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Journal of Virology, October 2009, p. 9901-9910, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00608-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Detection of Mammalian Virulence Determinants in Highly Pathogenic Avian Influenza H5N1 Viruses: Multivariate Analysis of Published Data{triangledown} ,{dagger}

S. J. Lycett,1* M. J. Ward,1 F. I. Lewis,1,{ddagger} A. F. Y. Poon,2 S. L. Kosakovsky Pond,2 and A. J. Leigh Brown1

Institute of Evolutionary Biology, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, United Kingdom,1 University of California at San Diego, 150 West Washington Street, Suite 100, San Diego, California 921032

Received 24 March 2009/ Accepted 10 July 2009

Highly pathogenic avian influenza (HPAI) virus H5N1 infects water and land fowl and can infect and cause mortality in mammals, including humans. However, HPAI H5N1 strains are not equally virulent in mammals, and some strains have been shown to cause only mild symptoms in experimental infections. Since most experimental studies of the basis of virulence in mammals have been small in scale, we undertook a meta-analysis of available experimental studies and used Bayesian graphical models (BGM) to increase the power of inference. We applied text-mining techniques to identify 27 individual studies that experimentally determined pathogenicity in HPAI H5N1 strains comprising 69 complete genome sequences. Amino acid sequence data in all 11 genes were coded as binary data for the presence or absence of mutations related to virulence in mammals or nonconsensus residues. Sites previously implicated as virulence determinants were examined for association with virulence in mammals in this data set, and the sites with the most significant association were selected for further BGM analysis. The analyses show that virulence in mammals is a complex genetic trait directly influenced by mutations in polymerase basic 1 (PB1) and PB2, nonstructural 1 (NS1), and hemagglutinin (HA) genes. Several intra- and intersegment correlations were also found, and we postulate that there may be two separate virulence mechanisms involving particular combinations of polymerase and NS1 mutations or of NS1 and HA mutations.

* Corresponding author. Mailing address: Ashworth Laboratories, Rm. 65, Institute of Evolutionary Biology, University of Edinburgh, Kings Buildings, West Mains Road, Edinburgh EH9 3JT, United Kingdom. Phone: 44 131 650 8683. Fax: 44 131 650 5456. E-mail: samantha.lycett{at}ed.ac.uk

{triangledown} Published ahead of print on 22 July 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: Epidemiology Research Unit, Drummondhill, Stratherrick Road, Scottish Agricultural College, Inverness IV2 4JZ, United Kingdom.

Journal of Virology, October 2009, p. 9901-9910, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00608-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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