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Sequential Acquisition of Adjacent Vintage H1N1 Polymorphisms
Recombinomics Commentary 22:35
August 21, 2008
Recently released H1N1 sequences from South Africa confirmed earlier reports indicating that Tamiflu (oseltamivir) resistance was running at 100% in the first 23 isolates sequenced. Recently, the South African data has been updated with results on the first 107 isolates sequenced, and all were Tamiflu resistant. Similarly, 100% of the first 10 isolates in Australia are also Tamiflu resistance.
The HA and NA sequences from South Africa fell into two major sub-clades. Five of the 8 HA sequences had a cluster of five polymorphisms (A599G, G604A, G605A, C609T, G616A), which created three non-synonymous changes (N187S, G189N, A193T). The A193T change had been seen earlier in H1N1 isolates from the 1940’s. The G616A change created a 16 BP region of identity between recent isolates and those from the 1940’s (see list below). All but one of the recent isolates had H274Y in the public NA sequence with the exception of A/New Jersey/08/2008, which had Q136R, which is likely associated with Relenza (zanamivir) resistance (Q136K has been shown to confer Relenza resistance).
The clustering of the five sequences suggested that the changes were acquired via homologous recombination. This mechanism was further supported by the subsequent acquisition of the adjacent polymorphism, C609T, which is also present in H1N1 isolates from the 1940’s. The sequential acquisition by these adjacent polymorphisms demonstrates how one acquisition can create larger islands of identity, which then lead to additional acquisitions from related parental strains.
Release of additional sequence data on the more recent resistant isolates would be useful. These changes surrounding the receptor binding domain sequence at position 190 further suggests that the new H1N1 vaccine targeting Brisbane/59 will once again be chasing H1N1 evolution, and will have limited utility.
Isolates with 16 BP of identity
Recombinomics Paper at Nature Precedings