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S246N Tamiflu Resistance - Recombination & Clonal Expansion
Recombinomics Commentary 23:15
June 10, 2011

The recent Eurosuveillace rapid communication, “Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation, describes a rapidly expanding NA genetic change, (S246N – N2 numbering) that confers modest resistance to the two major influenza anti-virals, Tamiflu (oseltamivir) and Relenza (zanamivir)>  This could have profound clinical significance due to the characteristics of the drugs, which are useful when used at optimal dosage, but frequently lead to further resistance when used at sub-optimal levels.  Further resistance would be a problem since the genetic change at position 246 can synergize with the more common position for N1 resistance, H274Y, producing a 6000 fold increase.

The paper provided support for the spread of S246N via two mechanisms, recombination and clonal expansion.  The phylogenetic tree below (larger version here) identifies isolates with S246N, including 2011 isolates in the expanded panel. 

S246N Phylogenetic Tree

The top branch in the expanded panel contains isolates from the S188T sub-clade (labeled HA-S202T in the figure), the largest current sub-clade in circulation.  This branch has three isolates with S246N (A/Singapore/KK64/11, A/Brunei/1/11, and A/Montana/03/11, but each isolate is on a separate branch, signaling the recent acquisition via recombination.

Recombination allows the same genetic change to jump from one branch to another, or one sub-clade to another.  S246N is concentrated in another sub-clade with A/Singapore/TT89/11 at its base, with 17 additional isolates from Singapore or Australia with S246N.  Thus, these additional 17 isolates, which were collected in 2011 or late 2010, all represent clonal expansion of an isolate containing S246N.

This jumping from genetic one genetic background to another, followed by the clonal expansion of a resistant sub-clade in the absence of drug treatment follows the pattern for the fixing of H274Y in seasonal H1N1 in the 2008/2009 season.

Concern for a repeat of this fixing of resistance is increased by recently released Pandemic H1N1 sequences from Italy.  In most cases only the HA sequence was released, which matched the clonally expanding sub-clade in Singapore and Australia.  The HA sequence for these isolates has E359A (labeled HA-E373A on tree) which is present in Italy (see list here and here).

The NA sequence from one Italian isolate was released.  Although it did not have S246N, it was virtually identical to Singapore/TT89/11 rising concerns that the sequence with S246N has already expanded in Italy and Europe, or will rapidly expand in the southern hemisphere in the current season, and become fixed in the northern hemisphere in late 2011.

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