Washington29 PB2 Virulence Factor Domain, Mixed Signal at residue 703 Matches Shanghai71T from May

Segment 1 (PB2) of the previously deposited TamiFlu Resistant Washington29 specimen was entered this evening at GenBank with a mixed signal at residue 703, downstream from a recognised Virulence Factor at 701.

We have seen movement at those residues within ΣPF11^* previously in a very important Chinese sequence.  The May 31 version of A/Shanghai/71T carried the following PF11 PB2 Polymorphisms including Virulence Factors¹.

• E627K
• D678N
• D680N
• D701N
• R703K

Considerable laboratory effort continued with this Chinese specimen due to the Trait-Enhancing nature of the E627K genetic acquisition.  The first Shanghai71T sub-clone also carried E627K; whereas, the second sub-clonal version published on 2009-06-24 of Shanghai71T reversed all but the 703K.

We have also noted variance within ΣPF11 and potential donor candidates in the adjacent upstream area to the Palese lab's PB2 Virulence Domain.  Movement at residues coding for amino acids 674T and 677G are noted in particular and may require additional study to determine trait correlation. 

674T features on a Hong Kong swine (HKswNS1659), a lab virulent Puerto Rico8 variant (LabVir_hvPF8), the last two previous Seasonal H1N1 reservoirs and is found in conjunction with 627K, the Seasonal NA Quadruple Combination (106I, 248N, 275Y, 286G) and TamiFlu Resistance on the 2009 H1N1 Seasonal specimen A/Shanghai/LWS1.  677G is found on the PF11 background throughout Europe and the US Eastern seaboard, but more importantly is in conjunction with 627K on 2006 and 2007 Indonesian H5N1 specimens.

The TamiFlu Resistant Washington29 sequence in the United States acquiring PB2 material in and around this recognised PB2 Virulence Domain begins to build a formidable virus.

1. Steel J, Lowen AC, Mubareka S, Palese P (2009) Transmission of Influenza Virus in a Mammalian Host Is Increased by PB2 Amino Acids 627K or 627E/701N. PLoS Pathog 5(1): e1000252. doi:10.1371/journal.ppat.1000252

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TamiFlu Resistance in Texas with no sample date, NA:H275Y

The NA and HA for A/Texas/47 was deposited today at GenBank with no sample date, host age or clinical notes and is a close amino acid match to the Washington28 resistant sequence.

The NA of TX47 is an exact nucleotide match at all positions (1409) but C823T (TamiFlu Resistance) with Nanjing02, Pennsylvania10, Illinois04 and Arkansas03.

TamiFlu Resistance is indicated via 275Y on the Neuraminidase.  The sequence displays the following NA Quadruple Combination:

106V, 248N, 275Y, 286S

The following permutations are now represented on the eight PF11 anti-viral resistant sequences:

106V, 248N, 275Y, 286S = WA28, WA29, TX47
106I, 248N, 275Y, 286S = Osaka180
106I, 248D, 275Y, 286S = HK2369, Yamaguchi22, Denmark528, Hunan SWL3
 
Until the 2009-08-21 deposit of the two Washington sequences, all 275Y TamiFlu-Resistant specimens on PF11 backgrounds were paired with 106I.  Today we see 3 of 8 with 106V.
 
The trending toward a stronger pairing of 248N with 275Y continues as discussed in the Washington Post with a 50 / 50 split of the specimens carrying Asparagine (N) and Aspartate (D). 
 
The Hydra Effect will be more strongly documented when the population size of the sequence database increases. 

An n equal to 8 gives little to contemplate.

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HA:237I Downstream from RBD in TaiwanT1821 and 4 Russian Specimens

A rare Isoleucine, 237I, occurs within ΣPF11 downstream from the Receptor Binding Domain in A/Taiwan/T1821 sampled 2009-05-30 and in 4 Russian sequences.  206T is shared in all five 237I sequences.

Three of the four Russian sequences are from Moscow and were sampled on 2009-05-26 in the same week as the Taiwan sequence.  The fourth is Irkutsk02 that also carries the RBD polymorphism 226R.

An intra-segment exclusivity exists between 206S and 237I at this time upon PF11 backgrounds.

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Italy HA Homology to two TamiFlu-Resistant Asian Specimens

• A/Italy/130, sampled 2009-06-10 from a 43M

Italy130 is an exact nucleotide match on segment 4 (Hemagglutinin/H1) with the TamiFlu-Resistant A/Hunan/SWL3 from China, with 21 North American sequences and with 1 sequence from Sao Paulo, Brasil.  Furthermore, Italy130 is a 1700/1701 nucleotide match to TamiFlu-Resistant A/Yamaguchi/22 from Japan.

No segment 6 (Neuraminidase/N1) is published  for any of the 6 Italian sequences released today, including Italy130; ergo, TamiFlu-Resistance cannot be invalidated by data. 

Absence of data is apparently being commissioned as the new art form?

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Taiwan Deposits 3 Sequences Today: 206T found in 7 of 8 Taiwan Samples on File, 296H in the 8th.

Taiwan has 8 PF11 sequences on file at GenBank from mid-May to June 2009 across a somewhat representative sample of host ages (5, 19, 22, 24, 27, 32, 32 and 52).

The 3 new sequences today, sampled in June, continue the local trend of 206T conservation on Hemagglutinin. 7 of the 8 Taiwan sequences on file carry the Threonine at 206.

Of special interest is the 8th sequence, A/Taiwan/T1773, submitted on 2009-08-10 from a 19F sampled in late May showing 206S and the only 296H in Taiwan, demonstrating again the intra-segment exclusivity of 296H and 206T. Though geographic and timing consensus is 206T in Taiwan, the 206S in the 19F appears with the 296H.

TaiwanT1773 also demonstrates the strong pairing between 296H and the 2E originally found in 1918 sequences and now several PF11 HA segments.

The TaiwanT1773 sequence matches Finland555 and its 19 equal worldwide sequences (NE US, Italy and Brasil) but for the disquieting combination SNP and downstream adjacent deletion near the tail of the HA. Furthermore, the TaiwanT1773 sequence is distinct at a different position from each of other regional 296H carriers, e.g. Shanghai143T, Tokushima1, and Shandong1.

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Toronto Adds 2 Sequences to NA Triple Combination Analysis with 286G

Toronto sequences filed at GenBank today add numbers 29 and 30 to ΣPF11 for 286G on Neuraminidase .  The bulk of the PF11 286G sequences cluster in Catalonia, but these two sequences from Toronto augment a NA Triple Combination occurring in Canada.  Canada and Catalonia are the only regions of the world currently reporting this PF11 coding that is also found in 1918 sequences, the high-CFR H5N1 Gharbiyah, Egypt specimens and is common in Seasonal Influenza from 2006, 2007 and 2008.

• A/Toronto/T5294/2009 (TorT5294) collected on 2009-05-30 from 22F
• A/Toronto/C0270/2009 (TorC0270) collected on 2009-05-24 from 33M

These two new Toronto specimens and the other four original Canadian sequences carrying 286G also code for 106V and 248N matching the two TamiFlu resistant sequences from Washington at 106 and 248.

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, 286G

These two sequences from Toronto in May 2009 follow the worldwide pattern exhibiting a particular permutation of the NA Triple Combination:

106V, 248N, 286G

The two sequences parallel the previously discussed TorontoT5308 sequence with the exception of TorT5294 also showing 382A.

Of the 30 sequences on file bearing 286G, all but Catalonia397 bear 248N and all 30 show 106V.  An intra-segment exclusivity on NA exists presently in PF11 between 106I and 286G though 106I donors are proximal in Catalonia and Canada.

Are we seeing enhanced conservation within a PF11 sub-clade being primed for TamiFlu Resistance?

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NA 106V and 248D in April 2009 Toronto Sequence Released Today, Distinct

A/Toronto/3184, sampled in April 2009, now becomes the ultimate origin on file for the Northern Hemisphere for the previously discussed 4th permutation of the NA Dual Combination at amino acid positions 106 and 248.

This early PF11 sequence demonstrates 106V and 248D and appears distinct from the April 2009, A/Auckland/4, and the A/Toronto/R8564 specimen sampled in July that are the only other sequences in the PF11 reservoir on file with these two amino acid codings.  The Toronto3184 NA is most similar (1422/1423) to a series from Stockholm, Zhejiang2 and Finland555 (all 106I).

The NA Dual Combination of 106V and 248D is found 3 times: New Zealand and Canada (April) and Canada (July).

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296H on Hemagglutinin in Young Victims Continues to Broaden into Canada

A/Toronto/T9842 sampled on 2009-06-17 from a 9 year old and A/Toronto/T5362 sampled 2009-06-09 from a 14 year old demonstrate the Genetic Acquisition of 296H.

As of this time in the PF11 reservoir, the rare 296H (in less than 40 specimens) remains exclusive of 206T.

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Toronto re-emergence of 4th PF11 Neuraminidase Permutation at positions 106 and 248

A/Toronto/R8564, sampled 2009-07-06, rescues the 4th permutation of the NA Dual Combination at amino acid positions 106 and 248.  The PF11 sequence demonstrates 106V and 248D, a combination that was previously found only once within ΣPF11, early in the pandemic in April 2009, A/Auckland/4. 

This re-emergence of the permutation returns a 4th version of the NA Dual Combination to activity on PF11.

The TorontoR8564 NA is an exact amino acid match to the Auckland4 sequence from April.  The certain interchange that occurs between the two cities on a regular basis would lead us to investigate for re-assortment potential.  However, re-assortment is impeached from this investigation due to the 2 polymorphisms at the nucleotide level:

Several Auckland sequences carry the G76A.

G355A is found in only 14 worldwide ΣPF11 strains:  Toronto, China, Japan, Spain, Australia and 5 in the Southern United States.

The N1 backgrounds are widening in a fashion suggestive of non-random genetic acquisition with this completion of the permutation set concerning the NA Dual Combination at positions 106 and 248.

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Hemagglutinin of NewYork4014 (2009-06-10) is exact match to Tokushima1 (2009-06-02) with 145I and 296H.

A sequence from Broome County, New York deposited today at GenBank, A/New York/4014, is an exact match on the Hemagglutinin to the Japanese sequence, A/Tokushima/1.  NY4014 was sampled 8 days after the Japanese sequence.

These two sequences are also an exact HA match to a previous NY sequence, A/New York/3573, taken 2009-05-21.

The NY4014 and Tokushima1 homology fails on other gene segments as the NY4014 appears relatively stable to the PB2, NA and NS1 segments' PF11 consensus. The NY4014 NS1 is an exact match to NY3573.

Of particular note on the NY4014, Tokushima1 and NY3573 HA segments is the 145I that sets apart only 6 sequences within ΣPF11:

As you can see from the table, the most current samples with 145I carry 296H, a polymorphism of interest on HA.

The intra-segment exclusivity trend between 296H and 206T continues to exist within ΣPF11.

A NY-Japan-NY segment transfer is not surprising given international air travel.  A more robust database would allow greater acuity into the interpretation of the ultimate origin of this rare HA event.

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