Commentary
Emergence
and Fixing of H1N1 Tamiflu Resistance
Recombinomics Commentary
15:01
December 24, 2008
The recent release
of H1N1 HA and NA sequences from this season in the United States,
coupled with the release of HA sequences from isolates collected last
season in Norway,
allows for phylogenetic analysis and polymorphism tracing to detail the
fixing of H274Y in clade IIB (Brisbane/59).
Earlier analysis indicated that the widespread distribution of H274Y
was linked to the emergence of a dominant sub-clade, which included
isolates in Norway, where H274Y levels in H1N1 exceeded 65%.
Previously, H274Y had been reported in clade IIC (Hong Kong) in China,
followed by clade I (New Caledonia) in the United
States and United
Kingdom, followed by clade IIB in Hawaii.
However, although H274Y could jump from one genetic background to
another, which is most easily explained by recombination, the ealier
isolates did not become dominant.
However, when H274Y jumped to a sub-clade with tandem NA changes, D344N
and D354G,
which had been found in earlier IIC isolates, frequencies of H274Y
rose. The jump of these two polymorphisms to clade IIB led to H274Y
dominance in Norway, as well as high levels in several countries in
northern Europe.
Over the summer, the dominance rose to 100% in South Africa.
Those isolates had the tandem NA changes, but they also had a stretch
of 16 BP near position 190 in the receptor binding domain, which was in
the dominant sub-clade in the United States, and also found in H1N1
isolates from the 1940’s.
This stretch encoded for A193T,
which is found in all of the public clade IIC sequences from the United
States this season.
Moreover, 49 out of 50 H1N1 isolates in the United
States are resistant, suggesting this sub-clade is
widespread. The published sequences are from isolates in Hawaii,
Texas, Pennsylvania, and Wisconsin, as well as a Washington
state isolate collected over the summer, which had the cluster of
changes in the South African sequences.
The presence of A193T may have influenced influenza serotypes in the
United States and Europe. Only one public
European sequence from last season contained A193T. It was
not present in the more than 30 HA sequences from Norway, or other
sequences from several European countries, but is in last season’s
dominant sub-clade in the United States last season, and all clade II
isolates published for this season. In the United States, most
influenza is H1N1 and all but one was clade IIB, while in Europe most
influenza A is H3N2.
Release of H1N1 sequences from Europe and Canada would be useful.
These sequences likely have A193T also since H274Y is fixed in clade
IIB in these locations.
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