Evolution of influenza virus binding receptors

21 January 2013

Researchers at NIMR have shown that recent influenza A(H3N2) viruses have very different receptor binding properties compared with older viruses. The research is published in PNAS.

The natural hosts of Influenza A viruses are wild birds and bats These viruses are classified by the properties of their surface glycoproteins: haemagglutinin (HA) and neuraminidase (NA). There are 17 HA and 10 NA subtypes that exist in a wide range of combinations. Human pandemic influenza occurs when a new virus carrying an HA component with novel antigenic properties enters the human population. As there is no immunity to the virus it can transmit human-to-human and spreads worldwide. Once the virus is established in humans variant viruses may emerge, through a combination of high mutation rate and selective pressure exerted by the host. These variants carry amino acid alterations in their HA that are antigenically distinct from circulating strains and these become able to circulate in the previously immune human population, leading to recurrent epidemics. The current A(H3N2) viruses first entered humans in 1968 and the A(H1N1)pdm09 viruses first entered humans in 2009.

Yipu Lin and Alex Xiong and their collaborators in the Divisions of Virology, Molecular Structure and Physical Biochemistry at NIMR have examined the receptor binding properties of antigenically evolved human influenza A(H3N2) viruses spanning the last 10 years. As the major antigenic sites on the HA are on the periphery of the receptor binding site, there is interplay between the receptor binding and antigenic properties of the HA.

Quantitative virus receptor binding assays, developed by Steve Martin and Peter Coombs at NIMR, revealed that influenza A(H3N2) viruses in circulation over the last 10 years show markedly different receptor binding properties compared with older A(H3N2) viruses. Recent viruses showed a much lower avidity for the sialic acid receptor compared with viruses from 1968 or 2001. Crystal structures of HA–receptor analogue complexes of viruses from 2004 and 2005 revealed significant differences in the conformation of the HA in the vicinity of the sialic acid receptor binding site that can explain the changes in receptor affinity.

It is striking that the reduction in the avidity of influenza A(H3N2) viruses for their cell receptor correlates with a reduction in the overall level of influenza disease that has been seen by general practitioners over the last ten years or so. We know that A(H3N2) viruses are still circulating, having survived the A(H1N1) pandemic that emerged in 2009, but they might be causing less severe symptoms than previously. Nevertheless, influenza remains a serious threat to public health and global surveillance is undertaken to monitor the evolution of influenza viruses to allow the production of updated vaccines to mitigate against the threat of influenza. This work provides us with a much clearer understanding of the changes in the properties of the virus over time and this will help us develop improved influenza vaccines.

John McCauley, Director of the WHO Collaborating Centre for Reference and Research on Influenza

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The structure of the receptor binding site of H3 HAs in complex with human receptor analogs. (A) Overlap of apo (grey) and the human receptor complex of 2004 HA (green), receptor in yellow; (B) overlap of the apo (grey) and the human receptor complex of 2005 HA (blue), receptor in yellow; (C) overlap of the human receptor complexes of the 1968 HA (magenta) and 2004 HA (green).

Original article

Yi Pu Lin, Xiaoli Xiong, Stephen A. Wharton, Stephen R. Martin, Peter J. Coombs, Sebastien G. Vachieri, Evangelos Christodoulou, Philip A. Walker, Junfeng Liu, John J. Skehel, Steven J. Gamblin, Alan J. Hay, Rodney S. Daniels, and John W. McCauley (2012)

Evolution of the receptor binding properties of the influenza A(H3N2) hemagglutinin

Proceedings of the National Academy of Sciences, USA 109(52): 21474-21479. Publisher abstract

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