United States TamiFlu Resistant NA Triple Combination Analysis

Until today, all ΣPF11 H275Y* cases on file carried 106I on Neuraminidase.

Two TamiFlu resistant sequences from Washington landed with 106V.  Each common amino acid at 106, Isoleucine and Valine, is now represented within ΣPF11 TamiFlu resistant sequences. Additionally, WA28 and WA29 are two of only three TamiFlu resistant strains to carry 248N; Osaka180 is the third. The remaining four GenBank sequences show 248D.

Note the reversal of amino acids in ΣPF11 at residue 248 on the pairings (248 and 275) from Seasonal H1N1. Seasonal H1N1 from 2008 into 2009 is predominately 248N on TamiFlu resistant strains with only three 248D sequences. Conversely, the largest percentage of PF11 TamiFlu resistant strains carry 248D (57%). Does the 248N from WA28, WA29 and Osaka represent the logical emergence of a second viable branching with 275Y on the PF11 background?

Surveillance is incomplete. No conclusions may be drawn at this point.

Human-fit Seasonal H1N1 from 2008 and 2009 typically demonstrates the H275Y TamiFlu Resistance marker and a NA Triple Combination at 106, 248 and 286:

106I, 248N, 275Y, 286G

Outside of the TamiFlu marker at residue 275, the remaining three aspects of the Seasonal H1N1 NA Triple Combination showing 106I, 248N and 286G are now represented in several dual permutations on the PF11 background. The variation through individual acquistion is trackable and continues in the past 12 weeks to increase geographically, suggesting a progression to a potential fixing of the entire human-fit, NA Triple Combination on PF11 templates.

At this time, 17 PF11 specimens carry 2 of the 3 NA Triple factors. 13 of those 17 cases are concentrated in a tourist area of southwestern Europe that also has PF11 specimens circulating in geographic proximity with the third seasonal marker, 286G, required to complete the NA Triple. These markers in the NA Triple Combination may herald as precursors for ease of TamiFlu resistance acquisition or may simply mark a more human-fit Neuraminidase.

With those prerequisites concerning the base of PF11 in place, now we return to examine the currently published PF11 TamiFlu resistant sequences against these NA Triple Combination markers. The following permutations are now represented on the seven PF11 anti-viral resistant sequences:

106V, 248N, 275Y, 286S = WA28, WA29
106I, 248N, 275Y, 286S = Osaka180
106I, 248D, 275Y, 286S = HK2369, Yamaguchi22, Denmark528, Hunan SWL3

Can we ascribe this set of unusual permuations to typical Pig=>Human Influenza Flux? As 248N continues to spread widely on PF11 backgrounds, will the pairing of 248N and 275Y become dominant or will we see a future Hydra Effect with two fit branches?

* N1 numbering equal to H274Y TamiFlu resistance in H5N1

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