachel E. Owen,^1,, Eriko Yamada,^1,, Catherine I. Thompson,^2, Louisa J. Phillipson,^2,3 Clare Thompson,¹ Elizabeth Taylor,¹ Maria Zambon,⁵ Helen M. I. Osborn,^3,4 Wendy S. Barclay,^2* and Persephone Borrow¹

The Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire RG20 7NN, United Kingdom,¹ School of Biological Sciences, The University of Reading, Whiteknights, Reading RG6 6AJ, United Kingdom,² School of Chemistry,³ School of Pharmacy, The University of Reading, Whiteknights, Reading RG6 6AD, United Kingdom,⁴ Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5HT, United Kingdom⁵

Received 4 June 2007/ Accepted 20 July 2007

Natural killer (NK) cell recognition of influenza virus-infected cells involves hemagglutinin (HA) binding to sialic acid (SA) on activating NK receptors. SA also acts as a receptor for the binding of influenza virus to its target host cells. The SA binding properties of H3N2 influenza viruses have been observed to change during circulation in humans: recent isolates are unable to agglutinate chicken red blood cells and show reduced affinity for synthetic glycopolymers representing SA--2,3-lactose (3'SL-PAA) and SA--2,6-N-acetyl lactosamine (6'SLN-PAA) carbohydrates. Here, NK lysis of cells infected with human H3N2 influenza viruses isolated between 1969 and 2003 was analyzed. Cells infected with recent isolates (1999 to 2003) were found to be lysed less effectively than cells infected with older isolates (1969 to 1996). This change occurred concurrently with the acquisition of two new potential glycosylation site motifs in HA. Deletion of the potential glycosylation site motif at 133 to 135 in HA1 from a recent isolate partially restored the agglutination phenotype to a recombinant virus, indicating that the HA-SA interaction is inhibited by the glycosylation modification. Deletion of either of the recently acquired potential glycosylation sites from HA led to increased NK lysis of cells infected with recombinant viruses carrying modified HA. These results indicate that alterations in HA glycosylation may affect NK cell recognition of influenza virus-infected cells in addition to virus binding to host cells.

Published ahead of print on 1 August 2007.

These authors contributed equally to this study.

Present address: Blood Systems Research Institute, 270 Masonic Ave., San Francisco, CA 94118.

Present address: NCI-Frederick, Frederick, MD 21702.

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