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 Post subject: D225N?
PostPosted: Thu Dec 10, 2009 3:32 pm 
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The reason for concern over D225G seems pretty obvious, everything points to it attacking cells deep in the lungs. But what do we know about D225N?

On a related note, I see a lot of references now to samples that show mixed signals for different polymorphisms at D225. How does that arise and what determines which one is created when the virus reproduces?

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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 3:45 pm 
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wotan wrote:
The reason for concern over D225G seems pretty obvious, everything points to it attacking cells deep in the lungs. But what do we know about D225N?

On a related note, I see a lot of references now to samples that show mixed signals for different polymorphisms at D225. How does that arise and what determines which one is created when the virus reproduces?

D225N is in H3N2 and was used to fix S31N (adamantane resistance). Position 225 not only affects tissue tropism, but also immune recognition, so the virus can chnage position 225 to infected patients who have antibodies to wild type.
Mixtures represent two or more viruses in the same host. That allows fro recombination, reassortment, and pseudotypes. Virus can take D225G gene and wrap it in wild tpe HA to get into host, and the use teh gene fro D225G to get into lungs.
The virus has a lot of survival mechanisms, over simplified sequence databases not withstanding.

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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 3:46 pm 
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If I understand correctly, the contagion and virility of the virus is based on viral load - which in turn is based on a couple of things including 1) length of time and proximity of contact with the ill person and 2) the level of evolvement of the actual virus itself in the contagious person.

Therefore, if these sequences (D225G, E, N) are in the infancy stage of development at this time (lets say since April at least), the contagion and virulence may be also in its infancy stage in the effect of the seriousness of infection and the ability to spread, ergo the lack of obvious clustering at this point.

Questions: These sequences are showing they have been around for awhile so

1) How long would it take for this sequence to develop the strength of contagion?
2) How long would it take for these sequences to develop the strength of virility?
3) Is there another or future sequence we should be watching for this to evolve to, since this was predicted earlier this year? If so, what?
4) Is there information relative to 1918 that would give data on dates such as lab info, scientific documentation, diaries?
5) Does the fact that it was so virulent in 1918 mean that it will do the same thing this time?
6) Are there other D225's that we should watch for, if so what and why?


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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 3:56 pm 
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gjs0708 wrote:
If I understand correctly, the contagion and virility of the virus is based on viral load - which in turn is based on a couple of things including 1) length of time and proximity of contact with the ill person and 2) the level of evolvement of the actual virus itself in the contagious person.

Therefore, if these sequences (D225G, E, N) are in the infancy stage of development at this time (lets say since April at least), the contagion and virulence may be also in its infancy stage in the effect of the seriousness of infection and the ability to spread, ergo the lack of obvious clustering at this point.

Questions: These sequences are showing they have been around for awhile so

1) How long would it take for this sequence to develop the strength of contagion?
2) How long would it take for these sequences to develop the strength of virility?
3) Is there another or future sequence we should be watching for this to evolve to, since this was predicted earlier this year? If so, what?
4) Is there information relative to 1918 that would give data on dates such as lab info, scientific documentation, diaries?
5) Does the fact that it was so virulent in 1918 mean that it will do the same thing this time?
6) Are there other D225's that we should watch for, if so what and why?

My guess is the damage that D225G and D225N do is dependent on viral load, which regulates how much virus gets into the lungs, or subsets of cells in lungs. The ratio of these chnages to wild type will also be driven by the immune response to wild type. A small change in ratio can have a major effect on host. The virus is still adapting to its new host(s) and the current situation is EXTREMELY unstable.

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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 4:03 pm 
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Good question, Wotan, and thanks for the reply Dr. Niman.


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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 4:31 pm 
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Does N attack as deeply in the lungs as G, or does it attack a little higher?

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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 5:05 pm 
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gjs0708 wrote:
1) How long would it take for this sequence to develop the strength of contagion?
2) How long would it take for these sequences to develop the strength of virility?
3) Is there another or future sequence we should be watching for this to evolve to, since this was predicted earlier this year? If so, what?
4) Is there information relative to 1918 that would give data on dates such as lab info, scientific documentation, diaries?
5) Does the fact that it was so virulent in 1918 mean that it will do the same thing this time?
6) Are there other D225's that we should watch for, if so what and why?

Thank you gjs0708 for sharing this set of important questions.
I confess I do not have the answer to most of them, but it's word taken.
I wish I had all the answers right now!
I already printed them since each deserve long reflection.


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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 7:35 pm 
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neuromedia
When you answer the questions from gjs0708, I would like you to define each of the areas so I can follow along! :D

for example what is"strength of contagion"

TKX


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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 8:58 pm 
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Here's where I am going with this. We know that D225G and D225N have both been associated with severe lung involvement. They may, however, attack different locations in the lungs. Similarly, wild-type and D225E apparently attack upper portions of the respiratory tract. We have seen instances where D225G (and N?) has been found in the mid to upper respiratory tract. And we have patients apparently infected with multiple types.

So, perhaps someone is infected with multiple types, and they reach the areas that they preferentially infect, but those overlap, allowing G and N to to mix, recombine possibly, and as new virions are released some of them may rise a little higher, mixing with E and wild-type, and by this method the D and N polymorphisms are allowed to survive and spread. In some instances one or both of these becomes dominant in an individual and the viral load in the lungs is driven up, leading to the more severe infections. And perhaps because they are so virulent when present in large quantities, that might explain why you won't necessarily see multiple members of the same family suffering in the same way.

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 Post subject: Re: D225N?
PostPosted: Thu Dec 10, 2009 9:18 pm 
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wotan wrote:
Here's where I am going with this. We know that D225G and D225N have both been associated with severe lung involvement. They may, however, attack different locations in the lungs. Similarly, wild-type and D225E apparently attack upper portions of the respiratory tract. We have seen instances where D225G (and N?) has been found in the mid to upper respiratory tract. And we have patients apparently infected with multiple types.

So, perhaps someone is infected with multiple types, and they reach the areas that they preferentially infect, but those overlap, allowing G and N to to mix, recombine possibly, and as new virions are released some of them may rise a little higher, mixing with E and wild-type, and by this method the D and N polymorphisms are allowed to survive and spread. In some instances one or both of these becomes dominant in an individual and the viral load in the lungs is driven up, leading to the more severe infections. And perhaps because they are so virulent when present in large quantities, that might explain why you won't necessarily see multiple members of the same family suffering in the same way.

The entire process is complex and the holes in the database are huge. Sequences are the "consensus" for each position, so mixed signals are only reported in the actual sequence when there is close to a 50/50 mix. If it is 90/10, only the 90 will be in the sequence (but the tracing of the data will have a major peak at teh position, with a minor peak under the major peak). This ratio can also vary by when and where the sampes are collected and of course there are host differences (as well as initial viral load issues).
Many of the questions are assuming a black and white situation, which is not the case. Moreover, deaths are rare, so to get a cluster of a rare evert is even rarer. However, when a population is tested, like fatal cases in Ukraine, a VERY clear picture emerges (6 of 6 have changed 225 to G or N).
The greater the frequency of these detections, the greater the liklihood that the virus is evolving toward a ratio that favors D225G or D225N which could create a DRAMATIC increase in deaths or severe cases if that ratio changes (especially if the change is driven by immune response against the wild type).

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