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These observations have implications for influenza surveillance and vaccine formulation; in particular, the possibility exists that parallel amino acid replacements could serve as a predictor of new dominant strains. Unlike most pathogens where exposure leads to lasting immunity in the host, influenza A virus presents a moving antigenic target, evading specific immunity triggered by previous infections. Antigenic shift occurs when the virus acquires an HA of a different influenza subtype via reassortment of one or more gene segments and is thought to be the basis for the more devastating influenza pandemics that occurred several times in the last century.
There have been three pandemics in the last hundred years: in 1918 (H1N1 subtype), 1957 (H2N2 subtype), and in 1968 (H3N2 subtype).
The Influenza Genome Sequencing Project, funded and managed by the US National Institute of Allergy and Infectious Diseases, has recently generated over 1000 fully sequenced influenza genomes from clinical isolates obtained between 19 and publicly available in Genbank .
One goal of this project was to provide researchers with a large set of sequenced isolates that represent a relatively unbiased, i.e., not enriched in antigenically novel isolates, view of influenza strains in the population .
The observations of extremely rapid evolution of influenza A, especially in the HA gene, has led to the suggestion that the evolution of the surface regions of the HA is driven by continual positive selection.
In particular, Ratner et al., in a phylogenetic analysis of human H3 subtype HA genes, found a significantly higher rate of amino acid replacements than silent changes in antigenic positions of the HA1 domain (which consists of the N-terminal 329 residues of HA and includes the epitopes recognized by the immune system) as compared to the same rates (or rate ratios) for the C-terminal HA2 domain .
The finding that stasis is the prevailing modality of H3N2 evolution suggests that antigenic changes that lead to an increase in fitness typically result from epistatic interactions between several amino acid substitutions in the HA and, perhaps, other viral proteins.
Given this bias, it has been proposed that these positions would be useful in predicting future dominant epidemic variants .It has been emphasized that the phylogenetic tree for the HA1 of H3N2 isolates has a distinct, "ladder-like" shape, with a prominent trunk (the path from the root to the base of the latest included cluster of isolates) and, typically, short side branches .This study supported earlier findings of positive selection for those amino acid positions involved in receptor and antibody binding and, more specifically, for a subset of 18 amino acid sites in HA1. found that 9 of these 18 positions showed evidence of positive selection only in the internal branches and not the terminal branches (i.e.A number of parallel amino acid replacements – the same amino acid substitution occurring independently in different lineages – were also detected in H3N2 HA.These parallel mutations were, largely, associated with periods of rapid fitness change, indicating that there are major limitations on evolutionary pathways during antigenic change.
We show that the common view of the evolution of influenza virus as a rapid, positive selection-driven process is, at best, incomplete.