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

24 November 2009

sialic-acid-2The 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.

ha_specificity

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

  • http://twitter.com/hniman Henry Niman

    No one questions the existance of H1N1 except internet nut cases, posting anonymously and frequently.

  • Tony

    Why are my valid scientific questions being hijacked?

  • Tony

    Here’s something for you to contemplate Henry, as it looks like you have sent me to Coventry as I cannot get you to answer simple valid questions why?????? I am not trying to disrupt useful discussions because there doesn’t seem to be any where you are concerned. You make bald staements that you are not prepared to back up by hard scientific evidence and you seem to get away with it and dismiss everything I say as ‘utter nonsense’ and either refuse, or have no intention of answering any of the simple sensible questions that I put to you.

    An argument throws heat; a discussion throws light.
    One stems from ego and a closed mind whereas the other comes from an open mind.
    An argument is an exchange of ignorance whereas a discussion is an exchange of knowledge.
    An argument is an expression of temper whereas a discussion is an expression of logic.
    An argument tries to prove who is right whereas a discussion tries to prove what is right.

    I wish to enter a discussion with you in order to prove what is right but you don’t even want any of it – you appear to prefer dogmatic assertion to scientifc debate. If this blogsite is here to promote lively and healthy scientific discussion then what or who is preventing it because it’s certainly not me?

  • Tony

    Henry, nobody questioned the existence of phlogiston and dephlogisticated air until Antoine Lavoisier came along and discovered Oxygen. He put chemistry which was standing on its head squarely on its feet and he wasn’t a nut case. He couldn’t post anonymously and frequently because the internet wasn’t invented in 1775! If people prefer not to question the existence of H1N1 then that’s their bad luck , but until you can prove otherwise, and so far you have not done so it will remain a virtual reality on your computer.

  • Tony

    Henry the questions that are being put to you are simple valid scientifc questions so why don’t you answer them in full, so others can decide whether or not I am posting ‘utter nonsense’ and ‘internet babble’ as you put it. Its fine to refer to peer reviewed stuff in journals but D225G is not the real issue here is it? And I think that you know that too well (or at least I hope that you do by now). Rather its the question of the isolation of the complete virus that D225G is allegedly derived from – who first isolated it, where, when, and what methods were used?
    The burden of scientific proof is on you my friend, not me, and so far you have delivered diddly squat – and all that you have delivered to date are a series of vague references to journals that can only speculate on the origins of D225G in the absence of an isolated virus.
    You have also turned me into a parrot because I have to keep on repeating my questions over and over because you either cannot or will not answer them and trying to dismiss them on the ‘utter nonsense’ or ‘internet babble’ excuse. Shame on you Henry.