Sweden deposited a sequence today from mid summer that carries indicators worthy of study.
Matches include the rare alternate coding for 225G found in the Norway3206-3 fatality sampled 6 weeks after the Swedish case and the NA syn291V on that same Norwegian sample. Six weeks appear to be enough time for these changes to travel across borders. The HA sequences are identical, except for the 140S on Norway3206-3.
The two Scandinavian NA segments show a shared polymorphism at syn291V, a change that is found in 103 GenBank sequences including TamiFlu Resistant HK2369, Almati01, Tomsk01, Poland and with deep penetration through Italy and Catalonia. The G873A coding for the syn291V is also present in CatNS2001 and CatNS2008. The NA segment of Norway3206-3 is identical to the Swedish NA.
Only this profiled private Swedish sequence from mid summer, CatNS2001 and CatNS2008 from early August and Norway3206-3 from September carry this variant Glycine coding at amino acid 225 that is seen as T717A, GGt->GGa. Neither of the cross segment pair, HA syn413K or NA syn407V, appears in the recent Scandinavian samples.
The Swedish sequence is a nucleotide match with Norway2674 and Norway2690 except for the RBD polymorphism 225E on the Norwegian sequences. Dialing back the resolution by 1 nucleotide, we find that the Swedish sequence is a 1724/1726 match with 2 more Norway 225E cases, Norway3059 and Norway4023. Delta is indicated after link to sequence.
2009-07-27 Norway2674 Δ 225E
2009-07-29 Norway2690 Δ 225E
2009-08-11 Norway3059 Δ 225E + 1 nucleotide
2009-10-14 Norway4023 Δ 225E + 1 nucleotide
If we return to the tighter resolution again, we find that the Swedish sequence is a exact nucleotide match except for the two nucleotides coding for 225D on 6 additional sequences from Sweden (1), Germany (1) and Russia (4). Delta is indicated after link to sequence.
2009-__-__ Bayern66 Δ 225D
2009-05-21 MoscowIIV01 Δ 225D
2009-05-30 Stockholm33 Δ 225D Traveler from US
2009-06-09 MoscowIIV04 Δ 225D
2009-06-20 MoscowIIV05 Δ 225D
2009-09-22 Russia01 Δ 225D
This particular background is far from isolated. The homology between these 225D, 225E and 225G sequences raises a very basic question.
Does some mechanism in the protocol from sample to sequence potentially vary the outcome or block 225G materialisation on the resultant sequence? We know that lungs are being destroyed across extensive geography, yet few 225G sequences are being produced? Backing studies lead us to believe that 225G bearing samples will grow well in a receptor environment rich in α2-3-linked sialic acid.
MDCK cell lines specialised to overexpress α2-6-linked sialic acid at the expense of α2-3-linkedSA are being employed in Neuraminadase Inhibitor sensitivity testing, demonstrating that these canine cell lines are adaptable in linkedSA expression. Exactly how sensitive is the culture environment that is being used as a predecessor to sequencing? How consistent are the protocols and materials between labs?
Does a possibility exist that current MDCK cell lines being used are underexpressing α2-3-linked sialic acid in a manner consistent with the low numbers of resultant 225G sequences that have been published? Are samples that are originating with 225G not growing well due to a limited ratio of matched receptors? We specifically enquire here on the cell lines, but obviously all aspects of the growth environment must be inspected for inhibitors to 225G materialisation if the presenting sample sequences are to be accurately elicited.
Similar rare codings across 4 geographically dispersed sequences for Glycine at HA residue 225 and an NA syn291V occurring in temporal sequence from Sweden in late summer, to Catalonia in early August, and onward to Norway on September 1st beg for any explanation other than "spontaneous" mutation within a pandemic reservoir, ΣPF11, that is actively demonstrating an ability to share data.
Is 225G transmitting? Is 225G transmitting in 2 variant forms? Is 225G now confirmed as Hydra?
Showing posts with label Hydra Effect. Show all posts
Showing posts with label Hydra Effect. Show all posts
2009-12-02
2009-11-20
225G New to Norway and Ukraine; Worldwide Evaluation Concerning Range and Co-Circulation with 225E
“… viruses with a similar mutation had been detected in several other countries, including Brazil, China, Japan, Mexico, Ukraine and the United States. "No links between the small number of patients infected with the mutated virus have been found and the mutation does not appear to spread," ...”
If the official statement in today’s Washington Post is accurate concerning the circulating geography of the Norway polymorphism associated with several fatalities, then the only probable selection is 225G. Evaluating the meta-data of available published and partially public sequences, no other SNP of interest corresponds to the range stipulated.
The positive statement indicating low transmissibility of 225G, however, is not supportable at this time by solid evidence due to lack of surveillance using the proper tools and testing protocols. The statement is perhaps intended to assuage rather than inform.
Countries with Probable * or Confirmed 225G
Though the clinical attributions are not presently noted as a corollary to fatal cases like 225G, the accompanying changes and multiple backgrounds onto which the Glutamate at 225 (225E) is found may eventually provide a substantially more capable viral strain and most certainly is providing co-circulating sub-species of high interest alongside the 225G.
225G does, of course, merit scrutiny due to patterning with 230I on H1N1 Seasonal 2008 and 2009 sequences. If the range of 225G continues to smoulder, an attractant effect may draw 230I due to co-infection in areas that continue to have Seasonal H1N1 strains in circulation. The very high level of bird involvement in transporting genetics across serotypes may provide proximity, attraction and opportunity for H5N1 as a donor candidate for 230I due to verified H5N1 ranges at geographic inflection points for PF11. The world may not yet be seeing this permutation (225G & 230I) because the shortened infection to expiration timing also provides less time for viral recombination.
This 1918 and Avian SNP travels with H1N1 and H5N1 Avian polymorphisms indicating potential wild bird transport vectors. In a human host, the Avian modifications may find advantage at certain tissue types due to body core proximity providing basal temperature increases and may drive replication behaviour. The human lung may be precisely the correct temperature to promote rapid replication, more efficient binding or improved cleavage capability.
Influenza Flux will eventually find the appropriate or optimal combination of genetics to achieve stasis, but until that stasis of PF11>Ω is achieved, these sub-species will continue to be quite dangerous, demonstrating varying levels of Cytokinic Dysregulation according the host-pathogen interplay and the viral strain's capacity for temporarily suspending early catalysts to the innate immune response, including suppression of RIG-I ubiquination as the viral NS1 protein binds TRIM25 ultimately leading to reduced intra-cellular synthesis of Type I IFN. The timing and the level of RIG-I ubiquination suppression, thus interferon synthesis blocking, may eventually be found as the primary effector of host pathology from this IDRREAV, PF11. We feel that the evidence is well structured toward timing as an effector equal in importance to the level of inactivation / suppression.
225G gets the virus situated in the lung tissue and NS1 blocks the innate response. Add back the rapid replication at a multiplier over the speed of a Seasonal Influenza strain and you find an overwhelming viral load before any cell has signalled for assistance. When millions of viral particles erupt in a concentrated area from the lysed cells, the detritus alone drives an surging cascade of inflammatory cytokines. A slow response creates deadly risk. Then the body must take into account the travelling circus of sub-species that waste no time returning to their hard work of re-engineering the next cell for a viral production line.
As the data on 225G cases are released, including the sequences, presentation and progression, testing protocols, sampling protocols, prognoses, sequencing lab procedures and epidemiology, a higher level of interpretation may be made concerning these polymorphisms based on facts, rather than speculation.
A present 225G sequence set of less than 25 instances within ΣPF11 and those few having little to no associated clinicals does not provide a stable foundation at this time for determination of emergent characteristics such as rate of transmissibility, probability of co-infection with wildtype or spontaneous revision from wt due to tropism upon attaining deep lung infection.
If the official statement in today’s Washington Post is accurate concerning the circulating geography of the Norway polymorphism associated with several fatalities, then the only probable selection is 225G. Evaluating the meta-data of available published and partially public sequences, no other SNP of interest corresponds to the range stipulated.
The positive statement indicating low transmissibility of 225G, however, is not supportable at this time by solid evidence due to lack of surveillance using the proper tools and testing protocols. The statement is perhaps intended to assuage rather than inform.
Countries with Probable * or Confirmed 225G
- United States
- Brasil
- Spain
- Japan
- China
- Mexico
- Russia
- Australia
- Saudi Arabia
- Ukraine
- Norway *
- Singapore (4 with 225X encoded from aNy nucleotide) *
Though the clinical attributions are not presently noted as a corollary to fatal cases like 225G, the accompanying changes and multiple backgrounds onto which the Glutamate at 225 (225E) is found may eventually provide a substantially more capable viral strain and most certainly is providing co-circulating sub-species of high interest alongside the 225G.
225G does, of course, merit scrutiny due to patterning with 230I on H1N1 Seasonal 2008 and 2009 sequences. If the range of 225G continues to smoulder, an attractant effect may draw 230I due to co-infection in areas that continue to have Seasonal H1N1 strains in circulation. The very high level of bird involvement in transporting genetics across serotypes may provide proximity, attraction and opportunity for H5N1 as a donor candidate for 230I due to verified H5N1 ranges at geographic inflection points for PF11. The world may not yet be seeing this permutation (225G & 230I) because the shortened infection to expiration timing also provides less time for viral recombination.
This 1918 and Avian SNP travels with H1N1 and H5N1 Avian polymorphisms indicating potential wild bird transport vectors. In a human host, the Avian modifications may find advantage at certain tissue types due to body core proximity providing basal temperature increases and may drive replication behaviour. The human lung may be precisely the correct temperature to promote rapid replication, more efficient binding or improved cleavage capability.
Influenza Flux will eventually find the appropriate or optimal combination of genetics to achieve stasis, but until that stasis of PF11>Ω is achieved, these sub-species will continue to be quite dangerous, demonstrating varying levels of Cytokinic Dysregulation according the host-pathogen interplay and the viral strain's capacity for temporarily suspending early catalysts to the innate immune response, including suppression of RIG-I ubiquination as the viral NS1 protein binds TRIM25 ultimately leading to reduced intra-cellular synthesis of Type I IFN. The timing and the level of RIG-I ubiquination suppression, thus interferon synthesis blocking, may eventually be found as the primary effector of host pathology from this IDRREAV, PF11. We feel that the evidence is well structured toward timing as an effector equal in importance to the level of inactivation / suppression.
225G gets the virus situated in the lung tissue and NS1 blocks the innate response. Add back the rapid replication at a multiplier over the speed of a Seasonal Influenza strain and you find an overwhelming viral load before any cell has signalled for assistance. When millions of viral particles erupt in a concentrated area from the lysed cells, the detritus alone drives an surging cascade of inflammatory cytokines. A slow response creates deadly risk. Then the body must take into account the travelling circus of sub-species that waste no time returning to their hard work of re-engineering the next cell for a viral production line.
As the data on 225G cases are released, including the sequences, presentation and progression, testing protocols, sampling protocols, prognoses, sequencing lab procedures and epidemiology, a higher level of interpretation may be made concerning these polymorphisms based on facts, rather than speculation.
A present 225G sequence set of less than 25 instances within ΣPF11 and those few having little to no associated clinicals does not provide a stable foundation at this time for determination of emergent characteristics such as rate of transmissibility, probability of co-infection with wildtype or spontaneous revision from wt due to tropism upon attaining deep lung infection.
2009-11-13
Spain Demonstrates 225E and 80% Hydra Effect in Final Week of October
The astoundingly alacritous and accurate Hospital Clinic of Spain today released a number of very contemporary sequences at GenBank, including 10 HA, 10 NA and 11 MP segments sampled from 2009-10-26 to 2009-10-29.
225E is found in 6 of the 10 Hemagglutinin sequences. No 225G, 225N or 226R are found in these 10 sequences. All 10 sequences display 206T.
225E is Fixed and Conserved, I'd say.
Several new faces come into the PF11 reservoir with this deposit and among the 10 sequences we find the following amino acid codings, several of which you've watched emerge and then have tracked with us:
33I, 35I, 71G, 225E, 264D, 298V, 377K, 387D, 447K, 463T, 480K, 519N.
As you can see from the amino acid codings list, Influenza Flux is at work and recombinations are being recycled in the Mediterranean and Adriatic geographies.
CatS1600, CatS1604, CatS1605, CatS1606, CatS1620, CatS1632, CatS1637 and CatS1650 appear at first glance to be novel in HA permutation to ΣPF11 at GenBank. Across 3 days in one country, the Hospital Clinic samples 8 distinct HA segments springing at one time that are novel to the worldwide reservoir and co-existent with at least 2 previously discussed circulating strains.
CatS1641 and CatS1651 are each characterised with independent homology to earlier Catalonia strains and, on CatS1651, with recent Singapore entries as well.
10 sequences with 10 distinct HA segments in 1 geography during 1 time period of 3 days.
The Hydra Effect has never been more evident.
Due to time limitations, this analysis is far from complete and may involve error. As always, we invite independent verification on this short study.
225E is found in 6 of the 10 Hemagglutinin sequences. No 225G, 225N or 226R are found in these 10 sequences. All 10 sequences display 206T.
225E is Fixed and Conserved, I'd say.
Several new faces come into the PF11 reservoir with this deposit and among the 10 sequences we find the following amino acid codings, several of which you've watched emerge and then have tracked with us:
33I, 35I, 71G, 225E, 264D, 298V, 377K, 387D, 447K, 463T, 480K, 519N.
As you can see from the amino acid codings list, Influenza Flux is at work and recombinations are being recycled in the Mediterranean and Adriatic geographies.
CatS1600, CatS1604, CatS1605, CatS1606, CatS1620, CatS1632, CatS1637 and CatS1650 appear at first glance to be novel in HA permutation to ΣPF11 at GenBank. Across 3 days in one country, the Hospital Clinic samples 8 distinct HA segments springing at one time that are novel to the worldwide reservoir and co-existent with at least 2 previously discussed circulating strains.
CatS1641 and CatS1651 are each characterised with independent homology to earlier Catalonia strains and, on CatS1651, with recent Singapore entries as well.
10 sequences with 10 distinct HA segments in 1 geography during 1 time period of 3 days.
The Hydra Effect has never been more evident.
Due to time limitations, this analysis is far from complete and may involve error. As always, we invite independent verification on this short study.
2009-11-02
225E on 45% of Catalonia HA Deposit from August and September
The Hospital Clinic of Barcelona, Spain deposited 21 HA/NA/MP segments at GenBank on Friday. The group as a whole demonstrates significant diversity and the velocity of change at residue 225 in the Receptor Binding Domain is remarkable.
The samples are primarily from August and September, as late as 2009-09-30. One sample is earlier, from July. 9 of 20 specimens (45%) in this deposit that were sampled in August and September demonstrate 225E paired with 206T. As of this accumulation, Spain shows 31 instances of 225E with no 206S and 3 instances of 225G with 206T. Additionally, several unique faces enter ΣPF11 with the Hospital Clinic's latest deposit.
HA Amino Acid Codings to 3 Novel Polymorphisms and 6 Rare Signals
CatS1305, CatS1411, CatS1414, CatS1435.
Rare to ΣPF11.
Found in 6 other sequences including recent TamiFlu-Resistant US sequence, A/Texas/47.
Progenitors may include:
H5N1 Avian
H5N1 Human
71G
CatS1436.
NY80 is the singular ΣPF11 peer.
142T
CatS1411.
Novel to ΣPF11.
188N
CatS1369.
CatS1187 and Niigata700 are the lone ΣPF11 peers.
193G
CatS1384.
Novel to ΣPF11.
225E
CatS1300, CatS1304, CatS1331, CatS1333, CatS1350, CatS1369, CatS1379, CatS1436, CatS1453.
Presently velocitised within recent ΣPF11.
240R
CatS1436.
Novel to ΣPF11.
Progenitors may include:
Zhuhai/790/2008
H1N2 Swine
298V
CatS1369, CatS1436.
Unique to Catalonia within ΣPF11.
CatNS2001, CatNS2008, CatS1237, CatS1248, CatS1286.
373H
CatS1353.
Unique to Catalonia within ΣPF11.
CatS1285.
Neuraminidase Triple Combination
106I, 248D, 286S 20 Sequences
106V, 248D, 286S CatS1369.
The pattern shown by CatS1369 is found in 4 other instances within ΣPF11. Three of those were very early in the pandemic and the most recent is A/Toronto/R8564 from a 7F in early July.
This Neuraminidase group displays some variety with exception in three sequences.
NA Amino Acid Codings to 4 Polymorphisms
CatS1402.
369T
CatS1307, CatS1402.
386D
CatS1384.
395R
CatS1402.
The samples are primarily from August and September, as late as 2009-09-30. One sample is earlier, from July. 9 of 20 specimens (45%) in this deposit that were sampled in August and September demonstrate 225E paired with 206T. As of this accumulation, Spain shows 31 instances of 225E with no 206S and 3 instances of 225G with 206T. Additionally, several unique faces enter ΣPF11 with the Hospital Clinic's latest deposit.
HA Amino Acid Codings to 3 Novel Polymorphisms and 6 Rare Signals
- 35I
- 71G
- 142T
- 188N
- 193G
- 225E
- 240R
- 298V
- 373H
CatS1305, CatS1411, CatS1414, CatS1435.
Rare to ΣPF11.
Found in 6 other sequences including recent TamiFlu-Resistant US sequence, A/Texas/47.
Progenitors may include:
H5N1 Avian
H5N1 Human
71G
CatS1436.
NY80 is the singular ΣPF11 peer.
142T
CatS1411.
Novel to ΣPF11.
188N
CatS1369.
CatS1187 and Niigata700 are the lone ΣPF11 peers.
193G
CatS1384.
Novel to ΣPF11.
225E
CatS1300, CatS1304, CatS1331, CatS1333, CatS1350, CatS1369, CatS1379, CatS1436, CatS1453.
Presently velocitised within recent ΣPF11.
240R
CatS1436.
Novel to ΣPF11.
Progenitors may include:
Zhuhai/790/2008
H1N2 Swine
298V
CatS1369, CatS1436.
Unique to Catalonia within ΣPF11.
CatNS2001, CatNS2008, CatS1237, CatS1248, CatS1286.
373H
CatS1353.
Unique to Catalonia within ΣPF11.
CatS1285.
Neuraminidase Triple Combination
106I, 248D, 286S 20 Sequences
106V, 248D, 286S CatS1369.
The pattern shown by CatS1369 is found in 4 other instances within ΣPF11. Three of those were very early in the pandemic and the most recent is A/Toronto/R8564 from a 7F in early July.
This Neuraminidase group displays some variety with exception in three sequences.
NA Amino Acid Codings to 4 Polymorphisms
- 321V
- 369T
- 386D
- 395R
CatS1402.
369T
CatS1307, CatS1402.
386D
CatS1384.
395R
CatS1402.
2009-10-30
Matching Pair of Human-Fit NA Novelty Emerges Independently in Two Distinct Locales during August 2009
The University of Padova deposited 23 Neuraminidase segments at GenBank yesterday. One particularly merits discussion. We were keyed to the sequence by the rare 106I and 248N human pairing, but even more human fitness acquisition was at work upon review. The NA of A/Italy/180, sampled in August 2009 from a 47M, brings another unique face into ΣPF11.
NA Amino Acid Codings to 1 Novel Polymorphism and 2 Independent Co-Emergent Signals
Neuraminidase Triple Combination
106I, 248N, 286S
Only 25 sequences currently match the 146 amino acids from 106I to 248N, including the Italy134 sequence recently profiled demonstrating the NA Triple Combination herald for Pandemic 2.0.
This new Italian sequence is a marvel in itself, but the argument against random mutation gains strength upon a similar and apparently independent co-emergence. Two perfectly novel introductions paired onto two divergent backgrounds in two different geographies suggest a randomness redundancy.
A/Catalonia/S1276, sampled 2009-08-19 from a 13F, also demonstrates two of the three novel introductions, but onto a separate NA background. CatS1276 is a perfect nucleotide match to Italy180 except at 742G generating 248D (1216 of 1217 aligned residues). Like many of the Catalonia sequences, the initial 47 amino acids of CatS1276 are absent or we might find the 45K there as well. Even without the full sequence, CatS1276 is unique and stand-alone within ΣPF11 due to the swine 248D conjoined with 386D and C1276T.
45K
Novel to ΣPF11.
Progenitors may include:
A/Washington/03/2009 H1N1 with HA 230I & NA 386D, syn426L
A/New Jersey/30/2008 H1N1 with HA 230I & NA 386D, syn426L
A/Thailand/271/2005 H1N1 with HA 225G, 261N, 263D, 270T & NA:45K, syn346V
386D
CatS1276 is the singular ΣPF11 peer.
Progenitors may include:
Seasonal H1N1 2005, 2006, 2007, 2008 and 2009 (Consensus)
Avian H1N1
syn426L
CatS1276 is the singular ΣPF11 peer.
Seasonal H1N1 2005, 2006, 2007, 2008 and 2009 (Extensive)
Swine H1N1 1990-1999
WSN33
Paired genetic introductions onto disparate backgrounds are not a spline for randomness. Perhaps a less random examination of the database at hand would provide additional observational evidence for a new school of logic? Without question, human-fit genetics from previous Seasonal H1N1 and H3N2 are being gained by the Hydra pandemic strains. In this case, the sub-segment acquisitions are precise and clear.
NA Amino Acid Codings to 1 Novel Polymorphism and 2 Independent Co-Emergent Signals
- 45K
- 386D
- 426L (synonymous C1276T)
Neuraminidase Triple Combination
106I, 248N, 286S
Only 25 sequences currently match the 146 amino acids from 106I to 248N, including the Italy134 sequence recently profiled demonstrating the NA Triple Combination herald for Pandemic 2.0.
This new Italian sequence is a marvel in itself, but the argument against random mutation gains strength upon a similar and apparently independent co-emergence. Two perfectly novel introductions paired onto two divergent backgrounds in two different geographies suggest a randomness redundancy.
A/Catalonia/S1276, sampled 2009-08-19 from a 13F, also demonstrates two of the three novel introductions, but onto a separate NA background. CatS1276 is a perfect nucleotide match to Italy180 except at 742G generating 248D (1216 of 1217 aligned residues). Like many of the Catalonia sequences, the initial 47 amino acids of CatS1276 are absent or we might find the 45K there as well. Even without the full sequence, CatS1276 is unique and stand-alone within ΣPF11 due to the swine 248D conjoined with 386D and C1276T.
45K
Novel to ΣPF11.
Progenitors may include:
A/Washington/03/2009 H1N1 with HA 230I & NA 386D, syn426L
A/New Jersey/30/2008 H1N1 with HA 230I & NA 386D, syn426L
A/Thailand/271/2005 H1N1 with HA 225G, 261N, 263D, 270T & NA:45K, syn346V
386D
CatS1276 is the singular ΣPF11 peer.
Progenitors may include:
Seasonal H1N1 2005, 2006, 2007, 2008 and 2009 (Consensus)
Avian H1N1
syn426L
CatS1276 is the singular ΣPF11 peer.
Seasonal H1N1 2005, 2006, 2007, 2008 and 2009 (Extensive)
Swine H1N1 1990-1999
WSN33
Paired genetic introductions onto disparate backgrounds are not a spline for randomness. Perhaps a less random examination of the database at hand would provide additional observational evidence for a new school of logic? Without question, human-fit genetics from previous Seasonal H1N1 and H3N2 are being gained by the Hydra pandemic strains. In this case, the sub-segment acquisitions are precise and clear.
2009-10-02
Spain's Addition to Third Sub-Clade with HA 225E RBD Change
A/Catalonia/S1120, sampled on 2009-07-20, Segment 4 (HA) and Segment 6 (NA), from a 1 year old child falls into a third sub-clade (with earlier Cat378 and Cat387) in this large sequence deposit from Spain that is varied by position 225 in the Receptor Binding Domain. Sao Paulo, Brasil showed a very similar hyper-morphic pattern at this position (225G & 225N) during the same timeframe though Brasil was in their winter. Spain is showing polymorphisms coding for 225G and 225E.
The CatS1120 sequence shows 225E paired with 206T.
Neuraminidase Quadruple Combination
CatS1120 = 106I, 248D, 275H, 286S
The CatS1120 sequence shows 225E paired with 206T.
Neuraminidase Quadruple Combination
CatS1120 = 106I, 248D, 275H, 286S
H5N1 Coding from 2009 Egypt Toddler Cases enters PF11 Reservoir via Japan, NA 450G
A/Shizuoka/793 was deposited yesterday at GenBank with Segment 4 (HA) and Segment 6 (NA) from a sample taken 2009-06-15.
Influenza Flux is at work demonstrating increasing Antigenic Diversity. The Japanese geography continues to produce genetically diverse PF11 strains with two significantly variant sub-clades represented in the two sequences deposited yesterday from the Shizuoka Prefecture.
Shizuoka793 is unique within ΣPF11 for several reasons. Though the Neuraminidase gene segment is identical at 1408 of 1410 residues to most recent geographically proximal Japan sequences and many NY specimens, the two exceptions provide us an exercise in origins:
450G found on the pandemic Shizuoka793 in mid-June appears in low density among several serotypes of human Influenza specimens worldwide at GenBank and 18 are H5N1 specimens collected and sequenced by the NAMRU-3 team in Egypt between January and June 2009, immediately prior to the Shizuoka infection. 16 of those patients were under the age of 5 and geographically dispersed.
Other recent matches are 7 H3N2 Seasonal 2009 cases, 17 H3N2 Seasonal 2008 cases, 5 H1N1 Seasonal 2008 cases, 13 H1N1 Seasonal 2007 cases, 11 H1N1 Seasonal 2006 cases and a swine farm worker from Iowa in 2005. Though the Glycine at 450 is an uncommon Human Influenza polymorphism, the coding appears to be easily donated, moving between Avian, Swine and Human species on H5N1, H3N2 and H1N1 serotypes. Clinical data on the Shizuoka case and the H5N1 infected toddlers would allow valuable insight.
The Neuraminidase Quadruple Combination on this sequence is 106I, 248D, 275H, 286S.
The Shizuoka793 Hemagglutinin is a perfect match (1701/1701) to 22 PF11 specimens from geographies including Sao Paulo, Finland, Italy and 18 specimens along the US Eastern Seaboard. The HA 296H polymorphism deepens in Japan with this deposit being only the second in Japan, the eighth in Asia and the fifty-first in the world. The sub-clades bearing 296H do not appear to have become dominant in any single geography, but have, nonetheless, continued alongside the dominant strains. As of this moment, the Intra-Segment Exclusivity between 296H and 206T continues within ΣPF11 though 206T is widely circulating proximally to this specimen.
Cross-segment linking is suggested with all HA:296H specimens sharing the NA combination of 106I, 248D, 275H, 286S (for those 44 with NA on record). No specimen bearing HA:296H is on record as TamiFlu Resistant or as carrying the NA:286G from Seasonal Influenza (H1N1/H3N2) or H5N1.
This specimen also demonstrates the strong pairing between 296H and the 2E originally found in 1918 sequences and now several PF11 HA segments.
We would be very happy to report that sub-clades are coalescing and stability is occurring within ΣPF11, but the data does not support such a view. Even casual observation of the sparsely available sequences shows ongoing genetic acquisition leading to Antigenic Diversity and widening sub-clades. Reversion and flux appear.
Tracking of these non-random linkings would certainly be assisted by a more robust database of recent sequences.
Influenza Flux is at work demonstrating increasing Antigenic Diversity. The Japanese geography continues to produce genetically diverse PF11 strains with two significantly variant sub-clades represented in the two sequences deposited yesterday from the Shizuoka Prefecture.
Shizuoka793 is unique within ΣPF11 for several reasons. Though the Neuraminidase gene segment is identical at 1408 of 1410 residues to most recent geographically proximal Japan sequences and many NY specimens, the two exceptions provide us an exercise in origins:
- A1028C coding for A343E (Glutamate)
- G1348A coding for S450G (Glycine)
450G found on the pandemic Shizuoka793 in mid-June appears in low density among several serotypes of human Influenza specimens worldwide at GenBank and 18 are H5N1 specimens collected and sequenced by the NAMRU-3 team in Egypt between January and June 2009, immediately prior to the Shizuoka infection. 16 of those patients were under the age of 5 and geographically dispersed.
Other recent matches are 7 H3N2 Seasonal 2009 cases, 17 H3N2 Seasonal 2008 cases, 5 H1N1 Seasonal 2008 cases, 13 H1N1 Seasonal 2007 cases, 11 H1N1 Seasonal 2006 cases and a swine farm worker from Iowa in 2005. Though the Glycine at 450 is an uncommon Human Influenza polymorphism, the coding appears to be easily donated, moving between Avian, Swine and Human species on H5N1, H3N2 and H1N1 serotypes. Clinical data on the Shizuoka case and the H5N1 infected toddlers would allow valuable insight.
The Neuraminidase Quadruple Combination on this sequence is 106I, 248D, 275H, 286S.
The Shizuoka793 Hemagglutinin is a perfect match (1701/1701) to 22 PF11 specimens from geographies including Sao Paulo, Finland, Italy and 18 specimens along the US Eastern Seaboard. The HA 296H polymorphism deepens in Japan with this deposit being only the second in Japan, the eighth in Asia and the fifty-first in the world. The sub-clades bearing 296H do not appear to have become dominant in any single geography, but have, nonetheless, continued alongside the dominant strains. As of this moment, the Intra-Segment Exclusivity between 296H and 206T continues within ΣPF11 though 206T is widely circulating proximally to this specimen.
Cross-segment linking is suggested with all HA:296H specimens sharing the NA combination of 106I, 248D, 275H, 286S (for those 44 with NA on record). No specimen bearing HA:296H is on record as TamiFlu Resistant or as carrying the NA:286G from Seasonal Influenza (H1N1/H3N2) or H5N1.
This specimen also demonstrates the strong pairing between 296H and the 2E originally found in 1918 sequences and now several PF11 HA segments.
We would be very happy to report that sub-clades are coalescing and stability is occurring within ΣPF11, but the data does not support such a view. Even casual observation of the sparsely available sequences shows ongoing genetic acquisition leading to Antigenic Diversity and widening sub-clades. Reversion and flux appear.
Tracking of these non-random linkings would certainly be assisted by a more robust database of recent sequences.
2009-09-29
E627K from July Discovered Retrospectively, Tied to Netherland's Vacation Island in Diabetic Patient and Adolescent Female
Though the sequences have not been released, the team at Erasmus MC in Rotterdam has done us all a great service by providing an early report of 627K in the Netherlands.
The multiple cases all vector from visits to a popular vacation island between July 13 and August 9. Two of the cases do not appear to be related via direct contact, potentially indicating an endemic and silent spread of a minor PF11 population carrying the human-fit virulence factor 627K in a sub-clade that may match the major circulating sub-clade there but for the Lysine recombination. Ten of twelve (83%) sample specimens from this geography fall into this sub-clade indicating the potential for dominant circulation in that area.
As this release of information via Promed is very limited, additional evalution and insight will require amendment and revision to this article as the matter is clarified on several accounts, including specification of the E627K sequence count and the various ratios confirming the certain Hydra Effect demonstrated in the study population.
In our reading, 3 distinct cases are described in the Osterhaus release. The researchers may have mentioned “two patients” because the family contact and the younger sister may have been directly evaluated by them in a clinical setting?
This highly interpretive post is preliminary based on inconclusive language in the press release.
No mention is made of the correlating PB2 virulence mediators 701N and 703K at this time in the information released. We suspect these to be absent due to the non-fatal clinical outcomes; however, confirmation would be useful.
As the samples were examined retrospectively, little new observational evidence will be forthcoming. Rational projections due to this 627K mid-Summer emergence in the Netherlands and the late May emergence in Shanghai71T could cause us to expect a geographically-dispersed, wild-type sub-population carrying this virulence factor.
Tenacious sub-clonal evaluation of current sequences in the United States will likely indicate mixed peaks at the PB2 residue coding for the Lysine at 627.
The multiple cases all vector from visits to a popular vacation island between July 13 and August 9. Two of the cases do not appear to be related via direct contact, potentially indicating an endemic and silent spread of a minor PF11 population carrying the human-fit virulence factor 627K in a sub-clade that may match the major circulating sub-clade there but for the Lysine recombination. Ten of twelve (83%) sample specimens from this geography fall into this sub-clade indicating the potential for dominant circulation in that area.
As this release of information via Promed is very limited, additional evalution and insight will require amendment and revision to this article as the matter is clarified on several accounts, including specification of the E627K sequence count and the various ratios confirming the certain Hydra Effect demonstrated in the study population.
In our reading, 3 distinct cases are described in the Osterhaus release. The researchers may have mentioned “two patients” because the family contact and the younger sister may have been directly evaluated by them in a clinical setting?
- Male Diabetic who may have shared activities with ill female camper, onset 2009-08-09
- Female camper, onset after returning home 2009-07-20
- Female family contact of ill camper, onset after camper returned on 2009-07-20
- Younger sister of female family contact, onset 2009-07-23
This highly interpretive post is preliminary based on inconclusive language in the press release.
No mention is made of the correlating PB2 virulence mediators 701N and 703K at this time in the information released. We suspect these to be absent due to the non-fatal clinical outcomes; however, confirmation would be useful.
As the samples were examined retrospectively, little new observational evidence will be forthcoming. Rational projections due to this 627K mid-Summer emergence in the Netherlands and the late May emergence in Shanghai71T could cause us to expect a geographically-dispersed, wild-type sub-population carrying this virulence factor.
Tenacious sub-clonal evaluation of current sequences in the United States will likely indicate mixed peaks at the PB2 residue coding for the Lysine at 627.
2009-09-24
Influenza Flux Continues High-CFR Risk Period as PF11Ω Remains Distant
The PF11 reservoir remains within the same category as H5N1, Interferon-Deranging, Rapidly Replicating Virus (IDRRV), in our estimation. The Influenza Flux (zoonotic transition period) may be the prime driver in this categorisation for each subtype. Though High-CFR H5N1 and today’s PF11 reservoir fall into the same category based on genetic expression, one profound difference in PF11 does emerge, a particularly strong advantage for this virus.
PF11 began with several key portions of the genetic material for human fitness but remains distant from human fitness in general; the virus is most certainly still hobbled even while demonstrating destructive clinical effects in individual hosts. As a matter of record, the rate of trait-enhancing genetic acquisition is dramatically higher than in H5N1, contrary to the daily social messaging, “No Mutations” phraseology.
Perhaps this higher and very consistent rate of genetic acquisition in PF11 is due to the current distance from full human fitness? The early foothold in partial human fitness within the reservoir remains bounded / limited by the continued shortcoming in achieving full human fitness. The enhanced speed of acquisition may be driven by the intersection of two pandemic aspects, distance from full human fitness and the deep reservoir of donor candidates for human-fit traits. Spark and Fuel. Implementing a sub-category to IDRRV due to the special nature of this PF11 reservoir, IDRREAV1, may establish useful language for further study. Regardless of what this pandemic reservoir is called, the time period between today’s partial human fitness and the future’s fully human-fit and virulence-downrated viral emergence is mankind’s window of High-CFR danger.
Some have postulated that 1918 was 50/50 swine and human influenza genetics. Knowledge cannot be attained to conclusively prove this bold idea because very little predecessor genetics is on record for comparison. At this time, PF11 is genetically less than 15% human-fit by nucleotide count including the full human-based segment and the total count of potentially human-fit SNPs across the other seven gene segments.
If this viral reservoir is marching toward a 50/50 ratio as 1918 has been postulated, then today’s 1.6% to 5% CFRs may eventually be much higher than the 1918 Case Fatality Rate. The achievement of an H5N1 CFR would entirely be conjecture at this time, but a doubling of the current PF11 median to a figure between 4% and 5% CFR is within educated consideration. At the practical moment of PF11Ω (PF11 Omega2), when the future dominant PF11 strain reaches the critical tipping point in the Influenza Flux where transmission is perfected and virulence peaks, a peaking CFR is a logical expectation.
We project that throughout the current Influenza Flux period prior to the critical mass of PF11Ω, the Hydra Effect that our team has documented in the related gene studies will continue to be demonstrated with many transmissible and virulent heads (strains) developing and persisting. Eventually the post-Omega, PF11>Ω, fully human-fit viral reservoir will coalesce, will downrate in virulence or will be replaced once the host population is depleted.
This viral reservoir progression is strikingly similar to the pattern our research team predicted 3 years ago for an emerging H5N1 pandemic, but for the fact that ΣPF11 has enhanced genetic acquisition rates demonstrating RNA gain from 5 or more Influenza serotypes. Timing cannot be predicted with accuracy; however, the recombinations of trait-enhancing, human-fit SNPs are directly trackable and fungible as evidence of progression under this proposed framework of study.
1 Interferon-Deranging, Rapidly Replicating, Enhanced Acquisition Virus (IDRREAV)
2 Glossary Updates
ΣPF11
Sigma PF11.
In general, the PF11 Reservoir of genetic material. Accumulation of all specimens trending to the established pandemic backgrounds.
PF11β
PF11 Beta.
Today. Current PF11 specimens. These strains have progressed beyond the initial Spring 2009 PF11 infections, yet continue to be only partially human-fit.
PF11Ω
PF11 Omega.
A proposed future PF11 momentary state of peak high-transmissibility and high-virulence potentially correlating to the zenith of the High-CFR window for humans.
PF11>Ω
PF11 Post-Omega.
A proposed future PF11 state occurring at some point after PF11Ω, having a progressively downrated virulence and the potential for establishing a smaller set of dominant strains in the PF11 Reservoir, ΣPF11.
PF11 began with several key portions of the genetic material for human fitness but remains distant from human fitness in general; the virus is most certainly still hobbled even while demonstrating destructive clinical effects in individual hosts. As a matter of record, the rate of trait-enhancing genetic acquisition is dramatically higher than in H5N1, contrary to the daily social messaging, “No Mutations” phraseology.
Perhaps this higher and very consistent rate of genetic acquisition in PF11 is due to the current distance from full human fitness? The early foothold in partial human fitness within the reservoir remains bounded / limited by the continued shortcoming in achieving full human fitness. The enhanced speed of acquisition may be driven by the intersection of two pandemic aspects, distance from full human fitness and the deep reservoir of donor candidates for human-fit traits. Spark and Fuel. Implementing a sub-category to IDRRV due to the special nature of this PF11 reservoir, IDRREAV1, may establish useful language for further study. Regardless of what this pandemic reservoir is called, the time period between today’s partial human fitness and the future’s fully human-fit and virulence-downrated viral emergence is mankind’s window of High-CFR danger.
Some have postulated that 1918 was 50/50 swine and human influenza genetics. Knowledge cannot be attained to conclusively prove this bold idea because very little predecessor genetics is on record for comparison. At this time, PF11 is genetically less than 15% human-fit by nucleotide count including the full human-based segment and the total count of potentially human-fit SNPs across the other seven gene segments.
If this viral reservoir is marching toward a 50/50 ratio as 1918 has been postulated, then today’s 1.6% to 5% CFRs may eventually be much higher than the 1918 Case Fatality Rate. The achievement of an H5N1 CFR would entirely be conjecture at this time, but a doubling of the current PF11 median to a figure between 4% and 5% CFR is within educated consideration. At the practical moment of PF11Ω (PF11 Omega2), when the future dominant PF11 strain reaches the critical tipping point in the Influenza Flux where transmission is perfected and virulence peaks, a peaking CFR is a logical expectation.
We project that throughout the current Influenza Flux period prior to the critical mass of PF11Ω, the Hydra Effect that our team has documented in the related gene studies will continue to be demonstrated with many transmissible and virulent heads (strains) developing and persisting. Eventually the post-Omega, PF11>Ω, fully human-fit viral reservoir will coalesce, will downrate in virulence or will be replaced once the host population is depleted.
This viral reservoir progression is strikingly similar to the pattern our research team predicted 3 years ago for an emerging H5N1 pandemic, but for the fact that ΣPF11 has enhanced genetic acquisition rates demonstrating RNA gain from 5 or more Influenza serotypes. Timing cannot be predicted with accuracy; however, the recombinations of trait-enhancing, human-fit SNPs are directly trackable and fungible as evidence of progression under this proposed framework of study.
1 Interferon-Deranging, Rapidly Replicating, Enhanced Acquisition Virus (IDRREAV)
2 Glossary Updates
ΣPF11
Sigma PF11.
In general, the PF11 Reservoir of genetic material. Accumulation of all specimens trending to the established pandemic backgrounds.
PF11β
PF11 Beta.
Today. Current PF11 specimens. These strains have progressed beyond the initial Spring 2009 PF11 infections, yet continue to be only partially human-fit.
PF11Ω
PF11 Omega.
A proposed future PF11 momentary state of peak high-transmissibility and high-virulence potentially correlating to the zenith of the High-CFR window for humans.
PF11>Ω
PF11 Post-Omega.
A proposed future PF11 state occurring at some point after PF11Ω, having a progressively downrated virulence and the potential for establishing a smaller set of dominant strains in the PF11 Reservoir, ΣPF11.
2009-09-15
TamiFlu Resistant Singapore57 Sequence Available at GISAID EpiFlu database; 106I, 248D, H275Y
The NA and HA for A/Singapore/57 from 2009-05-30 are again downloadable from the European EpiFlu database as GISAID has thankfully been able to re-establish scientific community access to their data.
The NA of Singapore57 is an exact nucleotide match with Denmark528.
Furthermore, Singapore57 is a match at all positions (1409) but C823T (TamiFlu Resistance) with:
A/Wisconsin/629-D01445 (1Y, 2009-5-24)
A/Bethesda/SP508 (14F, mid June)
RhodeIsland07 (HA:296H)
Massachusetts08 (14M)
Michigan06 (14M)
NewYork (many sequences from young people)
WestVirginia01 (15M)
Texas39 (12F, late May)
Arizona05 (4F, late April)
Utah02 (8F)
Utah04 (9F, late May)
Utah11 (9M, mid June)
Nevada03 (2F, late April)
Montana06 (14M, early May)
Georgia08
Oregon20
Canada (several)
Thailand (several, mid June)
Taiwan (several)
Germany (2 including Bayern66)
The geographic range of this PF11 background is extensive, with exceptional breadth in the United States and the background correlates to young people.
TamiFlu Resistance is indicated in typical PF11 fashion via a Single Nucleotide Polymorphism on Singapore57 coding for 275Y on the Neuraminidase. The sequence displays the following NA Quadruple Combination:
106I, 248D, 275Y, 286S
The following permutations are now represented on the nine 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, Singapore57
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 9 with 106V.
The addition of Singapore57 re-leverages position 248 to Aspartate (D) with 5 specimens versus 4 with Asparagine (N). No TamiFlu Resistant specimen on file displays 286G as yet.
Many TamiFlu Resistant cases have been reported that have not been sequenced and deposited in the United States and worldwide. Dr. Jonathan McCullers of St. Jude Children's Research Hospital in Tennessee reported a TamiFlu Resistant case yesterday, along with 12 child ICU cases and one child death. Dr. McCullers indicates "a tremendous rise in cases" which began approximately one week after school resumed, well within the 3-10 day incubation period that we predicted post-congregation. Dr. McCullers maintains that we are in the beginning of a two year pandemic that will have multiple peaks. We agree that a period of 13 to 24 months from March 2009 is well within the expected duration. Considering PF11's current position in the inter-species Influenza Flux and the high genetic variance demonstrated by the Hydra Effect, the lower boundary of our estimate (13 months) is unlikely unless the Case Fatality Rate increases significantly because PF11 rapidly depletes the population of potential hosts.
23 clinical observations have been publically discussed as TamiFlu Resistant in recent weeks around the world and most are not yet sequenced and deposited. These cases concur with many of the geographic regions having sequences on file that match current TamiFlu Resistant sequences but for the H275Y. In other words, the genetic acquisitions were predictable and expected to occur upon a proximal donor with 275Y co-infecting a host in that region. An opportunity to review the full diversity of the anti-viral resistant strains would allow determination if, in fact, a silent spread of human-fit and reasonably transmissible TamiFlu Resistant strains is underway at this time or if we are seeing the improbability of an extensive and accurate selection due to treatment that is currently being purported as an explanation. Evidence exists tending toward a silent spread, including that a substantial list is described with very early sampling and detection of H275Y, prior to any acceptable period for de novo / selective revision. A minor sub-population of 275Y may be incorporated widely into the PF11 reservoir at this time.
The two youth in early July attending the North Carolina summer camp either spread their PF11 version one to the other or were each infected from a common carrier with a parental PF11 275Y Neuraminidase as is evidenced by the co-factor SNP on the NA of their sequences coding for 223V, known to amplify the 275Y TamiFlu resistance in H3N2.
A more robust database of sequences would be useful to invigorate the scientific community and the public in navigating this distant journey.
An n higher than 9 may assist us to align.
The NA of Singapore57 is an exact nucleotide match with Denmark528.
Furthermore, Singapore57 is a match at all positions (1409) but C823T (TamiFlu Resistance) with:
A/Wisconsin/629-D01445 (1Y, 2009-5-24)
A/Bethesda/SP508 (14F, mid June)
RhodeIsland07 (HA:296H)
Massachusetts08 (14M)
Michigan06 (14M)
NewYork (many sequences from young people)
WestVirginia01 (15M)
Texas39 (12F, late May)
Arizona05 (4F, late April)
Utah02 (8F)
Utah04 (9F, late May)
Utah11 (9M, mid June)
Nevada03 (2F, late April)
Montana06 (14M, early May)
Georgia08
Oregon20
Canada (several)
Thailand (several, mid June)
Taiwan (several)
Germany (2 including Bayern66)
The geographic range of this PF11 background is extensive, with exceptional breadth in the United States and the background correlates to young people.
TamiFlu Resistance is indicated in typical PF11 fashion via a Single Nucleotide Polymorphism on Singapore57 coding for 275Y on the Neuraminidase. The sequence displays the following NA Quadruple Combination:
106I, 248D, 275Y, 286S
The following permutations are now represented on the nine 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, Singapore57
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 9 with 106V.
The addition of Singapore57 re-leverages position 248 to Aspartate (D) with 5 specimens versus 4 with Asparagine (N). No TamiFlu Resistant specimen on file displays 286G as yet.
Many TamiFlu Resistant cases have been reported that have not been sequenced and deposited in the United States and worldwide. Dr. Jonathan McCullers of St. Jude Children's Research Hospital in Tennessee reported a TamiFlu Resistant case yesterday, along with 12 child ICU cases and one child death. Dr. McCullers indicates "a tremendous rise in cases" which began approximately one week after school resumed, well within the 3-10 day incubation period that we predicted post-congregation. Dr. McCullers maintains that we are in the beginning of a two year pandemic that will have multiple peaks. We agree that a period of 13 to 24 months from March 2009 is well within the expected duration. Considering PF11's current position in the inter-species Influenza Flux and the high genetic variance demonstrated by the Hydra Effect, the lower boundary of our estimate (13 months) is unlikely unless the Case Fatality Rate increases significantly because PF11 rapidly depletes the population of potential hosts.
23 clinical observations have been publically discussed as TamiFlu Resistant in recent weeks around the world and most are not yet sequenced and deposited. These cases concur with many of the geographic regions having sequences on file that match current TamiFlu Resistant sequences but for the H275Y. In other words, the genetic acquisitions were predictable and expected to occur upon a proximal donor with 275Y co-infecting a host in that region. An opportunity to review the full diversity of the anti-viral resistant strains would allow determination if, in fact, a silent spread of human-fit and reasonably transmissible TamiFlu Resistant strains is underway at this time or if we are seeing the improbability of an extensive and accurate selection due to treatment that is currently being purported as an explanation. Evidence exists tending toward a silent spread, including that a substantial list is described with very early sampling and detection of H275Y, prior to any acceptable period for de novo / selective revision. A minor sub-population of 275Y may be incorporated widely into the PF11 reservoir at this time.
The two youth in early July attending the North Carolina summer camp either spread their PF11 version one to the other or were each infected from a common carrier with a parental PF11 275Y Neuraminidase as is evidenced by the co-factor SNP on the NA of their sequences coding for 223V, known to amplify the 275Y TamiFlu resistance in H3N2.
A more robust database of sequences would be useful to invigorate the scientific community and the public in navigating this distant journey.
An n higher than 9 may assist us to align.
2009-09-13
United States (NorthEast) HA Diversity at 206; 296H Intra-Segment Exclusivity Continues
A pair of sequences each from Pennsylvania and Rhode Island deposited at GenBank on 2009-09-10 demonstrate continued Hemagglutinin diversity within single geographies and similar time frames. Multiple PF11 sub-clades in the United States and worldwide show ongoing human fitness and co-existance ability producing a Hydra Effect.
As of this moment, the Intra-Segment Exclusivity between 296H and 206T continues on the PF11 background. Pennsylvania, Rhode Island and Massachusetts have observed candidate donors of 206T; however, the genetic diversity of 206S with 296H remains in those states and with similar occassion in many international locales.
- A/Pennsylvania/06 (PA06) demonstrates 206S and 296H
- A/Pennsylvania/14 (PA14) demonstrates 206T and 296Q, 218X
- A/Rhode Island/07 (RI07) demonstrates 206S and 296H
- A/Rhode Island/08 (RI08) demonstrates 206T and 296Q
- A/Massachusetts/10 (MA10) demonstrates 206S and 296H
- A/Indiana/17 (IN17) demonstrates 206S and 296H
As of this moment, the Intra-Segment Exclusivity between 296H and 206T continues on the PF11 background. Pennsylvania, Rhode Island and Massachusetts have observed candidate donors of 206T; however, the genetic diversity of 206S with 296H remains in those states and with similar occassion in many international locales.
The highly correlative 2E is found in the 4 referenced 296H Hemagglutinins in this United States deposit.
PA06, RI07, MA10 and IN17 are an exact nucleotide match to A/Italy/127 from 2009-06-17, the only PF11 sequence in the world to carry the 256L on Neuraminidase (with 106I/248N).
The rare 256L is originally found on the 1918 Brevig Mission sequence. 256L candidate donors include many H3N2 2008 Seasonal Influenza specimens and several H1N2 2008 swine from Oklahoma and Texas.
RI07 on Segment 6 (Neuraminidase) is an exact nucleotide match to a pivotal sequence that will be detailed later from Germany, A/Bayern/66. The IN17 NA also tracks to RI07 and Bayern66 at 1409 of 1410 nucleotide positions. Bayern66 is strongly related to the HA of the Russian and Northern European heralds of HA:226R, Omsk01, Ekaterinburg01 and Finland553 and to the HA of Tomsk01.
The rare 256L is originally found on the 1918 Brevig Mission sequence. 256L candidate donors include many H3N2 2008 Seasonal Influenza specimens and several H1N2 2008 swine from Oklahoma and Texas.
RI07 on Segment 6 (Neuraminidase) is an exact nucleotide match to a pivotal sequence that will be detailed later from Germany, A/Bayern/66. The IN17 NA also tracks to RI07 and Bayern66 at 1409 of 1410 nucleotide positions. Bayern66 is strongly related to the HA of the Russian and Northern European heralds of HA:226R, Omsk01, Ekaterinburg01 and Finland553 and to the HA of Tomsk01.
2009-08-21
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
- A/Washington/28/2009 (WA28) collected on 2009-07-14
- A/Washington/29/2009 (WA29) collected on 2009-07-28
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
2009-08-01
Introduction to PF11
PF11: Pandemic InFLUenza H1N1
Genetic Acquisition Analysis
A managed campaign of political and laboratory messages in the media continues to state that no changes are found in Pandemic Influenza H1N1. The underlying genetics database, however, demonstrates many acquisitions and a consistent trend of fitness-inducing polymorphisms. As samples have been added each week around the world, a pattern has emerged.
The pattern indicates a persistent hyper-morphic state on the PF11 background at certain positions within particular species. Of certain note is the directional movement on the Hemagglutinin (variously termed HA and H1) and Neuraminidase (variously termed NA and N1) segments. Though all Influenza consistently recombines with existing genetic material from proximal non-self strains, PF11 has demonstrated a march toward human-fit acquisition that is remarkable in speed and geographic spread.
The purpose of these point by point studies is to indicate and discuss several of those key polymorphisms and examine the potential next steps in humans. As you have seen finally released in the media, PF11 in the human-form has now been sequence-confirmed in birds and in swine, allowing hundreds of species as additional “mixing vessels” or recombination reservoirs. This predicted species jump, more importantly, provides flight-based transportation vectors that will easily number in the millions of infected birds with a potential pool of billions in various seasons.
Recall the CDC reports that 70% of all emerging diseases are zoonotic (originate in animals). The asymptomatic flight-based animals transport the disease from their land-based counterparts, the swine, who are playing their normal role as ideal mixing reservoirs for recombination due to their robust tolerance to many strains of Influenza. Pig=>Duck=>Human=>Chicken=>Pig and dozens of additional paired vectors of transmission have been confirmed between human, swine and avian species. The genetic transition state between species, the Influenza Flux, is dangerous for humans due to continual creation of novel antigen and species-specific phenotypical traits that strain the human immune system, elevate the potential for vaccine escape and may produce a negative interplay with that nemesis of vaccine scientists, Original Antigenic Sin (OAS).
OAS, in a few words, describes the physiological phenomenon observed since 1960 that antibody production to a novel virus is mediated and frequently downgraded by the priming epitope or first infection in an individual host from that species of virus (original childhood infection). Frequent exposure to novel antigens within a virus species (notably Influenza), via vaccine and/or natural infection, tends to create fewer and fewer new antibodies that bind properly to the slightly dissimilar recent virus / antigen. The documented process counter-intuitively invokes high-specificity memory B cells from the priming epitope (original childhood infection) which then feeds back signals to reduce the activation of naive B cells toward the new antigen. Studies observe situations where Antibody Secreting Cells (ASC) produce antibodies to earlier infections in a ratio higher than antibodies to the new infection.
In short, PF11 at this time continues to create a Hydra Effect, attacking the human with many different heads or genetic variations. The Hydra Effect coupled with the observed Interferon-Deranging, Rapid Replicating Viral (IDRRV) property creates a unique and daunting foe.
We will overview our findings on four gene segments with discussion on inter-segment correlations.
Glossary
PF11
Pandemic InFLUenza H1N1.
Triple Reassortment Virus with Avian, Swine and Human Influenza Genetics, 2009 emergence.
ΣPF11
Sigma PF11.
In general, the PF11 Reservoir of genetic material. Accumulation of all specimens trending to the established pandemic backgrounds.
PF11β
PF11 Beta.
Today. Current PF11 specimens. These strains have progressed beyond the initial Spring 2009 PF11 infections, yet continue to be only partially human-fit.
PF11Ω
PF11 Omega.
A proposed future PF11 momentary state of peak high-transmissibility and high-virulence potentially correlating to the zenith of the High-CFR window for humans.
PF11>Ω
PF11 Post-Omega.
A proposed future PF11 state occurring at some point after PF11Ω, having a progressively downrated virulence and the potential for establishing a smaller set of dominant strains in the PF11 Reservoir, ΣPF11.
PHz
Polymorphic Homology to Zoonotic Reservoirs.
Found in Influenza A from any animal reservoir.
PHzAv
Polymorphic Homology to Zoonotic Avian Reservoirs.
Found in a primarily Avian Influenza Serotype sampled from any species or in an Influenza A reservoir sampled from an Avian species.
IDRRV
Interferon-Deranging, Rapidly Replicating Virus.
Classification system considering viral expression traits.
IDRREAV
Interferon-Deranging, Rapidly Replicating, Enhanced Acquisition Virus.
Classification system considering viral expression traits.
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