DINIS JM, Florek NW, Fatola OO, Moncla LH, et al. Deep sequencing reveals potential antigenic variants at low frequency in influenza A-infected humans. J Virol. 2016 Jan 6.
Influenza vaccines must be frequently reformulated to account for antigenic changes in the viral envelope protein, hemagglutinin (HA). The rapid evolution of influenza virus under immune pressure is likely enhanced by the virus´s genetic diversity within a host, though antigenic change has rarely been investigated on the level of individual infected humans. We used deep sequencing to characterize between- and within-host genetic diversity of influenza viruses in a cohort of patients that included individuals who were vaccinated and then infected in the same season. We characterized influenza HA segments from the predominant circulating influenza A subtypes during the 2012-2013 (H3N2) and 2013-2014 (pandemic H1N1; H1N1pdm) flu seasons. We found that HA consensus sequences were similar in non-vaccinated and vaccinated subjects. In both groups purifying selection was the dominant force shaping HA genetic diversity. Interestingly, viruses from multiple individuals harbored low-frequency mutations encoding amino acid substitutions in HA antigenic sites at or near the receptor-binding domain. These mutations included two substitutions in H1N1pdm viruses, G158K and N159K, which were recently found to confer escape from virus-specific antibodies. These findings raise the possibility that influenza antigenic diversity can be generated within individual human hosts, but may not become fixed in the viral population even when they would be expected to have a strong fitness advantage. Understanding constraints on influenza antigenic evolution within individual hosts may elucidate potential future pathways of antigenic evolution at the population level
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