Receptor binding in bird flu

Enhanced human receptor binding by H5 haemagglutinins

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Virologists and public health officials share an interest in the mechanism of influenza virus cross-species transmission because of the potential of newly introduced viruses to cause pandemics. Analyses of naturally and experimentally transmitted viruses indicate roles for several gene products in the process of transmission and common among these are the two functions of the haemagglutinin glycoprotein (HA) required in the first stages of virus infection; receptor binding and membrane fusion (Herfst et al., 2012; Imai et al., 2012).

Following the first serious infections in 1997 in Hong Kong, which marked the beginning of a continuing pandemic threat, the HAs of avian H5N1 viruses have been investigated in detail and our recent paper adds to these studies. In it we describe the structural basis of the changes in receptor binding specificity observed in HAs of H5N1 isolates from Vietnam and Egypt which are now widespread internationally.

The viruses studied contain amino-acid substitutions in the receptor binding site by comparison with previously isolated viruses; Asn-186→Lys or Ser-227 →Asn combined with Gln197 →Arg in the case of the Vietnam HA and Ile-155 →Thr in the Egyptian HA. In addition the Egyptian HA has a deletion at position 133. The Vietnam viruses showed increased affinity for human receptors and decreased affinity for avian receptors; the Egyptian virus had increased affinity for human receptor but little change in affinity for avian receptor. Structurally the HA mutants of the Vietnam viruses are very similar to that of the previous wild-type virus and the complex formed with human receptor is indistinguishable. In contrast the bound avian receptor adopts a different conformation that may result in the decreased affinity observed. Again in contrast, the deletion in the  Egyptian HA changes the structure of the receptor binding site and together with the Ile-155 → Thr substitution creates a more polar environment in which bound water molecules mediate additional interactions with both human and avian receptors.

Our data indicate that mutations other than those observed in HAs of pandemic viruses or in experimentally selected mutant H5 viruses can influence receptor binding specificity. Unlike these transmissible viruses (Xiong et al., 2013), however, they retain a preference for avian receptors. Nevertheless, if their increased affinity for human receptors increases the possibility for human infection, they may serve as intermediates in the evolution of a virus that could transmit between humans.

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Structures and receptor binding characteristics of H5 HAs described in this study.

 

Introducing the authors

Xiaoli Xiong Haixia Xiao

Joint lead authors: Xiaoli Xiong; Haixia Xiao.

About the research

Enhanced human receptor binding by H5 haemagglutinins
Virology, Volume 456-457, May 2013, Pages 179-187
Xiaoli Xiong, Haixia Xiao, Stephen R. Martin, Peter J. Coombs, Junfeng Liu, Patrick J. Collins, Sebastien G. Vachieri, Philip A. Walker, Yi Pu Lin, John W. McCauley, Steven J. Gamblin, John J. Skehel

Read the full article on ScienceDirect.

References

Herfst, S., Schrauwen, E.J., Linster, M., Chutinimitkul, S., de Wit, E., Munster, V.J., Sorrell, E.M., Bestebroer, T.M., Burke, D.F., Smith, D.J., et al. (2012). Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336, 1534-1541.
Imai, M., Watanabe, T., Hatta, M., Das, S.C., Ozawa, M., Shinya, K., Zhong, G., Hanson, A., Katsura, H., Watanabe, S., et al. (2012). Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486, 420-428.
Xiong, X., Coombs, P.J., Martin, S.R., Liu, J., Xiao, H., McCauley, J.W., Locher, K., Walker, P.A., Collins, P.J., Kawaoka, Y., et al. (2013). Receptor binding by a ferret-transmissible H5 avian influenza virus. Nature 497, 392-396.

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