Commentary
Global Expansion of H274Y Tamiflu Resistance
Recombinomics Commentary 16:42
July 12, 2008
The recent release of phylogenetic trees with 2008 NA sequences with H274Y has allowed for more detailed analysis. Previously, analysis was possible using public NA sequences, which were almost exclusively sequences from the United States generated by the CDC. There was also one full sequence from England, as well as partial sequences from Turkey and Hong Kong.
The public sequences contained H274Y in sequences from five individual infected during the 2006/2007 season inI the United States. All five were infected with the H1N1 New Caledonia/20 strain. Previously, no H1N1 public sequence contained H274Y.
The level of H274Y increased markedly in the 2007/2008 season. Initial reports came from Norway, where more than 50% of H1N1 isolates had H274Y. In the United States, the number of isolate also jumped, and all isolates were the emerging Bisbane/59 strain. Thus the over-all rate in the US was only 10% of H1N1, but the H1N1 infections in the US included Solomon Island/3 isolates, which did not have H274Y.
However, the data in the US indicated there were at least three separate introductions. The largest sub-clade was found throughout the country and accounted for the vast majority of isolates. However, two isolates in Hawaii mapped to a branch with other isolates from Hawaii and California. However, since of two isolates had H274Y, that introduction was after that branch formed.
Similarly, a 2008 isolate from Florida with H274Y fell onto a branch with 2007 isolates from Florida, which did not have H274Y, indicating the Florida case was a third independent introduction.
The recent release of a phylogenetic tree from Japan indicated there were many independent introductions there, even though most of the H274Y positive patients did not take Tamiflu in the two weeks prior to samples collection. Only 2 of the 22 H274Y patients were known to have take Tamiflu (and the Tamiflu status of four additional patients was unknown). Thus, like the H274Y patients in other countries, the presence of H274Y was not linked to Tamiflu usage.
The phylogram from Japan included several of the isolates from the US, as did other phylograms by others, such as slide 9, slide 6, and slide 24 On the phylogram from Japan, the branch labeled “Northern EU-like” has a series of isolates which have H274Y. Analysis of the other phylograms creates a list of isolates which match to this large branch, which are listed below. This list includes isolates from Norway, the United States, Canada, Russia, Japan, and Trindad indicating this subclade is widespread and present in the countries with the highest incidence of H274Y. Since all isolates on this branch have H274Y, they could have had a common origin.
However, the Hawaii and Florida isolates described above fall on lower branches, as do isolates from Japan (see second list below). These isolates on the phylogram from Japan represent multiple independent introductions. Similarly isolates from the other phylograms indicate there are additional introductions in France, Greece, and Thailand signaling new introductions of H274Y onto multiple Brisbane/59 genetic backgrounds (clade 2B).
Thus, the global expansion of H274Y is dependent of the spread of the Northern-EU-like strain, but is also spreading via a series on new introductions onto multiple genetic backgrounds with are also clade 2B, but distinct from the isolates in the countries with the highest levels of H274Y.
This global expansion is almost certainly due to the acquisition of these other sub-clades via recombination with Northern EU-like sequences. These sequences are closely related and differ by a single amino acid at the protein level, although there are many additional differences at the nucleotide level. Thus, these synonymous changes generate the new branches on the phylogenetic trees, but these isolate are antigenically close.
This acquisition of H274Y onto multiple closely related genetic backgrounds, is similar to G743A concurrent acquisitions onto NA in H5N1 isolates. Like the H274Y example above, the global expansion was sudden and involved a large number of similar (clade 2.2) but distinct genetic backgrounds, which mapped to branches that included isolates without the acquisition.
This type of expansion of a signal nucleotide polymorphism is most easily explained by homologous recombination with a common source, which leads to sudden and dramatic expansion of a given polymorphisms onto multiple genetic backgrounds.
For H274Y, the expansion has serious implications for use of Tamiflu to control a pandemic H5N1. H274Y is also the major Tamiflu resistance change on N1 in H5N1, so an efficiently transmissible H5N1 could easily infect H1N1 positive people, leading to Tamiflu resistance on H5N1, even in the absence of Tamiflu usage.
Thus, even though H274Y on seasonal flu does not lead to changes in the clinical course, the dramatic increase in the N1 pool of H274Y raises serious pandemic concerns.
Northern EU-like isolates with H274Y
Arizona/03/07
Arizona/13/07
Arizona/14/07
Arizona/15/07
British Columbia/RV1585/07
England/557/07
Illinois/10/07
Sydney/142/07
Sydney/143/07
Sydney/144/07
Maryland/04/07
New Jersey/15/07
New Jersey/16/07
New Jersey/20/07
Norway/1630/07
Norway/1651/07
Norway/1684/07
Norway/1687/07
Norway/1701/07
Norway/1731/07
Norway/1736/07
Norway/1743/07
Norway/1745/07
Norway/1747/07
Ontario/RV0131/2007
Paris/0577/07
Paris/0644/07
Hawaii/01/08
Hawaii/02/08
Indiana/01/08
Lisbon/3/08
Memphis/3/08
Minnesota/1/08
New Jersey/05/08
New Jersey/06/08
New Jersey/10/08
North Carolina/2/08
Pennsylvania/02/08
St Petersburg/16/2008
Trinadad/14/2008
Washington/01/08
Wisconsin/01/08
Yokohama/77/08
Yokohama/78/08
Yokohama/79/08
"Hawaii" like isolates with H274Y
Hawaii/21/07
Hawaii/28/07
Lyon/1337/07
Thailand/1577/2007
Aichi/76/08
Athens/41/2008
Florida/2/08
Gifu-C/17/08
Gifu-C/38/08
Kobe/27/08
Shimane/59/08
Tochigi/8/08
Tochigi/34/08
Tochigi/39/08
Tottori/21/08
Tottori/23/08
Tottori/28/08
Tottori/29/08
Volos/108/2008
Yamagata/68/08
Yokohama/22/08
Yokohama/30/08
Yokohama/31/08
Yokohama/34/08
Yokohama/35/08
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