Abstract
BackgroundReassortment between the RNA segments encoding haemagglutinin (HA) and neuraminidase (NA), the major antigenic influenza proteins, produces viruses with novel HA and NA subtype combinations and has preceded the emergence of pandemic strains. It has been suggested that productive viral infection requires a balance in the level of functional activity of HA and NA, arising from their closely interacting roles in the viral life cycle, and that this functional balance could be mediated by genetic changes in the HA and NA. Here, we investigate how the selective pressure varies for H7 avian influenza HA on different NA subtype backgrounds.ResultsBy extending Bayesian stochastic mutational mapping methods to calculate the ratio of the rate of non-synonymous change to the rate of synonymous change (dN/dS), we found the average dN/dS across the avian influenza H7 HA1 region to be significantly greater on an N2 NA subtype background than on an N1, N3 or N7 background. Observed differences in evolutionary rates of H7 HA on different NA subtype backgrounds could not be attributed to underlying differences between avian host species or virus pathogenicity. Examination of dN/dS values for each subtype on a site-by-site basis indicated that the elevated dN/dS on the N2 NA background was a result of increased selection, rather than a relaxation of selective constraint.ConclusionsOur results are consistent with the hypothesis that reassortment exposes influenza HA to significant changes in selective pressure through genetic interactions with NA. Such epistatic effects might be explicitly accounted for in future models of influenza evolution.
Highlights
Reassortment between the RNA segments encoding haemagglutinin (HA) and neuraminidase (NA), the major antigenic influenza proteins, produces viruses with novel HA and NA subtype combinations and has preceded the emergence of pandemic strains
We find substantial differences between gene-wide dN/dS for avian influenza H7 HA on different NA subtype backgrounds, consistent with the hypothesis that the selective pressure experienced by HA can be affected by its genetic context
Distribution of avian influenza H7 HA sequences We downloaded all available unique avian influenza HA coding sequences from the NCBI Influenza Virus Resource and labelled them according to the NA subtype of the virus
Summary
Reassortment between the RNA segments encoding haemagglutinin (HA) and neuraminidase (NA), the major antigenic influenza proteins, produces viruses with novel HA and NA subtype combinations and has preceded the emergence of pandemic strains. The HA and NA proteins play complementary roles in the life cycle of the influenza virus Both HA and NA bind to host cell receptors containing sialic acid residues: HA to initiate viral entry into the host cell, and NA to permit the release of viral progeny from infected cells. When the low-yield H3N1 culture was passaged, a number of changes occurred in the HA which reduced its receptor binding affinity, apparently to match that of the NA in the reassortant rather than to return to the high levels of HA activity found in the H3N8 parent virus
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