Mutated H5N1 binds to human receptors

Two mutations in the viral hemagglutinin surface protein independently enable H5N1 influenza A virus to bind to human receptors, researchers report in Nature this week. The sequence changes might serve as molecular markers to assess the pandemic potential of H5N1."Before avian influenza viruses can replicate efficiently in humans, they must switch recognition from avian to human receptors," senior author Yoshiro Kawaoka of the University of Wisconsin-Madison told The Scientist. Avian and human influenza viruses differ in the receptor they bind. Avian hemagglutinin recognizes sugars ending in sialic acid a2,3-galactose, whereas human hemagglutinin recognizes a slightly different ending: sialic acid a 2,6-galactose.To look for evidence of the switch in recognition, Kawaoka and his colleagues screened avian and human isolates from individuals infected by H5N1 viruses. They analyzed receptor specificity with an assay that measured direct binding to sialylglycopolymers possessing either the 2,3 or the 2,6 sugars. Whereas viruses from chickens and ducks could only recognize avian receptors, some viruses from human patients could recognize both human and avian cell receptors. "Once we identified the differences between the isolates, we narrowed down the specific changes that make avian H5N1 recognize the 2,6 receptors," Kawaoka explained. The changes were just two mutations, at positions 182 and 192 on the hemagglutinin sequence. H5N1 has already infected about 250 people, half of whom have died. "That tells you that a lot of its genes are already just fine for virulence once the virus has infected an individual," James Paulson of the Scripps Research Institute, who was not involved in the study, told The Scientist. "That's why the focus has been placed on the initial events of infection, on the ability of hemagglutinin to change specificity from the avian type to the human type.""This paper is interesting because it provides direct evidence that replication of the H5N1 in humans has already begun to select for a change in receptor specificity," Paulson added. "However, the virus does not yet have the ability to transmit from human to human," he said. "It might require a complete switch, in which it might recognize primarily the 2,6 linkage but not the 2,3 linkage. It might also require other characteristics that are not being studied in this paper at all."The switch has certainly not yet taken place, and it might never happen, according to James Stevens, also at the Scripps Research Institute. "This paper shows that certain mutations that are naturally appearing in H5N1 show some kind of binding to the human receptor, an increase in human preference. It's interesting in that sense, but it's not a total switch by any stretch of the imagination," Stevens, who did not participate in the research, told The Scientist.Stevens also noted that the Nature paper does not include a human virus as a positive control, which would show what a human-adapted virus would look like. "This is an obvious drawback. It would probably be quite revealing as to what the natural binding profile should be and how good or poor these mutations are in comparison."The authors propose that the changes in hemagglutinin sequence might be used to keep track of the virus as additional human infection occurs, as is being done with a mutation in one of the polymerase proteins that enabled avian H5N1 viruses to grow better in mammalian hosts. "That specific marker is now showing that the H5N1 viruses currently circulating among birds in Europe have this specific mutation, even if this virus is only circulating among poultry," Kawaoka explained. "Now we can say that the viruses that contain [the 182 or 192] mutations in the hemagglutinin protein are one more step closer to replication in humans," Kawaoka said. "How close, we don't know." Graciela Flores mail@the-scientist.comLinks within this article:S. Yamada, et al., "Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors," Nature, doi:10.1038/nature05264, November 16, 2006. http://www.nature.com/nature/journal/v444/n7117/abs/nature05264.htmlC. Holding C, "Flu virulence linked to species jump," The Scientist, February 6, 2004. http://www.the-scientist.com/article/display/21979/Yoshiro Kawaoka http://www.vetmed.wisc.edu/people/kawaokayJames Paulson http://www.scripps.edu/mb/paulson/index.htmK. Schlatter, "H5N1 spreading among humans?," The Scientist, May 20, 2005. http://www.the-scientist.com/article/display/22683James Stevens http://www.scripps.edu/mb/wilson/wl_people.htmC. Holding, "Polymerase may be key to flu's virulence," The Scientist, December 6, 2005. http://www.the-scientist.com/article/display/22852/

Mutated H5N1 binds to human receptors

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