H5N1 and H1N1(2009) reassortment – are we quacking up the wrong tree?

[sharon sanders]

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Click on image to enlarge
<dl><dd>
</dd><dt>

</dt></dl>





​

Figure 4
The fitness landscapes of avian influenza virus.
(a) The fitness landscapes observed in HA, NA and NS, and represented here by NA. Each colored cone represents an individual subtype. These subtypes are connected by a bifurcating tree. The lack of ?intermediate? subtypes ? those falling below the pink disc ? reflects major valleys in fitness, such that any virus falling in this area will experience a major reduction in fitness, most likely due to an elevated cross-protective immune response. Occasionally, individual subtypes jump species barriers and spread in new hosts (such as humans), where they experience a continued selection pressure and hence accumulate amino acid substitutions in a progressive manner, as shown. (b) The fitness landscapes observed in the remaining internal protein segments of avian influenza virus ? PB2, PB1, PA, NP and M (represented by different colors). In this case, there is little functional difference among the genetic variants of each segment, so that the fitness landscape is flat. This equivalence in fitness among genome constellations also means that reassortment is frequent among them (as reassortants suffer no fitness cost), represented by the horizontal lines connected each internal gene segment.

 

[SusanC]

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Thank you!! :tiphat:

 

[JJackson]

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Well, I'd say, while the close proximity of species is always a contributing factor to virus jumping across species barriers, that in itself cannot tell us which way the virus tends to jump - wild birds to chickens? Or vice versa? Or both ways?

The finding of E627K in wild birds is a different class of evidence than the kind cited by Gary Butcher, because this is a distinctly mammalian adaptation that is not seen in any other avian viruses, and therefore constitutes pretty strong if not solid evidence of H5N1 being able to cross BACK into wild birds. However, this is anomalous to the sum total of evidence on sampling of avian flu viruses in wild birds, from Dugan et al, suggesting that the behavior of H5N1 is likely to be the exception to the rule. Which means it's probably a good idea to not extrapolate information from H5N1 to other subtypes, since H5N1 does seem to be an unusual virus quite unlike the more 'everyday' ones like H1N1.

I just thought that this might be an important point to bear in mind, in our assessment of H1N1, since there is no evidence of H1N1 crossing back into wild birds since its emergence from them , even though obviously there are avian H1N1s in wild birds as well! (again this pic explains it well, if someone can help load it. Thanks!! http://www.ncbi.nlm.nih.gov/pmc/arti...-1000076-g004/

As you say the closeness of two species is not a guarantee that that is the way the virus will jump. There are specific requirements that must be met that may be a better fit in relatively remotely related species. In influenzas case receptor binding specificity is an obvious example. However the chances of any basket of features being a good match will tend to be better the closer the species are. This will become more pronounced when we jump not merely between species but between families.
Your example of E627K (PB2) is a good one as it relates to the optimum operating temperature for the viral polymerase, which is higher for avians than mammalians, so groups all the species into their respective family sets. It is also interesting as, while you have used it to illustrate a point about it being an avian trait, I would like to dragoon it into making almost the opposite point. There are in fact rare examples of birds which do have E627K (A/Pheasant/Hong Kong/FY155/01-MB (H5N1)). The pandemic strain is assumed to have come from swine &#150; as its last stop before us &#150; however it has the avian form. If you look at the diagram below
and follow the very top line all the way form the top left corner to its exit on the right this is the history of the pandemic PB2 gene (the genes are numbered from 1 to 8 by length, PB2 is the longest and at the top - HA is segment 4 &#150; they are listed on the right. They average around 1500 bases = 500 AAs). We can trace PB2 back to its not too distant avian roots but why, when K627 is such a clear human marker, has this strain managed to spread happily without it. It seems &#150; according to this paper - that various strategies can be applied. The &#146;57 & &#146;68 pandemic strains incorporated a human PA in an otherwise avian polymerase complex and our current one is getting around the restriction with changes at 590 & 591 on PB2. More worryingly the paper also shows that while happy now an E627K change enhances polymerase function further. The point I am keen to make is that this virus is very adept at finding novel sequence combinations - often across more than one segment - which confound our attempts to pigeonhole SNPs as being &#145;required&#146; for a function. The rapid fixing of H274Y (NA) in seasonal H1N1, after regularly cropping up only to be outperformed by the wild type, seems to be highly correlated to an arrangement including A193T (HA).
While it is true there are no wild bird sequences, yet, with pandemic H1N1 there are domestic poultry sequences, as I noted in the opening post in this thread, so H5N1 is not currently alone in its ability to family hop. There is no way of knowing how they became infected form a human, a pig or another bird but I have looked at the HA on A/turkey/Chile/28317-6504-3/2009(H1N1) and it is as good an alignment with A/California/7/2009 as most human pandemic sequences. This is as big a deal as HP H5N1 but in the other direction. Here we have a predominantly mammalian virus adapted well enough to cause occasional avian infections while H5N1 is happier in birds but can infect mammals. Either way when one of these family hops occurs a dual infection leaves us open to a very extensive pool of reassortment combinations. The odd infection in humans with H5N1 is much more likely to be spotted, & sequenced (by humans), than the odd H1N1(2009) infection in a wild bird so I am less sanguine than you about it not occurring, it is a lot newer than H5N1 and lot lower priority.

Edit: link to the source for the H1N1 gene history diagram
http://www.nature.com/nature/journal...ture08182.html

 

[Vibrant62]

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

I have been searching for a recent study/ studies that were reported here that also adds to the overall picture discussed in this thread, but have not been able to find it - I dont know if this comment might jog someone's memory so that the study can be posted here to add to the overall discussion.

Essentially the paper examined Pandemic H1N1 and its novel approach to human adaptation, with mutations not normally seen/ expected in human influenza. The researchers believed that this genetic configuration may have allowed pandemic H1N1 to jump species without the presence of more 'normal' markers.

I think the findings of this study may have a bearing on this discussion (Edit - if it works for avian > mammalian cross adaptation, then there is no reason why a similar mechanism could not occur in reverse). I think this may cuase us to rethink what we believe we know, as comment was passed (if memory serves) that this configuration appears to confer general fitness to a wide range of species, obviating the need for slow (and restrictive) adaptation mechanisms discussed here.

China reported H1N1 infection in dogs with a 99% identical virus, cat infections are also reported with a similar degree of identical genetics, and there is easy transmission to and between pigs and turkeys with almost no genetci changes whatsoever. We can also add ferrets, mice etc to this list and I beleive a few other mammalian species. Only H5N1 shares such characteristics i.e occasional interspecies transmission with little or no genetic change - but H1N1 appears far more adept at this.

This news report it is the best I can find at the moment on one of the studies I have in mind. http://www.berkeley.edu/news/media/releases/2009/12/08_h1n1_flu_virus.shtml

http://www.eurekalert.org/pub_releases/2009-12/uoc--hia120809.php

As always I mentally 'picked up' the overall conclusions without paying sufficient attention to the mechanistic detail (lesson to self - dont do this again!). I believe there is a second study that is relevant here that addresses why this virus may be more adapted to mammals generally rather than individual species, and will keep looking for it.

 

[mixin]

Re: H5N1 and H1N1(2009) reassortment – are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment – are we quacking up the wrong tree?

Is this the one: Adaptive strategies of the influenza virus polymerase for replication in humans

http://www.flutrackers.com/forum/showthread.php?t=136741&highlight=Doudna

Transmission of influenza viruses into the human population requires surmounting barriers to cross-species infection. Changes in the influenza polymerase overcome one such barrier. Viruses isolated from birds generally contain polymerases with the avian-signature glutamic acid at amino acid 627 in the PB2 subunit. These polymerases display restricted activity in human cells. An adaptive change in this residue from glutamic acid to the human-signature lysine confers high levels of polymerase activity in human cells. This mutation permits escape from a species-specific restriction factor that targets polymerases from avian viruses. A 2009 swine-origin H1N1 influenza A virus recently established a pandemic infection in humans, even though the virus encodes a PB2 with the restrictive glutamic acid at amino acid 627. We show here that the 2009 H1N1 virus has acquired second-site suppressor mutations in its PB2 polymerase subunit that convey enhanced polymerase activity in human cells. Introduction of this polymorphism into the PB2 subunit of a primary avian isolate also increased polymerase activity and viral replication in human and porcine cells. An alternate adaptive strategy has also been identified, whereby introduction of a human PA subunit into an avian polymerase overcomes restriction in human cells. These data reveal a strategy used by the 2009 H1N1 influenza A virus and identify other pathways by which avian and swine-origin viruses may evolve to enhance replication, and potentially pathogenesis, in humans.

 

[Vibrant62]

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Thankyou Mixin - That is the Berkley abstract I could not find - the press release gives a little more info (see links in earlier post) since the full paper does not seem to be accessible.

There is another mechanistic paper that is relevant here to the overall picture, and I will keep looking.

 

[mixin]

Re: H5N1 and H1N1(2009) reassortment – are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment – are we quacking up the wrong tree?

Here is the 5 page .pdf with all the tables:

http://www.pnas.org/content/early/2009/12/04/0911915106.full.pdf

 

[gsgs]

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

> AIV in wild birds exists as a large pool of functionally equivalent,
> and so often inter-changeable, gene segments that form
> transient genome constellations,

only in HA and NA !

in the inner segment it's close to an "index" in wild birds and
protein-diversity only starts when it evolves for prolonged time
in poultry or mammals.

 

[gsgs]

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

H5N1 was a threat before we saw E627K in the Qinghai strain (where is it ?)

The Qinghai strain was created by H5N1 going from poultry
back to wild birds and reassorting.

the semi-wild grazing rice-field ducks in SE-Asia were a problem,
no such thing in America,Europe AFAIK

 

[gsgs]

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

Re: H5N1 and H1N1(2009) reassortment ? are we quacking up the wrong tree?

one case, where it went back from swine to wild birds
seem to be the South Dakota ducks
A/mallard/SD/Sg-00125/2007(H3N2)
and others.
They caught a swine virus similar to ****** which was preserved for 10 years.
Some other lab please confirm, please test some more SD-ducks