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H274Y Tamiflu Resistance Explodes in Tottori Japan
Recombinomics Commentary 22:15
July 11, 2008

According to the preliminary report from a local health laboratory, oseltamivir resistance prevalence have been dramatically increasing in Tottori prefecture located at west of the main island of Japan (30% of total isolates in the prefecture, analysis in detail is ongoing).

The above comments are from Japan’s recent update on H274Y in H1N1 seasonal flu.  Although overall, the incidence of H274Y in H1N1 isolates was only 1.6%, as noted above the Tamiflu resistance frequency is exploding in Tottori.  In addition to a description of many of the resistant cases, the report has an NA phylogenetic tree of the isolates from Japan along with several of the public sequences from the United States and England.

The largest group outside of Japan is listed as “Northern EU-like” and this version of H5N1 has also reached Japan (in isoaltes from Yokohama).  However, the tree has four of the isolates from Tottori, which map onto two branches which are distinct from the large branch which also has isolates from the United States, France, and England.

One of the branches with 2008 Tottori isolates (numbers 28 and 29) also has A/Washington/28/07, which is a public sequences that is closely related to other isolates from the state of Washington (33, 34, and 40).  None of these four closely related isolates from the state of Washington have H274Y, but both isolates from Tottori do, indicating the H274Y was acquired after this set of isolates formed a separate branch.  Thus, the acquisition of H274Y by these two Tottori isolates was independent of the isolates in the larger “Northern EU” group.

Similarly, the other two Tottori isolates (numbers 23 and 21) fall onto another branch which include other public sequences from the United States.  The upper portion of this branch include two H274Y isolates from Hawaii (21 and 28), but the upper branch has other isolates that do not have H274Y, as seen in the tree from Japan (Hawaii/31/07 and Miyagi23/08).  Other public sequences also map to the upper portion of this branch (Hawaii/35/07, Hawaii/18/07, California/28/07), indicating the two positives from Hawaii are distinct from the positives listed above.

Moreover, on the lower portion of the branch, which has the two isolates from Tottori, are other isolates from Japan that are negative for H274Y (Shiman/7/08, Yamaguchi/14/08, Kyoto-C/1/08) along with two isolates that are positive (Gifu-C/17/08 and Gifu-C/38/08), indicating these isolates are also due to introductions that are independent of the isolates above.

The acquisition of the same polymorphisms onto different genetic backgrounds circulating in the same geographical area is similar to H5N1 data for poultry in the Nile Delta.  In those cases distinct genetic backgrounds acquired the same change (G743A) at the same time, which was supported by related sequences which did not acquire the change.  Thus, the same change among a small number of acquistions cannopt be easily explained by a "random mutation" mechanism.

Attempts to explain these acquisitions via the current basic tenet from influenza drift, selection of random mutations, is difficult.  The H5N1 examples involved a synonymous change.  Similarly the sudden appearance of H274Y has appeared on multiple genetic backgrounds in patients who were not taking Tamiflu.

Consequently, influenza “experts” have been startled by the sudden appearance of Tamilu throughout the world on multiple Brisbane/59 genetic backgrounds.  However, these acquisitions are readily explained by recombination between closely related sequences, such as those defined above.

These concurrent acquisitions of single nucleotide polymorphisms continue to raise serious doubt about the roll of de novo mutations in the creation of antigenic or genetic drift.

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