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Concurrent Acquisition of Tamiflu H274Y on H1N1 Subclades

Recombinomics Commentary 15:26
February 15, 2008

The sudden appearance of the oseltamivir (Tamflu) resistance marker H274Y on seasonal H1N1 from residents in countries where oseltamivir usage is low, has created problems for explanations invoking adaptive mutations.  There have not been reports of recent changes in oseltamivir usage for treatment of seasonal flu, and the country with the highest reported use, Japan, has been negative for the change in nthe most recent 71 isolates tested.  Moreover, the resistance is limited to H1N1 and involves the same change, H274Y.

The report on vaccine selection for 2009 provides some additional data.  Recent human isolates are most closely related to A/Brisbane/59/2007, which is a genetic variant of the current vaccine target, A/Solomon Island/3/2006.  The report lists isolates which are more closely related to the Brisbane/59 strain, and two of those isolates, A/Paris/577/2007 and A/Norway/1735/2007 are oseltamivir resistant.

However, NA sequences from six additional oseltamivir resistant isolates from the United States are available at Los Alamos.  Three of the isolates are from Hawaii, and phylogenetic analysis shows that they, like the two isolates above, are closely related to the Brisbane strain.

However, the three other isolates (from Kansas, Minnesota, and Texas) are New Caledonia-like, which are distinctly different than either Solomon Island or Brisbane.  Thus, the concurrent acquisition of H274Y into seasonal H1N1 involved at least two independent events.

The acquisition of the sample polymorphism onto multiple genetic backgrounds is similar to the acquisition of G743A onto multiple clade 2.2 genetic backgrounds.  Like the H274Y acquisitions, the isolates with the change map to the tips of branches on the phylogenetic trees, indicating the acquisitions are recent and independent of acquisitions on other branches.

This type of acquisition is easily explained by recombination with a common donor sequence.  For H274Y, there are no reports of dramatic increases in oseltamivir treatment of H1N1 seasonal flu, but there are reports of widespread use of Tamiflu blankets in areas with H5N1, and the most commonly reported change in N1 in H5N1 is H274Y.

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