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J. Virol. doi:10.1128/JVI.02827-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Amino acid 226 in the hemagglutinin of H9N2 influenza viruses determines cell tropism and replication in human airway epithelial cells

Department of Veterinary Medicine, University of Maryland, College Park and Virginia-Maryland, Regional College of Veterinary Medicine, 8075 Greenmead Drive, College Park, MD 20742

^* To whom correspondence should be addressed. Email: dperez1{at}umd.edu.

	Abstract

Influenza A viruses of H9N2 subtype are endemic in poultry in many Eurasian countries and have occasionally caused clinical respiratory diseases in humans. While some avian H9N2 viruses have glutamine (Q) at amino acid position 226 of the hemagglutinin (HA) receptor-binding site, an increasing number of isolates have Leucine (L) at this position, which has been associated with the establishment of stable lineages of H2 and H3 subtype of viruses in humans. Little is known about the importance of this molecular trait in the infection of H9N2 viruses in humans. We show here that during the course of a single cycle of infection in human airway epithelial (HAE) cells cultured in vitro, the L-226 containing H9N2 viruses display human virus-like cell tropism (preferentially infecting nonciliated cells), different from the tropisms showed by Q-226 containing H9N2 isolates (which infect both ciliated and nonciliated cells at ratios of 1:1 to 3:2) or other waterfowl viruses (which preferentially infect ciliated cells). During multiple cycles of replication in HAE cultures, L-226 containing H9N2 isolates grew consistently more efficiently and reached approximately 100-fold higher peak titers than those containing Q-226, although peak titers were significantly lower than those induced by human H3N2 viruses. Our results suggest that the variation in residue 226 in the HAs affects both cell tropism and replication of H9N2 viruses in HAE cells, and may have implications for the ability of these viruses to infect humans.

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