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Journal of Virology, December 2008, p. 11880-11888, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01445-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Compatibility among Polymerase Subunit Proteins Is a Restricting Factor in Reassortment between Equine H7N7 and Human H3N2 Influenza Viruses{triangledown}

Chengjun Li,1 Masato Hatta,1 Shinji Watanabe,1 Gabriele Neumann,1 and Yoshihiro Kawaoka1,2,3*

Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, Wisconsin 53706,1 Division of Virology, Department of Microbiology and Immunology,2 International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan3

Received 10 July 2008/ Accepted 11 September 2008

Reassortment is an important driving force for influenza virus evolution, and a better understanding of the factors that affect this process could improve our ability to respond to future influenza pandemics and epidemics. To identify factors that restrict the generation of reassortant viruses, we cotransfected human embryonic kidney cells with plasmids for the synthesis of viral RNAs of both A/equine/Prague/1/56 (Prague; H7N7) and A/Yokohama/2017/03 (Yokohama; H3N2) viruses together with the supporting protein expression plasmids. Of the possible 256 genotypes, we identified 29 genotypes in 120 randomly plaque-picked reassortants examined. Analyses of these reassortants suggested that the formation of functional ribonucleoprotein (RNP) complexes was a restricting factor, a finding that correlated with the activities of RNP complexes composed of different combinations of the proteins from the two viruses, as measured in a minigenome assay. For at least one nonfunctional RNP complex (i.e., Prague PB2, Prague PB1, Yokohama PA, and Prague NP), the lack of activity was due to the inability of the three polymerase subunit proteins to form a heterotrimer. Adaptation of viruses possessing a gene encoding a chimera of the PA proteins of the two viruses and the remaining genes from Prague virus resulted in compensatory mutations in the PB2 and/or PA protein. These results indicate substantial incompatibility among the gene products of the two test viruses, a critical role for the RNP complex in the generation of reassortant viruses, and a functional interaction of PB2 and PA.

* Corresponding author. Mailing address: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706. Phone: (608) 265-4925. Fax: (608) 265-5622. E-mail: kawaokay{at}svm.vetmed.wisc.edu

{triangledown} Published ahead of print on 24 September 2008.

Journal of Virology, December 2008, p. 11880-11888, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01445-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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