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Tamiflu Resistance in H1N1 in Turkey

Recombinomics Commentary 18:50
April 17, 2008

Five NA sequences from H1N1 isolates in Turkey were just released.  All five were collected in 2008, and one of the five, A/Bursa-TR/28/2008(H1N1), had the oseltamivir (Tamiflu) resistant marker, H274Y.  The sudden appearance of H274Y this season has startled influenza experts.  The frequency was highest in Europe, where levels exceeded 40% in Norway, France, and Russia, which are countries not known to commonly use Tamiflu.  In contrast, the level in the country that regularly uses Tamiflu, Japan, was only at 2%.  All of the above resistance has been in H1N1 seasonal flu.

The resistance marker on N1 of H1N1 is identical to the major resistance marker on N1 in H5N1.  Tamiflu use to treat H5N1 has increased markedly since 2005, and H274Y was found in wild birds in Astrakhan in late 2005.  In early 2006, H5N1 was confirmed in humans in Turkey, and Tamiflu usage was widespread.  Thus, the increase in H274Y in H1N1 seasonal flu follows widespread use of Tamiflu to treat H5N1 and the detection of H274Y in wild birds infected with clade 2.2 H5N1.

Similarly, the data for transfer of mammalian polymorphisms to H5N1 is also increasing.  The recently released H5N1 sequence from Israel had acquired a number of mammalian polymorphisms in PB2, including three consecutive polymorphisms.  These acquisition patterns are most easily explained by recombination between avian H5N1 genes and human seasonal flu.  The series of three polymorphisms is also found in 1918 H1N1.

Papers coming out this week in Nature and Science describe the movement of seasonal flu from Asia to the rest of the world.  However, these studies fail to track individual polymorphisms, which identify animal reservoirs for these new acquisitions.  The reservoirs include bird and swine sources in Asia.

Thus, the role of recombination in the evolution of influenza is being increasingly obvious, as more influenza sequences are released.  An understanding of this mechanism would reduce the number of influenza experts who are startled by the appearance of avian polymorphisms in human seasonal flu.

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