"In pandemic H1N1, both H274Y and D225G have been found on multiple genetic backgrounds raising concerns that H274Y will soon be fixed in pandemic H1N1 and this fixing may be linked to receptor binding domain changes associated with severe and lethal infections."
Fixing Fatal Tamiflu Resistance in Pandemic H1N1 Recombinomics Commentary 18:53 December 11, 2009
The recent report of H274Y cases doubling in the Netherlands in the past week, including 4 of 11 fatalities, has raised concerns that Tamiflu resistance has not only jumped to an evolutionarily fit pandemic H1N1 , but a lethal sub-clade. Similar numbers were reported in the United States where 10 new cases of resistance were described and four were fatal.
The report this week out of Vietnam left little doubt that H274Y was being efficiently transmitted to previously healthy young adults when seven students were infected during a train ride. Six were among ten students in one car, while a seventh was in another car, suggesting at least two independent transmission events. However, these patients recovered, even though the treatment with Tamiflu had little value since they were Tamiflu resistant prior to treatment. Sequences from these patients have not been released, so the relationship of this cluster to reports of sporadic cases is unclear.
However, sequences from the first Tamiflu resistant case without exposure to Tamiflu have been released and the HA sequence had a receptor binding domain change, D225E. Linkage between H274Y resistance and receptor binding domain changes was of concern because the fixing of H274Y in seasonal flu was linked to receptor binding domain changes. The key change in the fixing of H274Y was A193T, which emerged near the end of the 2007/2008 season and become dominant in the summer of 2008 in the southern hemisphere. This gave rise to an increase in H274Y to almost 100% of seasonal H1N1, with additional changes involving various combinations of polymorphisms at positions 187, 189, and 196,
The linkage between receptor binding domain changes and fixing of anti-viral resistance was also seen in S31N in seasonal H3N2. That change was linked to a change at position 193 (S193F),, as well as a change at position 225 (D225N).
Thus, when the H274Y in pandemic H1N1 was found in an isolate that had D225E, there was concern that the receptor binding domain could facilitate the spread of H274Y via a fit H1N1. These concerns were increased by a recent sequence from Tennessee which had H274Y and D225E.
However, two additional changes at position 225 were reported in pandemic H1N1 (D225G and D225N) and these changes were associated with fatal lung cases in Sao Paulo. The concerns were increased when sequences from Ukraine were released, which identified D225G in four of four fatal cases. Recently released sequences have added to the concern when the two new sequences, which were likely from fatal cases, had D225N. Both of these changes were found in a fatal case from Utah.
Concern that H274Y was pairing up with D225N was increased in a report from France which cited two fatal cases with D225N and one of the two had H274Y. An expansion of this pairing could have dire consequences, because of the recent linkage between severe ad fatal cases with D225N, since Tamiflu remains as a first line defense against more severe cases of H1N1.
These concerns could be more appropriately addressed with the release sequences from the recent cases, including those that were fatal.
The fixing of H274Y In seasonal fu was linked to the jumping of H274Y and key polymorphisms from one genetic background to another via recombination. In pandemic H1N1, both H274Y and D225G have been found on multiple genetic backgrounds raising concerns that H274Y will soon be fixed in pandemic H1N1 and this fixing may be linked to receptor binding domain changes associated with severe and lethal infections.
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