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Influenza Virus A/h1n1 Resistant To Oseltamivir: W.h.o. Preliminary Summary

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Niman: The jumps can be easily seen with phylogenetic trees.
H5N1 knows what it is doing and its evolution is NOT random.

gs: you keep saying this, yet noone seems to agree.

Au Contrare! Not only is the pattern NOT random, specific factors determine where, when and why. The 'how' is largely known.


>And noone including you could so far predict flu-evolution.

It's not a matter of predicting evolution, it's a matter of understanding polymorphic adaptation, the fixing of those traits and their spread by migrating birds (and to a much lesser extent, locally by other bird species, and through poultry trade/smuggling).

gs: You can't distinguish the mutations with phylo-trees, only their counts.

Sure you can map the spread of specific mutation and co-local mutations through construction of these relational probability trees.

What are 'counts'?

What is 'genetical'?

(your made-up terminology)

The fact is, you haven't enough basic science knowledge to be a productive contributor to advanced discussion. Therefore, you tend to postulate insupportable theories, then you ignore patient explanation as to why they are improbable, and you continue to troll your knowledge-impaired logic throughout numerous threads here.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

I renew my call for a more understandable discussion also for unexperienced members and readers in general.

For this reason, sometimes attempts to break an hair in parts could result in the loss of discussion aim, meaningful wording as well.

Why do not try to make a clear summary of more recent issues?

It may be for great help in understanding the members' positions and overall antiviral resistance question.

Thank all the readers for their contributions. IOH
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

ironorehopper said:
I renew my call for a more understandable discussion also for unexperienced members and readers in general.

For this reason, sometimes attempts to break an hair in parts could result in the loss of discussion aim, meaningful wording as well.

Why do not try to make a clear summary of more recent issues?

It may be for great help in understanding the members' positions and overall antiviral resistance question.

Thank all the readers for their contributions. IOH
Click to expand...
Here is the key issue on the H274Y appearance. The data to date really focuses on the Brisbane/25 (clade 2B), which can clearly support H274Y without penalty, so it can easily compete with other H1N1.

Some of the H274Y is simply due to an expansion of the "northern EU" version. That version can account for much of the resistance without any changes in H274Y because it is already present in that lineage.

The key question is the new acquistions. These new acquisitions require a new change at position 274. The question is were these new acquistions are due to Tamiflu, which is rare but amplified because the acquistion is without a fitness penalty, or if it is due to recombination with H1N1 that already has H274Y.

For G743A, there is little doubt that the acquistions are due to recombination, because G743A has previously been on many genetic backgrounds.

For H274Y it is leass clear because H274Y has not previously been seen in "fit" H1N1, although has been seen in fit H5N1.

The evidence for H274Y being due to recombination the appearance of new acquisitions where Tamiflu use is not common. In Japan it is increasing late in the past season, which would point to recombination (unless Tamiflu use increased late in the season, which is highly ulikely). This can also be addressed by increases in southern Europe, if the increase is due to new acqusitions and a lack of Tamiflu.

The prior results for G743A points toward recombination (and there are MANY additional examples of acquistions of SNPs by recombination, but not quite as dramatic as G743A).
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

ironorehopper said:
I renew my call for a more understandable discussion also for unexperienced members and readers in general.

For this reason, sometimes attempts to break an hair in parts could result in the loss of discussion aim, meaningful wording as well.

Why do not try to make a clear summary of more recent issues?

It may be for great help in understanding the members' positions and overall antiviral resistance question.

Thank all the readers for their contributions. IOH
Click to expand...
I had a chance to update the trees rom the US. I count 121 Brisbane sequences, with 23 having H274Y.

The branch with the Florida isolate with H274Y has one more Florida isolates from 2007 without H274Y, and the Hawaiian branch has one more earlier Hawaiian isolate (also without H274Y), so the frequency in the US is around 20% of Brisbane, and there are three introductions that are clearly independent.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

niman said:
I had a chance to update the trees rom the US. I count 121 Brisbane sequences, with 23 having H274Y.

The branch with the Florida isolate with H274Y has one more Florida isolates from 2007 without H274Y, and the Hawaiian branch has one more earlier Hawaiian isolate (also without H274Y), so the frequency in the US is around 20% of Brisbane, and there are three introductions that are clearly independent.
Click to expand...
It is worth noting that the HA of the Hawaiian branch has V223I (and of course also has M230I).
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000103;jsessionid=87C4FA82DB60E00F10C344BB59069B7A
Enzymatic Properties of the Neuraminidase of Seasonal H1N1 Influenza Viruses Provide Insights for the Emergence of Natural Resistance to Oseltamivir

Marie-Anne Rameix-Welti<sup>1</sup>, Vincent Enouf<sup>2</sup>, Frédérique Cuvelier<sup>2</sup>, Patricia Jeannin<sup>2</sup>, Sylvie van der Werf<sup>1</sup><sup>,</sup><sup>2</sup><sup>*</sup>
1 Unité de Génétique Moléculaire des Virus Respiratoires, URA3015 CNRS, EA302 Université Paris Diderot, Paris, France2 National Influenza Center (Northern-France), Institut Pasteur, Paris, France


Surveillance of the antiviral susceptibility of influenza viruses in Europe revealed the emergence of influenza A(H1N1) viruses naturally resistant to the anti-neuraminidase inhibitor oseltamivir (Tamiflu) [1]. Currently, resistant viruses are most prevalent in Europe (25%) but less prevalent in the Americas (16%) or the Western Pacific region (4%) [2]. In Europe, the prevalence varies between countries, with highest levels in Norway (66.5%) and France (46.6%) [3]. These frequencies are in sharp contrast with those observed for H1N1 viruses during previous seasons (0 to <1%) [4]–[8].
Resistance was linked to the H275Y mutation (H274Y in N2 numbering) of the N1 known to confer high level resistance to oseltamivir but not to the other anti-neuraminidase inhibitor, zanamivir (Relenza) [9]–[12]. Resistant H1N1 viruses with the H275Y change have been isolated from patients treated with oseltamivir and more frequently in children, especially in Japan, the country with the highest per capita usage of oseltamivir [10],[13]. The current frequencies of resistant H1N1 viruses are not correlated with oseltamivir usage, which suggests that selective drug pressure has not been associated with continued transmission, although it may have been involved in their initial emergence.

Clinical H1N1 isolates with the H275Y mutation were previously found to be generally less fit in terms of replication, infectivity for mice or ferrets, or transmission potential [14],[15], although the mutation had a less pronounced and variable effect on virus fitness for laboratory strains such as WSN or PR8 viruses or for H5N1 viruses [9], [16]–[18]. To understand the molecular basis of the apparent fitness of the resistant H1N1 viruses that emerged during the 2007–2008, season we determined the enzymatic characteristics of their neuraminidase.


snip


It should be emphasized, however, that the relative fitness and ability to be transmitted of the resistant versus sensitive viruses may be modulated by characteristics of other genes. This will require whole genome sequencing. The circulation of H1N1 viruses naturally resistant to oseltamivir underlines the fact that genetic variations may result in variations in sensitivity to oseltamivir in the absence of selective drug pressure, as shown for H5N1 viruses [20],[29]. Genetic variations of the hemagglutinin and neuraminidase are mainly driven by the immune response, and adventitious properties that result in changes in fitness may be co-selected. Such a phenomenon could potentially take place for H5N1 viruses and also for H3N2 viruses. Genetic variations like these emphasize the need to carefully monitor the affinity of the neuraminidase for its substrate and anti-neuraminidase inhibitors in relation with the binding affinity of the hemagglutinin for its receptor for influenza viruses circulating in the population, as well as for avian influenza viruses with pandemic potential.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

gsgs said:
google has it in html:
http://209.85.135.104/search?q=cach...A/Denmark/4/2008"&hl=en&ct=clnk&cd=2&ie=UTF-8
from 21.Febr.2008
not much sprinkling of the indentations at that time.
Full genomes are better to determine the distances, we got many full genomes of
H1N1 from USA season 2006/7 in Oct.2007 , so maybe we'll get them in 3 months for 2007/8
http://www.setbb.com/fluwiki2/viewtopic.php?t=196&mforum=fluwiki2

the German report also has phylo-trees, last year the deadline was 15.July,
http://influenza.rki.de/agi/GetBericht?id=180 (page 36)
so this year's report may appear soon


with months ,
◄ :Amantadine resistant
@ : Oseltamivir resistant
#: egg isolate

phylo-sorted (algorithm unclear to me)

Code: 
HA
------
niid A/Toyama/108/2007 Oct LR
aus A/Guam/1/2007 ◄ Oct
A/Guam/6495/2007 ◄ Oct LR
A/Oregon/07/2007 Dec LR
A/Oregon/06/2007 ◄ Dec
A/Lyon/1388/2007 ◄ Dec LR
A/Hong Kong/4703/2007 ◄ Sep LR
A/Cambodia/0371/2007 ◄ Aug #
niid A/Hiroshima/93/2007 Oct LR #
A/Korea/6612/2007 ◄ Oct
aus A/Philippines/3150/2007 ◄ Sep
A/Hong Kong/2652/2006 ◄ Jul LR #
A/Ulaanbaatar/116/2007 ◄ Jan #
niid A/Yokohama/75/2007 Oct LR
niid A/Hiroshima/109/2007 Dec #
A/Minnesota/25/2007 ◄ Oct
A/Hawaii/19/2007 ◄ Oct #
A/Liaoning/Huanggu1183/2007 Oct #
A/Lyon/1350/2007 Dec LR
  nimr A/Norway/1630/2007 @
  A/Illinois/10/2007 Dec @
  A/Lyon/1337/2007 Dec LR @
A/South Dakota/06/2007 Jul #
  A/New Jersey/16/2007 Dec LR @
A/Florida/10/2007 Dec #
A/Toulouse/1401/2007 Nov
A/Texas/70/2007 Dec #
A/Texas/74/2007 Nov
A/Illinois/11/2007 Dec LR
A/Arizona/07/2007 Dec LR
A/Nepal/4606/2007 Jul LR
A/Alaska/13/2007 Dec LR
A/Texas/78/2007 Dec
A/Massachusetts/14/2007 Dec
A/New York/16/2007 Dec LR
A/Washington/34/2007 Dec
niid A/Hiroshima/99/2007 Nov #
A/Pennsylvania/01/2008 Jan LR
A/Qatar/1124/2007 Nov LR
A/Hawaii/31/2007 Oct #
  A/Hawaii/21/2007 Oct @
A/Iowa/04/2007 Nov
A/Florida/15/2007 Dec
aus A/Brisbane/59/2007 IVR148 #
aus A/Brisbane/59/2007 Jul #
A/Illinois/13/2007 Dec
A/Colorado/21/2007 Nov #
A/California/40/2007 Dec LR
A/Fukushima/141/2006 #
A/Solomon Islands/03/2006 #
A/Solomon Islands/03/2006 IVR145 #
A/Florida/3/2006 #
A/El Salvador/582/2007 Sep LR
A/Honduras/643/2007 Oct LR
A/New Caledonia/20/1999

Code: 
NA
---
niid A/Toyama/108/2007 Oct LR
niid A/Hiroshima/93/2007 Oct LR #
A/Korea/6612/2007 ◄ Oct
A/Oregon/07/2007 ◄ Dec
A/Oregon/06/2007 ◄ Dec
A/Guam/6495/2007 ◄ Oct LR
A/Cambodia/0371/2007 ◄ Aug #
A/Lyon/1388/2007 ◄ Dec
A/Hong Kong/4703/2007 ◄ Sep
A/Ulaanbaatar/116/07 ◄ Jan #
A/Hong Kong/2652/2006 ◄ Jul #
A/Liaoning/Huanggu1183/2007 Oct #
niid A/Yokohama/75/2007 Oct LR
niid A/Hiroshima/109/2007 Dec #
A/Minnesota/25/2007 ◄ Oct
A/Hawaii/19/2007 ◄ Oct #
A/Texas/70/2007 Dec #
A/Texas/74/2007 Nov
A/Arizona/07/2007 Dec LR
A/Illinois/11/2007 Dec LR
A/Toulouse/1401/2007 Nov
A/Nepal/4606/2007 Jul LR
A/Washington/34/2007 Dec
A/Florida/10/2007 Dec #
A/Lyon/1350/2007 Dec
A/South Dakota/06/2007 Jul #
  nimr A/Norway/1630/2007 @
  A/Lyon/1337/2007 Dec @
  A/Illinois/10/2007 Dec @
  A/New Jersey/16/2007 Dec @
A/Pennsylvania/01/2008 Jan
A/Qatar/1124/2007 Nov LRniid 
A/Hiroshima/99/2007 Nov #
A/Colorado/21/2007 Nov #
  A/Hawaii/21/2007 Oct @
A/Hawaii/31/2007 Oct #
A/Brisbane/59/2007 Jul #
A/California/40/2007 Dec
A/Illinois/13/2007 Dec
A/Iowa/04/2007 Nov
A/Massachusetts/14/2007 Dec
A/Fukushima/141/2006 #
A/Solomon Islands/03/2006 #
A/Solomon Islands/3/06 IVR-145 #
A/Florida/3/2006 #
A/El Salvador/582/2007 Sep
A/Honduras/643/2007 Oct
A/New Caledonia/20/1999
Click to expand...
German isolates are Bisbayne/59 (but measured using Solomon Island/3

<TABLE class=overview rules=groups><THEAD><TR><TH class=overview>Virusisolat</TH><TH class=overview>Entnahme</TH><TH class=overview>A/NewCaledonia/20/99-IS</TH><TH class=overview>A/SolomonIslands/3/2006-IS</TH></TR></THEAD><TBODY><TR><TD>A/Berlin/98/07</TD><TD class=number>19.12.2007</TD><TD class=number>10</TD><TD class=number>160</TD></TR><TR><TD>A/Rheinland-Pfalz/63/07</TD><TD class=number>19.12.2007</TD><TD class=number>20</TD><TD class=number>320</TD></TR><TR><TD>A/Brandenburg/29/07</TD><TD class=number>19.12.2007</TD><TD class=number>80</TD><TD class=number>320</TD></TR><TR><TD>A/Niedersachsen/63/07</TD><TD class=number>20.12.2007</TD><TD class=number>80</TD><TD class=number>640</TD></TR><TR><TD>A/Baden-W?rttemberg/1/08</TD><TD class=number>02.01.2008</TD><TD class=number>80</TD><TD class=number>640</TD></TR><TR><TD>A/Th?ringen/1/08</TD><TD class=number>02.01.2008</TD><TD class=number>80</TD><TD class=number>640</TD></TR><TR><TD>A/Baden-W?rttemberg/5/08</TD><TD class=number>09.01.2008</TD><TD class=number>40</TD><TD class=number>320</TD></TR><TR><TD>A/Berlin/2/08</TD><TD class=number>14.01.2008</TD><TD class=number>40</TD><TD class=number>320</TD></TR><TR><TD>A/Sachsen/3/08</TD><TD class=number>15.01.2008</TD><TD class=number>40</TD><TD class=number>320</TD></TR><TR><TD>A/Nordrhein-Westfahlen/1/08</TD><TD class=number>15.01.2008</TD><TD class=number>40</TD><TD class=number>320</TD></TR></TBODY></TABLE>
http://influenza.rki.de/index.html?c=viren
 
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