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Commentary
Silent Spread of
Tamiflu Resistance in Texas
Recombinomics
Commentary 17:41
December 16, 2009
The associate of H274Y with a receptor binding domain change raised concerns, because the fixing of H274Y in seasonal H1N1 also involved a receptor binding domain change, A189T. Moreover, the same position change, S193F, was linked to the fixing of Adamantane resistance, S31N. A second receptor binding domain change, D225N, was also associated with fixing of S31N, raising additional concerns over linkage of H274Y with changes at position 225.
Recently, JCVI in association with Baylor University and the Methodist Research Institute released a large number of H1N1 collected in Brownsville and the Houston area in the spring and summer. None of these sequences had H274Y, but three sequences, A/Texas/45061755/2009, A/Texas/45061670/2009, A/Texas/45034157/2009, had D225E. Moreover, the three sequences with D225E also had the same changes found in A/Hong Kong/2369/2009 and A/Tennessee/17/2009, raising concerns that the samples were mixtures wit H274Y in a minor species that wasn't represented in the published consensus sequence.
Concerns about mixtures were increased by the recently released detail on the Hong Kong sequence. Although the sequence itself had no mixed signals, the tracing that produced the sequence did show a minor wild type sequence for codon 274. Moreover, when clone were generated from the original clinical sample mixtures at codon 274 were also found, but at frequencies that were almost equal. Thus, approximately half of the sequences from the patient had H274, raising concerns that mixtures were widespread and transmitted.
The latest ECDC report on influenza also noted that the H274Y sequences from the Netherlands also were mixtures and suggested H274Y was due to spontaneous mutations within the patient. However, there has been no evidence present to support spontaneous generation. There have been several reports of H274Y in samples that were from patients who initially tested as wild type, but the detection of H274Y was shortly after the start of Tamiflu treatment, indicating the H274Y was detected because of selection of a minor population already present prior to treatment.
Thus, the sequences from Texas, which were wild type but had markers associated with H274Y, raise concerns that H274Y was silently spreading and sequencing of additional clones from these patients would be useful.
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