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  • VB - The D225G change in 2009 H1N1 influenza virus is not a concern

    The D225G change in 2009 H1N1 influenza virus is not a concern
    by Vincent Racaniello on 24 November 2009
    http://www.virology.ws/2009/11/24/th...not-a-concern/

    The Norwegian Institute of Public Health recently identified a mutation in 2009 H1N1 influenza virus isolated from two patients who died and one with severe disease. It has been suggested that this mutation, which causes a change from the amino acid aspartic acid to glycine at position 225 of the viral HA protein (D225G), could make the virus more likely to infect deeper in the airways and cause more severe disease. What is the basis for this concern and does it have merit?

    Attachment of all influenza A virus strains to cells requires sialic acids. There are a number of chemically different forms of sialic acids, and influenza virus strains vary in their affinity for them. Human influenza A strains bind preferentially to sialic acids linked to galactose by an alpha(2,6) bond, while avian and equine strains prefer alpha(2,3) linked sialic acids.

    The type of sialic acid preferred by influenza viruses is controlled by amino acids in the HA protein. Amino acids 190 and 225 are important determinants of receptor binding specificity of the 1918 H1 hemagglutinin. The HA of the 1918 strain A/South Carolina/1/18 prefers alpha(2,3) linked sialic acids; the New York variant, isolated in September 1918, binds both alpha(2,3) and alpha(2,6) sialic acids. These two H1 hemagglutinins differ only by a single amino acid, position 225, which is aspartic acid (D) in the South Carolina strain and glycine (G) in the NY strain. When amino acid 190, which is D in both strains, is changed to E in the NY HA, the virus (AV18) preferentially binds alpha(2,3) sialic acids. These findings are summarized in the table.



    Different isolates of the 2009 H1N1 influenza virus have D at HA at amino acid 190 and mostly D at amino acid 225. The virus prefers to bind to alpha(2,6) linked sialic acids. The amino acid change D225G would be expected to produce a virus with preference for both alpha(2,3) and alpha(2,6) linked sialic acids.

    In the human respiratory tract, alpha(2,6) linked sialic acids are dominant on epithelial cells in the nasal mucosa, paranasal sinuses, pharynx, trachea, and bronchi. Alpha(2,3) linked sialic acids are found on nonciliated bronchiolar cells at the junction between the respiratory bronchiole and alveolus, and on type II cells lining the alveolar wall.

    Based on these considerations, it could be hypothesized that the D225G change would allow the 2009 H1N1 virus to replicate deeper in the respiratory tract. But 2009 H1N1 virus without this amino acid change can already replicate deep in the respiratory tract of ferrets, and probably also in humans. Cells with alpha(2,6) linked sialic acids are present in the lower respiratory tract of humans. So it’s not clear if any effect on virulence would be conferred by the ability of the 2009 H1N1 strain to bind alpha(2,3) linked sialic acids.

    An important consideration is that the D225G amino acid change has a negative impact on transmission. The change from D to G at amino acid 225 of the 1918 HA significantly impairs transmission among ferrets. When both D225G and D190E are present, transmission is abolished. These changes do not impair viral replication or virulence in the respiratory tract of inoculated animals.

    Transmissibility is clearly a positive selection factor for viral evolution. There may be selection for increased virulence only if there is no negative impact on viral transmission. Given these considerations, the choice between an H1 HA amino acid at position 225 that allows efficient transmission (D225) or one that impairs transmission and might or might not allow multiplication deeper in the lung (D225G) seems obvious.

    Tumpey, T., Maines, T., Van Hoeven, N., Glaser, L., Solorzano, A., Pappas, C., Cox, N., Swayne, D., Palese, P., Katz, J., & Garcia-Sastre, A. (2007). A Two-Amino Acid Change in the Hemagglutinin of the 1918 Influenza Virus Abolishes Transmission Science, 315 (5812), 655-659 DOI: 10.1126/science.1136212

    Shen J, Ma J, & Wang Q (2009). Evolutionary Trends of A(H1N1) Influenza Virus Hemagglutinin Since 1918. PloS one, 4 (11) PMID: 19924230
    I'm interested in expert panflu damage estimates
    my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

  • #2
    Re: VB - The D225G change in 2009 H1N1 influenza virus is not a concern

    comments:

    -----------------------------------------
    But 2009 H1N1 virus without this amino acid change can already replicate deep in the respiratory tract of ferrets

    How labile are flu viruses within an individual patient? Is the D225G polymorphism transmitting between patients, or is the same mutation recurring in many different patients? One could hypothesise a scenario where only virus particles with a D at position 225 are able to transmit, but the subsequent course of the infection depends on whether the the virus happens to pick up a G at position 225 within each given patient. Whether you detect a D or a G when you come to sequence a sample would depend on how long-established the infection was, how deep you were sampling within the respiratory tree, etc.

    On a related note, how certain are we about what was going on in the ferrets? If I remember rightly, the study infected ferrets with H1N1 flu (i.e. with D at 225) and observed deep lung pathology. Did they then re-isolate the virus from the deep lung lesions and check whether it still had a D at position 225?

    Perhaps the pathogenic factor is not whether a given strain has G at 225, but the ease (or otherwise) with which it can acquire a G as it replicates within the host.

    Same goes for any other polymorphism that increases lethality but decreases transmission. If you need half a dozen nucleotide changes to get from the transmissible sequence to a lethal sequence, you're safer than if it's only a single hop away.
    ----------------------------------------------
    Good questions pjie2.

    However, the question remains which selective advantages such sporadic "in-patient-mutated" virus could have over its non-mutated competitors during the course of the infection within the patient ?

    As long as the "front of the infection wave" has not reached the deep lung tissue, the reproduction rate of the non-mutated version would be superior... and will thus stop before the deep lung tissue is reached.

    Maybe it is only those rare cases where the "jump" happen to occur in a virus particle just at the peripheric border of the infection wave far enough down the respiratory tree to reach the first susceptible "2,3"-type cells. from which point on a "second wavefront" of the infection would be started running down the lower part of the respiratory tract.

    just a thought ...
    pjie2 3 days ago in reply to h1n1_watcher

    ----------------------------------------------------------

    Eh, that implies spread of flu in the respiratory tree is like some kind of slow-moving fluid, rather like the adverts for cough syrup. Does flu actually work like that? I mean, an air molecule can get from the outside world down to the deepest parts of the respiratory tree within a single breath - it's how breathing works. Virus particles won't be quite that mobile, but even so...

    The picture I had in mind was a lot simpler - you have an active upper respiratory infection with D at 225. Periodically, random mutations happen which create a G at 225 - along with a host of other mutations, of course, since the sheer number of viral RNAs synthesised pretty much guarantees that any given mutation will arise at least once. These mutant particles get released and go wherever the air flow takes them, be that up or down.

    If they get coughed out and land on someone else, there's no effect as they don't transmit well. If they get inhaled deeper into the lungs, then they may set up shop there. They won't get outcompeted by the parent virus because the parent virus isn't infecting the same cells.

    I wonder if new deep sequencing technology will help answer these questions. Would it let you look at the whole population of viral sequences within an infection, and/or at different locations within the lung, rather than getting a consensus sequence?
    ------------------------------------------------
    gsgs 3 days ago
    I read, that there are 10 sequences from Ukraine at the secret database "GISAID"
    and 4 of these are from lethal cases and exactly those 4 have 225G.
    Is it true ? Why no comment on this , WHO,CDC,ECDC,journalists ?
    ----------------------------------------------
    profvrr 2 days ago in reply to gsgs
    Maybe after they read this post they will realize that the mutation
    doesn't matter.
    ---------------------------------------------------
    Your table doesn't seem consistent with the text above it. Text: "The HA of the 1918 strain A/South Carolina/1/18 prefers alpha(2,3) linked sialic acids". Table: cross in the (2,6) column and none in the (2,3) column. I don't know which is right?

    Below the table, you write "Different isolates of the 2009 H1N1 influenza virus have D at HA at amino acid 190 and mostly D at amino acid 225. The virus prefers to bind to alpha(2,3) linked sialic acids." and I think you mean (2,6) here too? If not I'm very confused.
    ---------------------------------------------
    profvrr 2 days ago in reply to Close reader

    Thank you for picking up those errors; I've corrected them. For some
    reason, when it comes to alpha(2,3) and alpha(2,6) preferences, I
    always mix them up. I just did it last week when I lectured medical
    students. One emailed me afterwards to let me know about it. At least
    I know some people are listening!
    -----------------------------------------------------
    Barnaby Dawson 2 days ago
    From what I've read we don't seem to have a great track record at predicting the clinical features of a virus from changes to its genome. We don't really know enough about the genetics to predict the effect of a certain new mutation. So I'm not convinced by this line of reasoning.

    The ferret model isn't terribly convincing either. An early study on the a Mexican strain of swine flu showed an astoundingly high death rate in ferrets although the same strain in people was relatively mild. Other experiments in ferrets concerning the transmissibility of the virus also seemed to contradict observations on human epidemiology.

    Equally, of course, I'm not convinced that the mutation should concern us just from genetic speculation.

    As far as I'm concerned the question, as to how concerned we should be, is best answered by observation of human clinical subjects.
    -----------------------------------------------------
    steveoliver 2 days ago

    "An important consideration is that the D225G amino acid change has a negative impact on transmission. The change from D to G at amino acid 225 of the 1918 HA significantly impairs transmission among ferrets. When both D225G and D190E are present, transmission is abolished"

    Is there more data on this statement? It would be great to review it.
    Thanks
    --------------------------------------------------
    profvrr 2 days ago in reply to steveoliver

    The data for that statement are included in the Science paper
    referenced at the bottom of the post.
    ---------------------------------------------------
    steveoliver 2 days ago in reply to profvrr

    Yes indeed That's what happens when you go from microscope to computer screen 12 hours a day.
    Thanks
    -----------------------------------------------------
    wii spiele 2 days ago

    Very informative. If I understand this correctly D225G does not necessarily mean that a given individual will contract a severe case if they are infected with it, as compared to the wild strain. Is this because it all depends on the G placement at position 225? From the article it appears that that between the two we are looking lots of infection , little death (Wild), or little infection, lots of death (mutant). If that is the case it seems at present there is a fight for supremacy going on. Would it be a fair assumption to suggest that because of the ever growing number of cases of D225G becoming visible that we may be at a tipping point between the two? If D225G does not match up with 1918/1919 exactly, what would be a clearer indicator that we are going down that path? Additionally since many people still have not been vacinated both healthy and otherwise, would it be a prudent move to get a Pneumovax? Thanks...
    ------------------------------------------------------------------
    gsgs 45 minutes ago

    47 comments 0 likes 2 points
    but only 12 comments are shown. Is there so much spam or censorship ?

    there are hundreds of HA-spikes, some may have 225D and some 225G,
    so such a virus could bind to both types of cells. If that combined HA-production
    sheme could be encoded genetically wouldn't that make a major advance in flu-genetics ?

    no forum yet, sigh
    ----------------------------------------------------------
    I'm interested in expert panflu damage estimates
    my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

    Comment


    • #3
      Re: VB - The D225G change in 2009 H1N1 influenza virus is not a concern

      Whether D222G (D225G) may alter the transmissibility pattern remains to be established.

      Other mutation may allow both alpha2,3 and alpha2,6 receptor affinity, for example at 190 position.

      Further, a change at RBD could reduce theoretically the transmissibility but the antibody evasion may add to this variant an evolutionary advantage against non-d222g viruses.

      Comment


      • #4
        Re: VB - The D225G change in 2009 H1N1 influenza virus is not a concern

        in each type of cells, type of tissue, there should be another
        optimal ratio of alpha2-3 vs. alpha2-6 affinity.

        The virus may "figure out" that ration by mutation and selection.

        Then it "goes" (how ?, how fast ?,how many ?) into some other
        type of tissue and the ratio changes.


        However, it seems reasonable for the swarm to have >1%
        of each type at each time


        so let the virus increase the mutation rate at that one position ...
        (if it only could)
        I'm interested in expert panflu damage estimates
        my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

        Comment


        • #5
          Re: VB - The D225G change in 2009 H1N1 influenza virus is not a concern

          From BBC: http://www.bbc.co.uk/blogs/thereport...mutations.html


          Death rates and mutations

          Fergus Walsh | 17:58 UK time, Friday, 27 November 2009


          I don't want to end the week on an alarming note, and - let's face it - there's been enough alarmist reporting about H1N1 swine flu.

          But I would like to draw your attention to a couple of issues which many of you are likely to pick up elsewhere on the web or perhaps in the papers.

          The first is a big jump in the global death toll. The World Health Organization said the number of deaths was up around 1,000 on a week ago, reaching at least 7,826 worldwide since the H1N1 virus emerged in April. That should neither surprise nor alarm you. We are now getting into the peak flu season. Seasonal flu kills several hundred thousand very elderly and frail people each year. The difference with swine flu is that the majority of deaths are in the under-65s.

          On a more positive note, the WHO said that the epidemic may have peaked in parts of the northern hemisphere. That seems to be the case in the UK and in the United States, which has had several weeks of falling levels of flu.

          Secondly, I have picked up via BBC Monitoring that two patients in France, in different hospitals, have died from mutated H1N1 swine flu. (For those who don't know, the BBC monitoring service is based in Caversham in Reading; it listens to news broadcasts from around the world and provides accurate translations.)

          The monitoring translation of La Chaine Info Television went like this:

          French newsreader: "The health authorities dreaded this. The H1N1 virus is in the process of mutating. The phenomenon reported in Norway has also been detected in France in two deceased patients who were not related in any way and who were in hospitals in two different cities. This mutation could increase the virus's ability to affect certain airways, as well as the lungs."
          Read like that, it seems pretty scary, and it is certainly not good news that mutations are occurring. But, as has been pointed out by me and by many of the wise men and women who post comments here, mutations are what we should expect with flu. Flu is an RNA virus in which genetic replication is pretty poor and which makes lots of mistakes. It's the reason that flu viruses drift and the reason we need a new flu jab every winter.

          The mutations reported in France have been seen in Norway and in several other countries, and the WHO put out some very clear advice on this recently.

          The French mutation has been found in two cities, but we need to know a lot more about it before becoming unduly alarmed. The patients may have been immuno-compromised, making them more susceptible to mutated viruses, and we don't have any evidence that mutated strains are spreading in the wider community.

          To sum up, mutation and deaths are sadly unavoidable when it comes to H1N1 swine flu. But this pandemic is still reassuringly mild for the vast vast majority of those infected.

          -
          -----

          Comment


          • #6
            Re: VB - The D225G change in 2009 H1N1 influenza virus is not a concern

            Fergus Walsh information page at BBC site: http://www.bbc.co.uk/blogs/thereport...s_on_flu.shtml

            Comment


            • #7
              Re: VB - The D225G change in 2009 H1N1 influenza virus is not a concern

              the Ukrainian virus could be more suitable for that mutation.
              I'm interested in expert panflu damage estimates
              my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

              Comment

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