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The CDC has deposited HA and NA sequences at Genbank, which will be available shortly (see list below). As expected, all are clade IIB (Brisbane) and have H274Y. One sequence from August, A/Missouri/06/2008, was also released and it is the only oseltamivir sensitive isolate. However, it is clade IIC, and like the clade IIC isolates in the US last season and over the summer, it is adamantidine resistant and oseltamivir sensitive.
The new sequences have evolved from the dominant sub-clade in circulation last season, and have changes that led to dominance last season and in the 2008 season for the southern hemisphere. As noted earlier, one US sequence from the summer had the clustered changes near the position 190 receptor binding domain. The current sequences have one of the polymorphisms in that cluster A193T.
Most of the new sequences formed a branch that included Memphis/03/2008 and Hawai/02/2008. The new isolates on this branch were from Hawaii, Texas, and Pennsylvania, so more samples are required to see the full distribution of this sub-clade.
However, the sequences from these initial isolates indicate that the changes that initiated dominance last season, have been maintained over the summer and into the new season. These dominance changes were acquired via recombination from clade IIC sequences.
"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
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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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
Both sequences for Hawaii/20 have K136 (Relenza resistant).
Correction. The above has to do with HA sequences which has nothing to do with Relenza resistance.
Other than two clade 2C HA sequences (one from summer and one from fall from isolates that are Tamiflu sensitive and amantadine resistant) all are clade 2B, map to the same branch, and appear to have A193T.
These isolates are spread out across the country and some were collected as recently as late december, 2008.
A193T Fixed in Tamiflu Resistant H1N1 in United States Recombinomics Commentary 15:52 February 11, 2009
The US CDC has released 43 HA and 42 NA sequences from H1N1 isolates. Two of the HA sequences were clade 2C (Hong Kong), which are oseltamivir sensitive and adamantine resistant. One of the isolates was from the summer, while the other was from the fall. The remaining 41 isolates were from the fall and the vast majority were collected in November and December, 2008. The CDC is to be commended for the timely release of these important and evolving sequences.
These recent 41 isolates are all clade 2B (Brisbane) and all had H274Y. Phylogenetic analysis indicated all isolates were related to a sub-clade that emerged last season in the United States and Europe. All HA sequences from this sub-clade had A193T. Over the summer the dominant sub-clade in South Africa was also from this sub-clade and had N187S and G189N in addition to A193T. Recent sequences from Kenya also had this series as did an isolate from Washington State collected over the summer.
Isolates from the early fall in the US also evolved from this sub-clade. All isolates had A193T and the dominant sequence also had G189V and H196R. This dominant sequence was from isolates in HI, TX, and PA. The same set of receptor binding domain changes, was report in Japan, including a large outbreak in elementary schools in Sendai. These data supported the emergence of H274Y via recombination and hitch hiking, which was described in a recent paper in Nature Precedings.
The recently released sequences support and extend the above observations. The majority of HA sequences have the same set of receptor binding domain changes, G189V, A193T, and H196R. However, sequences with these changes were collected from isolates throughout the US (see list below).
A smaller series (see list below) was similar to the South Africa/Kenya sequences and had S187N and A193T. However, these isolates had G189S instead of G189N, which was also noted in an earlier phylogenetic analysis, which included isolates from Seychelles.
Although there were some additional variations, all recent clade 2B isolates from the US had A193T and supported its role in the genetic hitch-hiking by H274Y, which has led to H1N1 levels approaching 100% across the northern hemisphere. A recent WHO update on isolates collected over the same time period in the last quarter of 2008. The only northern hemisphere country with levels lower than 97% was China.
"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
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