Adaptation of Pandemic H1N1 Influenza Viruses in Mice

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[SIZE=-1]Journal of Virology, September 2010, p. 8607-8616, Vol. 84, No. 17
0022-538X/10/$012.00+0 doi:10.1128/JVI.00159-10
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http://jvi.asm.org/cgi/content/abstract/84/17/8607

Adaptation of Pandemic H1N1 Influenza Viruses in Mice<sup>

</sup>

Natalia A. Ilyushina,¹^,2<sup>,

</sup> Alexey M. Khalenkov,¹ Jon P. Seiler,¹ Heather L. Forrest,¹ Nicolai V. Bovin,³ Henju Marjuki,¹ Subrata Barman,¹ Robert G. Webster,¹^,4 and Richard J. Webby¹^* Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678,¹ the D. I. Ivanovsky Institute of Virology RAMS, Moscow 123098, Russia,² Shemyakin Institute of Bioorganic Chemistry, Moscow 117997, Russia,³ Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38105⁴
Received 23 January 2010/ Accepted 17 June 2010
<!-- ABS --> The molecular mechanism by which pandemic 2009 influenza A viruseswere able to sufficiently adapt to humans is largely unknown.Subsequent human infections with novel H1N1 influenza virusesprompted an investigation of the molecular determinants of thehost range and pathogenicity of pandemic influenza viruses inmammals. To address this problem, we assessed the genetic basisfor increased virulence of A/CA/04/09 (H1N1) and A/TN/1-560/09(H1N1) isolates, which are not lethal for mice, in a new mammalianhost by promoting their mouse adaptation. The resulting mouselung-adapted variants showed significantly enhanced growth characteristicsin eggs, extended extrapulmonary tissue tropism, and pathogenicityin mice. All mouse-adapted viruses except A/TN/1-560/09-MA2grew faster and to higher titers in cells than the originalstrains. We found that 10 amino acid changes in the ribonucleoprotein(RNP) complex (PB2 E158G/A, PA L295P, NP D101G, and NP H289Y)and hemagglutinin (HA) glycoprotein (K119N, G155E, S183P, R221K,and D222G) controlled enhanced mouse virulence of pandemic isolates.HA mutations acquired during adaptation affected viral receptorspecificity by enhancing binding to

2,3 together with decreasingbinding to

2,6 sialyl receptors. PB2 E158G/A and PA L295P aminoacid substitutions were responsible for the significant enhancementof transcription and replication activity of the mouse-adaptedH1N1 variants. Taken together, our findings suggest that changesoptimizing receptor specificity and interaction of viral polymerasecomponents with host cellular factors are the major mechanismsthat contribute to the optimal competitive advantage of pandemicinfluenza viruses in mice. These modulators of virulence, therefore,may have been the driving components of early evolution, whichpaved the way for novel 2009 viruses in mammals.