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PostPosted: Wed Nov 18, 2009 10:08 am 
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niman wrote:
Two of the travel logs for the Sydney isolate

gb|CY049691.1| Influenza A virus (A/Singapore/GP2711/2009(H1N... 32.2 12
gb|CY047150.1| Influenza A virus (A/Catalonia/S1138/2009(H1N1... 32.2 12
gb|GU014748.1| Influenza A virus (A/Gifu-C/67/2009(H1N1)) seg... 32.2 12
gb|GQ377064.1| Influenza A virus (A/Virginia/05/2009(H1N1)) s... 32.2 12
gb|GQ232009.1| Influenza A virus (A/Kentucky/05/2009(H1N1)) s... 32.2 12

************************

gb|CY049691.1| Influenza A virus (A/Singapore/GP2711/2009(H1N... 38.2 0.19
gb|GU014748.1| Influenza A virus (A/Gifu-C/67/2009(H1N1)) seg... 38.2 0.19

The Sydeny isolate shares its 5' portion with the Singapore and Gifu isoaltes, but neither has D225G. Thus, the Sydney isolate acquired the D225G via recombination, and thsi backlground is different than teh background in China.
The concurrent acquisition of the same polymorphism (D225G) onto multiple genetic backgrounds at tehsame time signals a selective advantage for that polymorphism as described in H5N1

http://precedings.nature.com/documents/459/version/4

When receptor binding domain polymorphisms are "in play", major changes follow.

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PostPosted: Wed Nov 18, 2009 10:22 am 
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I'm trying to understand what exactly the receptor binding domain is/does. The name, to me, implies that affects how the virion attaches to a host cell, which indicates that certain changes can increase the "efficiency" of an infection and thereby lead to higher viral load. Is this a fair assessment, at least for the layman?

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PostPosted: Wed Nov 18, 2009 10:26 am 
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wotan wrote:
I'm trying to understand what exactly the receptor binding domain is/does. The name, to me, implies that affects how the virion attaches to a host cell, which indicates that certain changes can increase the "efficiency" of an infection and thereby lead to higher viral load. Is this a fair assessment, at least for the layman?

Yes, the receptor binding domain affects the affinity of teh virus for teh cell receptor and can affect transmission efficiency, tissue tropism (which cell types can be infected), or antigenicity (escape from existing immunity).
When these polymorphisms (like D225G) start jumping from one H1N1 background to another, major changes can follow (like Ukraine).

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PostPosted: Wed Nov 18, 2009 10:33 am 
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niman wrote:
wotan wrote:
I'm trying to understand what exactly the receptor binding domain is/does. The name, to me, implies that affects how the virion attaches to a host cell, which indicates that certain changes can increase the "efficiency" of an infection and thereby lead to higher viral load. Is this a fair assessment, at least for the layman?

Yes, the receptor binding domain affects the affinity of teh virus for teh cell receptor and can affect transmission efficiency, tissue tropism (which cell types can be infected), or antigenicity (escape from existing immunity).
When these polymorphisms (like D225G) start jumping from one H1N1 background to another, major changes can follow (like Ukraine).


So I think I understand now your comment about how it lead to the spread of H274Y. The H274Y change attached itself to a particular strain or clade of seasonal H1N1 that had a favourable trait at D225 that allowed it to spread more readily via the hitch-hiking you have mentioned before.

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PostPosted: Wed Nov 18, 2009 11:08 am 
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Commentary

http://www.recombinomics.com/News/11180 ... D225G.html

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Last edited by niman on Wed Nov 18, 2009 12:39 pm, edited 1 time in total.

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PostPosted: Wed Nov 18, 2009 11:57 am 
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wotan wrote:
niman wrote:
wotan wrote:
I'm trying to understand what exactly the receptor binding domain is/does. The name, to me, implies that affects how the virion attaches to a host cell, which indicates that certain changes can increase the "efficiency" of an infection and thereby lead to higher viral load. Is this a fair assessment, at least for the layman?

Yes, the receptor binding domain affects the affinity of teh virus for teh cell receptor and can affect transmission efficiency, tissue tropism (which cell types can be infected), or antigenicity (escape from existing immunity).
When these polymorphisms (like D225G) start jumping from one H1N1 background to another, major changes can follow (like Ukraine).


So I think I understand now your comment about how it lead to the spread of H274Y. The H274Y change attached itself to a particular strain or clade of seasonal H1N1 that had a favourable trait at D225 that allowed it to spread more readily via the hitch-hiking you have mentioned before.

You have the general concept right, but the specifics wrong. The general concept is mixing and matching of genetic changes via recombination. Thus, a given change like H274Y, which confers Tamiflu resistance, jumped from one seasonal flu H1N1 background to another until it found a powerful driver. Thus, H274Y wasn't the powerful driver. It was the hitchhiker and for seasonal H1N1, A193T was the driver. Such drivers are frequently receptor binding domain changes. A similar event happened with another viral resistance marker, S31N on M2 of seasonal H3N2. Once again the viral resistance (Adamantane) marker was the hitchhiker, and receptor binding domain changes were the driver. For S31N in H3N2 that was position 193 again (S193F) as well as 225 (D225N).

Thus, position 225 has been in the "driver" position, which helped lead to the widespread distribution of S31N in seasonal H3N2. That same change is in swine H1N1, which is why all swine H1N1 is adamantane (S31N) resistance.

However, in addition to hitchhikers jumping from one background to another via recombination, drivers can also jump from one background to another to create a combination that offers a strong selective advantage. On this thread I described D225G, one of three changes at position 225 in swine H1N1 (the other two are D225N and D225E).

So far I have described D225G hoping onto a China genetic background, as well as a jump in Australia (anto a Singapore/Japan backbone.

I had also previously described its appearance on yet another backbone in Sau Paulo, where it was in samples from lungs of fatal cases.

The recent jumping of D225G onto so many backgrounds raise concerns that it has done the same in Ukraine, leading to transmission or tropism changes and the associated lung destruction and death.

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PostPosted: Wed Nov 18, 2009 1:26 pm 
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Here is the travel log for the other isolate in Sydney (2501) with a chnage at position 225. However, this time it is D225N (as a mixture, wild type D225 is also present). The front end of this gene matches Sydney 2503, but instead of adding D225G, it added D225N (once again supporting recombination, but with a different donor sequence). However, the back end of the gene matches the isolates from China (which have D225G). This the gene has three parts. The front is Singapore/Japan, the middle is D225N, and the back is China. Thus, even though the front and back are from genes with D225G, it has D225N.

Sydney/2501/2009 travel log

gb|CY049691.1| Influenza A virus (A/Singapore/GP2711/2009(H1N... 40.1 0.048
gb|CY047150.1| Influenza A virus (A/Catalonia/S1138/2009(H1N1... 40.1 0.048
gb|GU014748.1| Influenza A virus (A/Gifu-C/67/2009(H1N1)) seg... 40.1 0.048
gb|GQ377064.1| Influenza A virus (A/Virginia/05/2009(H1N1)) s... 40.1 0.048
gb|GQ232009.1| Influenza A virus (A/Kentucky/05/2009(H1N1)) s... 40.1 0.048

**************************

gb|CY049691.1| Influenza A virus (A/Singapore/GP2711/2009(H1N... 36.2 0.76
gb|GU014748.1| Influenza A virus (A/Gifu-C/67/2009(H1N1)) seg... 36.2 0.76

**************************

gb|CY050190.1| Influenza A virus (A/New York/4576/2009(H1N1))... 40.1 0.048
gb|GQ915021.1| Influenza A virus (A/Sao Paulo/53845/2009(H1N1... 40.1 0.048
gb|GQ915020.1| Influenza A virus (A/Sao Paulo/53838/2009(H1N1... 40.1 0.048
gb|CY045061.1| Influenza A virus (A/New York/4099/2009(H1N1))... 40.1 0.048

**************************

gb|GU189649.1| Influenza A virus (A/Zhejiang/DTID-ZJU03/2009(... 38.2 0.19
gb|GU112090.1| Influenza A virus (A/Zhejiang/DTID-ZJU02/2009(... 38.2 0.19
gb|GU108486.1| Influenza A virus (A/Zhejiang-Yiwu/11/2009(H1N... 38.2 0.19
gb|CY047712.1| Influenza A virus (A/Hangzhou/1/2009(H1N1)) se... 38.2 0.19
dbj|AB434336.1| Influenza A virus (A/swine/Saraburi/NIAH13021... 38.2 0.19
gb|EU296607.1| Influenza A virus (A/swine/Saraburi/NIAH13021/... 38.2 0.19
gb|AY060052.1| Influenza A virus (A/SW/MN/17138/01(H1N2)) hem... 38.2 0.19

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PostPosted: Wed Nov 18, 2009 3:24 pm 
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Do we understand specifically the importance of D225G versus any other change at that position? Is it known to increase the ability of the virus to attack the lungs?

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PostPosted: Wed Nov 18, 2009 3:39 pm 
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Commentary

http://www.recombinomics.com/News/11180 ... irmed.html

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PostPosted: Wed Nov 18, 2009 3:45 pm 
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OK, Dr Niman you got the sequence change,we read the commentary. Now what does that all mean and I see you said there will be more forthcoming.

This was the same thing that happened in Brazil and Austrailia, correct?

What does this mean for us here, or has it already happened.

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