How far (genetically) to a human H5N1?
An article in press at the journal Virology by Gambaryan and her Russian and CDC colleagues has interesting, and somewhat disquieting data on the evolution of H5N1. As noted in somewhat more detail on our Primer II piece at the Flu Wiki, influenza viruses adapted to birds have a slightly different predilection for binding to cells than those adapted to humans. To infect a cell the virus looks for a "receptor" on the cell's surface, essentially the door it uses to enter. The receptor for influenza viruses is a combination of a fat, sugar and protein tipped by sialic acid. How the sialic acid is connected (what kind of linkage) seems to be one determinant for a preference for bird cells or human cells. Bird viruses prefer the α 2-3 sialic acid linkage while human viruses prefer α 2-6 linkages. The α 2-3 links are characteristic of the intestinal tract of birds, while the α 2-6 linkages are the predominant receptors in the human respiratory tract. However it was recently reported that humans also have a significant number of α 2-3 receptors (on ciliated cells) in the respiratory tract and it is likely through these cells that the H5N1 virus transmitted from chickens grabs on and replicates. We don't know why it doesn't happen more often, however. The human virus seems to prefer to start off in the α 2 -6 linked cells. This is apparently not a problem in the intestinal tract of birds.
This overall picture is even more confused because the pathology of influenza A by human-adapted viruses shows a great deal of replication in the ciliated cells (that is, the ones with the α 2 - 3 linkages) of the human respiratory tract (in the trachea, the large part of the conducting system; see Primer I at the Flu Wiki). Thus human viruses seem to initially infect the non-ciliated cells that have the α 2-6 receptors but then are able to replicate efficiently in the ones with α 2-3 receptors after infection is underway. Exactly what is going on here isn't clear yet.
That's by way of background to the new paper. Gambaryan et al. looked at binding to α 2-3 and α 2-6 receptors of a variety of influenza A/H5 viruses, including those from 2003 - 2004. Most of them, including those isolated from humans in 1997 and 2004, retained their α 2-3 specificity, that is, seemed still to have bird cell preferences. But two isolates from Hong Kong from February 2003 showed decreased binding to the bird α 2-3 receptor and increased binding to the human α 2-3 receptor. Moreover, sequencing revealed that they differed only in a single amino acid in the HA protein, i.e., a single change in the protein switched the virus from a bird preferring one to one with an increased ability to bind to human cells. This is not genetic shift. It is genetic drift, the result of a random mutation. No co-infection or reassortment is needed to bring this about. The paper also presents evidence that H5N1 has been adapting to life in poultry from its previous home in aquatic wildfowl.
The more virus there is out there the more likely it is to happen by chance on the recipe for efficient infection of humans and then efficient transmission. It has already done this for terrestrial birds (poultry). This work shows that the genetic distance the virus needs to travel to find a successful recipe may not be large.
Addendum, 10/23/05: Niman at Recombinomics has a Commentary on this paper as well. He makes the intriguing suggestion that recombination with an H9N2 in the Middle East (on the migratory bird flyway) might result in the HA change that is permissive for α 2 - 6 binding and efforts should be made to shelter birds in this area.
This overall picture is even more confused because the pathology of influenza A by human-adapted viruses shows a great deal of replication in the ciliated cells (that is, the ones with the α 2 - 3 linkages) of the human respiratory tract (in the trachea, the large part of the conducting system; see Primer I at the Flu Wiki). Thus human viruses seem to initially infect the non-ciliated cells that have the α 2-6 receptors but then are able to replicate efficiently in the ones with α 2-3 receptors after infection is underway. Exactly what is going on here isn't clear yet.
That's by way of background to the new paper. Gambaryan et al. looked at binding to α 2-3 and α 2-6 receptors of a variety of influenza A/H5 viruses, including those from 2003 - 2004. Most of them, including those isolated from humans in 1997 and 2004, retained their α 2-3 specificity, that is, seemed still to have bird cell preferences. But two isolates from Hong Kong from February 2003 showed decreased binding to the bird α 2-3 receptor and increased binding to the human α 2-3 receptor. Moreover, sequencing revealed that they differed only in a single amino acid in the HA protein, i.e., a single change in the protein switched the virus from a bird preferring one to one with an increased ability to bind to human cells. This is not genetic shift. It is genetic drift, the result of a random mutation. No co-infection or reassortment is needed to bring this about. The paper also presents evidence that H5N1 has been adapting to life in poultry from its previous home in aquatic wildfowl.
The more virus there is out there the more likely it is to happen by chance on the recipe for efficient infection of humans and then efficient transmission. It has already done this for terrestrial birds (poultry). This work shows that the genetic distance the virus needs to travel to find a successful recipe may not be large.
Addendum, 10/23/05: Niman at Recombinomics has a Commentary on this paper as well. He makes the intriguing suggestion that recombination with an H9N2 in the Middle East (on the migratory bird flyway) might result in the HA change that is permissive for α 2 - 6 binding and efforts should be made to shelter birds in this area.
posted by Revere at
10/22/2005 08:24:00 AM
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