title: Mismatched hemagglutinin and neuraminidase specificities in recent human H3N2 influenza viruses.
abstract: The hemagglutinin (HA) of influenza viruses initiates infection by binding to sialic acid on the cell surface via alpha2,6 (human) or alpha2,3 (avian) linkage. The influenza neuraminidase (NA) can cleave both alpha2,3- and alpha2,6-linked sialic acids, but all influenza NAs have a marked preference for the non-human alpha2,3 linkage. Recent H3N2 influenza viruses have lost the ability to agglutinate chicken red blood cells. To determine if changes in HA specificity or affinity correlate with NA specificity or activity, we examined red cell binding and elution of a series of H3N2 viruses. We found that the NA activity of many influenza viruses does not release binding by their HA. In some egg-adapted strains, lack of elution correlates with low levels of viral NA activity, and these elute rapidly when bacterial NA is added. However, a Fujian-like virus, A/Oklahoma/323/03, does not elute by its own NA or with Vibrio cholerae sialidase, and it binds to red cells pre-treated with V. cholerae sialidase. It elutes after addition of the broad specificity Micromonospora viridifaciens sialidase. Human glycophorin inhibits A/Oklahoma/323/03 hemagglutination 6-fold better than fetuin. We conclude that specific forms of sialic acid are used as receptor by recent human H3N2 influenza viruses, perhaps involving branched alpha2,6 sialic acid or alpha2,8 sialic acid structures on O-linked carbohydrates. The virus itself has no O-linked glycans, so even though the NA is not able to cleave receptors on cells, the viruses will not self-aggregate. It will be important to monitor efficacy of neuraminidase inhibitors in case there are NA-resistant receptors in the human respiratory tract that allow the viruses to be less dependent on NA activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. upma-gulati@ouhsc.edu
authors.forename: Upma
authors.initials: U
authors.lastname: Gulati
authors.forename: Wenxin
authors.initials: W
authors.lastname: Wu
authors.forename: Shelly
authors.initials: S
authors.lastname: Gulati
authors.forename: Kshama
authors.initials: K
authors.lastname: Kumari
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Waner
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Air
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000821:virology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype; D009980:Influenza A virus / Q000378:metabolism*; D009439:Neuraminidase / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; C483468:hemagglutinin, human influenza A virus; D009439:Neuraminidase