Infect Genet Evol: Evolution of drug resistance in multiple distinct lineages of H5N1 avian influenza

Laidback Al · Jan 7, 2009

(in press) Infection, Genetics and Evolution
Journal of Molecular Epidemiology and Evolutionary Genetics of Infectious Diseases (MEEGID)

doi:10.1016/j.meegid.2008.10.006

Evolution of drug resistance in multiple distinct lineages of H5N1 avian influenza

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Andrew W. Hilla, Corresponding Author Contact Information, E-mail The Corresponding Author, Robert P. Guralnicka, b, Meredith J.C. Wilsona, Farhat Habibc, d and Daniel Janiesd

aDepartment of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO, United States

bUniversity of Colorado Museum, University of Colorado, Boulder, CO, United States

cDepartment of Plant Pathology, Kansas State University, Manhattan, KS, United States

dDepartment of Biomedical Informatics, The Ohio State University, Columbus, OH, United States

Received 31 May 2008;
revised 12 October 2008;
accepted 13 October 2008.
Available online 30 October 2008.

Abstract

Some predict that influenza A H5N1 will be the cause of a pandemic among humans. In preparation for such an event, many governments and organizations have stockpiled antiviral drugs such as oseltamivir (Tamiflu?). However, it is known that multiple lineages of H5N1 are already resistant to another class of drugs, adamantane derivatives, and a few lineages are resistant to oseltamivir. What is less well understood is the evolutionary history of the mutations that confer drug resistance in the H5N1 population. In order to address this gap, we conducted phylogenetic analyses of 676 genomic sequences of H5N1 and used the resulting hypotheses as a basis for asking 3 molecular evolutionary questions: (1) Have drug-resistant genotypes arisen in distinct lineages of H5N1 through point mutation or through reassortment? (2) Is there evidence for positive selection on the codons that lead to drug resistance? (3) Is there evidence for covariation between positions in the genome that confer resistance to drugs and other positions, unrelated to drug resistance, that may be under selection for other phenotypes? We also examine how drug-resistant lineages proliferate across the landscape by projecting or phylogenetic analysis onto a virtual globe. Our results for H5N1 show that in most cases drug resistance has arisen by independent point mutations rather than reassortment or covariation. Furthermore, we found that some codons that mediate resistance to adamantane derivatives are under positive selection, but did not find positive selection on codons that mediate resistance to oseltamivir. Together, our phylogenetic methods, molecular evolutionary analyses, and geographic visualization provide a framework for analysis of globally distributed genomic data that can be used to monitor the evolution of drug resistance.

Keywords: Influenza; H5N1; Viral evolution; Adamantane; Oseltamivir; Drug resistance; Antiviral; Tamiflu?; Neuraminidase; M2 protein; Mutation
Article Outline

1. Introduction
2. Materials and methods

2.1. Sequence sampling and alignment
2.2. Phylogenetic analysis
2.3. Translation to amino acid sequences and screening for drug-resistant positions
2.4. Reassortment analysis
2.5. Analysis of selective pressure
2.6. Measure of molecular covariation
2.7. Geographic mapping and visualization

3. Results

3.1. Reassortment leading to proliferation of drug-resistant genotypes
3.2. Selection at sites of adamantane resistance
3.3. Selection at sites of oseltamivir resistance
3.4. Covariation of resistance-conferring mutations with other positions

4. Discussion

4.1. Evolution of resistance to adamantane derivatives
4.2. Evolution of resistance to oseltamivir

Acknowledgements
Appendix A. Supplementary data
References

http://www.sciencedirect.com/scienc...serid=10&md5=4a3e72f424bc90f5fa05a0fc1dc69bbc

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Infect Genet Evol: Evolution of drug resistance in multiple distinct lineages of H5N1 avian influenza

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