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Journal of Virology, December 2008, p. 11599-11608, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01393-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Experimental Evolution of Human Influenza Virus H3 Hemagglutinin in the Mouse Lung Identifies Adaptive Regions in HA1 and HA2{triangledown}

Liya Keleta,1 Aida Ibricevic,2 Nicolai V. Bovin,3 Steven L. Brody,2 and Earl G. Brown1*

Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada,1 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri,2 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow V-437 117997, Russia3

Received 3 July 2008/ Accepted 22 September 2008

The genetic basis for virulence and host switching in influenza A viruses (FLUAV) is largely unknown. Because the hemagglutinin (HA) protein is a determinant of these properties, HA evolution was mapped in an experimental model of mouse lung adaptation. Variants of prototype A/Hong Kong/1/68 (H3N2) (wild-type [wt] HK) human virus were selected in both longitudinal and parallel studies of lung adaptation. Mapping of HA mutations found in 11 independently derived mouse-adapted populations of wt HK identified 27 mutations that clustered within two distinct regions in or near the globular frameworks of the HA1 and HA2 subunits. The adaptive mutations demonstrated multiple instances of convergent evolution involving four amino acid positions (162, 210, and 218 in HA1 and 154 in HA2). By use of reverse genetics, convergent HA mutations were shown to affect cell tropism by enhancing infection and replication in primary mouse tracheal epithelial cells in vitro and mouse lung tissue in vivo. Adaptive HA mutations were multifunctional, affecting both median pH of fusion and receptor specificity. Specific mutations within both adaptive regions were shown to increase virulence in a mouse lung model. The occurrence of mutations in the HA1 and HA2 adaptive regions of natural FLUAV host range and virulent variants of avian and mammalian viruses is discussed. This study has identified adaptive sites and regions within the HA1 and HA2 subunits that may guide future studies of viral adaptation and evolution in nature.

* Corresponding author. Mailing address: University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5. Phone: (613) 562-5800, ext. 8310. Fax: (613) 562-5452. E-mail: ebrown{at}uottawa.ca

{triangledown} Published ahead of print on 1 October 2008.

Journal of Virology, December 2008, p. 11599-11608, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01393-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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