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Curious Tamiflu Resistance in Florida
Recombinomics Commentary 23:30
May 21, 2008

Lina's team tested more than 2,600 samples of flu viruses from patients in Europe and found baffling patterns of this resistance that appeared to have nothing to do with actual use of Tamiflu.

For instance in France, 54 percent of those tested in Paris carried the mutation that would give resistance to Tamiflu, compared to 29 percent in southeastern France. "Which makes absolutely no sense," Lina said.
Patients showed no difference in their symptoms if they were infected with resistant virus, he noted.
"It's difficult to understand. I have no idea why these viruses emerged," he said.

The above comments indicate that the influenza experts are still baffled by the sudden emergence of oseltamivir (Tamiflu) resistance in H1N1.  Although H274Y was thought to develop with an associated fitness penalty, the rapid spread of the polymorphisms clear shows that there is no fitness penalty.

Some of the sequences have been made public, including a recent partial sequence from Hong Kong.  It was virtually identical to isolates from England, Turkey, and multiple locations in the US, further confirming that the H1N1 with H274Y was fit.

However, in the US the change has appeared on multiple genetic backgrounds, indicating spread was also facilitated by independent events.  The change first began to appear in public sequences from the 2006/2007 season.  These initial isolated were the New Caledonia strain.  However, this season the incidence increased markedly and the H274Y was on a Brisbane genetic background.  The movement of H274Y from one genetic background to another can be accomplished by recombination, and the timing of the initial outbreaks raise concerns that they originated in H5N1, which has the identical change and has been reported in patients as well as wild birds.

In the US, the change also appeared in isolates from Hawaii, which mapped with other isolates from Hawaii and California.  The detection of H274Y in a subset of isolates on this branch indicates these patients were infected more recently.

Similarly, one of the newly released sequences from Florida, A/Florida/02/2008, also had the change, and it mapped with other isolates from Florida which did not have the change, again signaling a recent independent event.  However, these Florida isolates also share a polymorphism that is almost exclusively found in N1 from H5N1 (see list here) again signaling recombination between N1 in H1N1 and N1 in H5N1.

In addition to avian polymorphisms in human isolates, there have been human polymorphisms in avian isolates, as described in the PB2 gene in H5N1 isolates in  Egypt, suggesting there may be significant interactions between these viruses.  Last season Egypt reported a large number of mild cases in its central and southern regions.  Only one in 17 confirmed cases was fatal and most patients did not develop pneumonia.  Such cases could be far greater than the number confirmed, because mild cases would frequently resolve without hospitalization or testing.

Thus, these interactions could be significant, and could explain the sudden appearance of H274Y in H1N1 following prophylactic use if oseltamivir to control H5N1.

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