Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans
Autor: | Jorge M. Dinis, Nicholas W. Florek, Edward A. Belongia, Jennifer K. Meece, Omolayo O. Fatola, Olivia K. Charlier, James Mutschler, Louise H. Moncla, Thomas C. Friedrich |
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Rok vydání: | 2015 |
Předmět: |
0301 basic medicine
Adult Adolescent 030106 microbiology Immunology Hemagglutinin Glycoproteins Influenza Virus Biology medicine.disease_cause Microbiology H5N1 genetic structure Polymorphism Single Nucleotide Antigenic drift 03 medical and health sciences Antigenic Diversity Young Adult Influenza A Virus H1N1 Subtype Virology Evolution of influenza Influenza Human Influenza A virus medicine Humans Original antigenic sin Child Antigens Viral Immune Evasion Genetics Influenza A Virus H3N2 Subtype Vaccination Antigenic shift High-Throughput Nucleotide Sequencing Sequence Analysis DNA Middle Aged Antigenic Variation Author Corrections 030104 developmental biology Viral phylodynamics Amino Acid Substitution Influenza Vaccines Insect Science |
Zdroj: | Journal of virology. 90(7) |
ISSN: | 1098-5514 |
Popis: | 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, although antigenic change has rarely been investigated on the level of individual infected humans. We used deep sequencing to characterize the 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 nonvaccinated 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. IMPORTANCE Influenza vaccines must be frequently reformulated due to the virus's rapid evolution rate. We know that influenza viruses exist within each infected host as a “swarm” of genetically distinct viruses, but the role of this within-host diversity in the antigenic evolution of influenza has been unclear. We characterized here the genetic and potential antigenic diversity of influenza viruses infecting humans, some of whom became infected despite recent vaccination. Influenza virus between- and within-host genetic diversity was not significantly different in nonvaccinated and vaccinated humans, suggesting that vaccine-induced immunity does not exert strong selective pressure on viruses replicating in individual people. We found low-frequency mutations, below the detection threshold of traditional surveillance methods, in nonvaccinated and vaccinated humans that were recently associated with antibody escape. Interestingly, these potential antigenic variants did not reach fixation in infected people, suggesting that other evolutionary factors may be hindering their emergence in individual humans. |
Databáze: | OpenAIRE |
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