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Predictable Evolution in Tamiflu Resistant H1N1
Recombinomics Commentary 14:18
March 18, 2009

Recently released H1N1 sequences at Genbank and GISAID include multiple receptor binding domain changes in emerging Tamiflu resistant H1N1. The predictability of these changes is quite remarkable.  The hitch-hiking paper is being updated with the more recently released sequences from this season, which describes the importance of the receptor binding domain changes.  Some of these changes are detailed in the HA tree (slide 14) from the CDC, but that tree is not fully annotated.  The emerging H1N1 isolates all have A193T, but each of the 5 newly formed branches is rooted in addition receptor binding changes, and all are at three flanking positions (187, 189, 196).  There are two polymorphisms at 187 (N187S and N187D) and 196 (H196R and H196N), as well as four at position 189 (G189A, G189N, G189S, G189V).

The top branch in the CDC tree is labeled with G189A (as well as S145N).  These acquisitions are widespread in Asia (including most isolates in Japan, South Korea, and Taiwan) and are associated with vaccine resistance.  All five of the first H1N1 isolates from Italy had these acquisitions, and three of the isolates were from patients who had been vaccinated this season.  Similarly, Taiwan reported that 70% of the H1N1 isolates there were vaccine resistant.  These changes are also in US isolates, but are fairly rare.

The second branch in the CDC tree is labeled with G189V and H196R.  All isolates are from the US and this is the dominant strain in the US.  However, this sub-clade is also in Japan and was linked to school closings in Sendai last fall, as described earlier.

The third branch in the CDC tree is labeled N187S, but there are actually two sub-clades in this branch. One was detailed in the hitch-hiking paper and has N187S and G189N.  These isolates were in South Africa and Australia in the summer of 2008 and are in Kenya in the fall.  There are a few isolates in the US.  However, a more common sub-clade in the US has N187S and G189S.

The fourth branch in the CDC tree only has two US isolates, and is not annotated.  However, this sub-clade is fairly widespread in the US and is also in Argentina.  These isolates have N187D.

The fifth branch in the CDC tree has one isolate from China (Jilin), but there are now multiple isolates from Jilin, as well as isolates from South Australia, which fall on this branch and these isolates have H196N.
Thus, ever major branch that has emerged this season has A193T (and hitch-hiking H274Y on NA) as well as at least one adjacent HA change, which is limited to three positions (187, 189, 196).

As described in the paper, the changes for the acquisitions can be found in other H1N1 isolates that are co-circulating with the emerging H1N1, providing additional support for acquisitions via recombination, and for predictions based on such circulating polymorphisms.

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