Wednesday, November 18, 2009

Rethinking a previous post.

This blog has been stale for too long, but I have had RL to deal with, including one known case of swine flu in my house and another suspected one. I will need to blog on those another time. But first:

My previous entry described a speculation I had about how an increase in transmissibilty could lead to a more severe pandemic. But now I have some new thoughts on that.

The biggest news in the pandemic lately has been the rapid and apparently severe outbreak in Ukraine. Deep in that long thread you will read about an apparently large number of deaths involving severe lung disease. We now have a possible explanation of that. New sequences from Ukraine released at GISAID indicate a relatively new polymorphism (for swine flu) showing up in the lungs of deceased patients: D225G.

I do not (at this time) know the exact significance of this, but of interest is the following:

http://fluboard.rhizalabs.com/forum/viewtopic.php?p=20564#p20564

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.


It appears that D225G may lead to an easier infection of the lungs. I had previously thought that the apparent prevalence of primary viral pneumonia in this pandemic was due to the presence of E627 from avian influenza, and not E627K from human influenza. This particular change affects the virus' thermostat, E627 to E627K would lower the ideal replication temperature to one that matches the temperature in the human nose versus the intestines of a bird. Therefore, I used to think that the spread of E627K (http://fluboard.rhizalabs.com/forum/viewtopic.php?p=8014#p8014 would make the virus easier to transmit but less virulent. Now I am met with the possibility of increasing the transmissibility of E627K and increasing the ability of the virus to attack the lungs via D225G. The spread of these two polymorphisms therefore warrants additional vigilance.

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