Evolution of Equine Influenza Virus in Vaccinated Horses

Baillie, Gregory J.; Stack, J. Conrad; Jervis, Carley; Elton, Debra; Mumford, J. A.; Daly, Janet M.; Kellam, Paul; Grenfell, Bryan T.; Holmes, Edward C.; Wood, James

doi:10.1128/jvi.03379-12

Cited by 36 publications

(39 citation statements)

References 16 publications

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“…However, we speculate that for antigenic variants to reach fixation in the virus population, compensatory mutations may be needed to enhance viral replicative fitness before the antigenic variant is lost by purifying selection. In accord with our observations, a previous study showed that prior immunity had little effect on the level and structure of genetic diversity of influenza viruses infecting vaccinated horses (46). In that study, Murcia et al speculated that purifying selection (i.e., more synonymous diversity relative to nonsynonymous diversity) is the dominant signal of influenza within individual hosts (46); this is consistent with the idea that influenza viruses are well adapted to replication and transmission in their natural hosts, and therefore most mutations are likely to be deleterious.…”

Section: Discussionsupporting

confidence: 80%

“…In accord with our observations, a previous study showed that prior immunity had little effect on the level and structure of genetic diversity of influenza viruses infecting vaccinated horses (46). In that study, Murcia et al speculated that purifying selection (i.e., more synonymous diversity relative to nonsynonymous diversity) is the dominant signal of influenza within individual hosts (46); this is consistent with the idea that influenza viruses are well adapted to replication and transmission in their natural hosts, and therefore most mutations are likely to be deleterious. Indeed, mutations that alter HA antigenicity may frequently exact a fitness cost that requires compensatory mutations to restore viral replicative capacity (47).…”

Section: Discussionsupporting

confidence: 80%

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Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans

Dinis

Florek

Fatola

et al. 2016

J Virol

100

121

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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 virusspecific 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. IMPORTANCEInfluenza 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. S easonal influenza A epidemics cause an estimated 3 to 5 million cases of severe respiratory illness each year, resulting in approximately 250,000 to 500,000 deaths worldwide (1). Available influenza vaccines only provide moderate protection against infection and illness...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 80%

Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans

Dinis

Florek

Fatola

et al. 2016

J Virol

100

121

View full text Add to dashboard Cite

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“…In IAVs, this research has focused on HA Murcia et al, 2010Murcia et al, , 2013. To the best of our knowledge, our study is the first to evaluate the intra-host diversity of the complete genome of IAV during infection of pigs using NGS, and our results are comparable with a recent study in children (Bourret et al, 2015).…”

Section: Discussionsupporting

confidence: 80%

Genome plasticity of triple-reassortant H1N1 influenza A virus during infection of vaccinated pigs

Díaz

Enomoto

Romagosa

et al. 2015

Journal of General Virology

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To gain insight into the evolution of influenza A viruses (IAVs) during infection of vaccinated pigs, we experimentally infected a 3-week-old naive pig with a triple-reassortant H1N1 IAV and placed the seeder pig in direct contact with a group of age-matched vaccinated pigs (n510). We indexed the genetic diversity and evolution of the virus at an intra-host level by deep sequencing the entire genome directly from nasal swabs collected at two separate samplings during infection. We obtained 13 IAV metagenomes from 13 samples, which included the virus inoculum and two samples from each of the six pigs that tested positive for IAV during the study. The infection produced a population of heterogeneous alleles (sequence variants) that was dynamic over time. Overall, 794 polymorphisms were identified amongst all samples, which yielded 327 alleles, 214 of which were unique sequences. A total of 43 distinct haemagglutinin proteins were translated, two of which were observed in multiple pigs, whereas the neuraminidase (NA) was conserved and only one dominant NA was found throughout the study. The genetic diversity of IAVs changed dynamically within and between pigs. However, most of the substitutions observed in the internal gene segments were synonymous. Our results demonstrated remarkable IAV diversity, and the complex, rapid and dynamic evolution of IAV during infection of vaccinated pigs that can only be appreciated with repeated sampling of individual animals and deep sequence analysis.

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“…The contact transmission model used here supports the transfer of a greater number of viruses than would be seen in a model where spread is limited to a respiratory droplet route. Nevertheless, data obtained using respiratory droplet models and from natural outbreaks indicate that transmission typically involves more than one infectious virus (33)(34)(35)(36)38). The results presented here suggest that, at least under the transmission-favorable conditions used, the timing and dose of coinfections achieved through transmission are compatible with robust reassortment.…”

Section: Discussionsupporting

confidence: 49%

“…Efforts to characterize intrahost viral genetic diversity are valuable in this regard, and a number of such studies have been performed using samples collected during natural outbreaks or from experimental transmission chains (31)(32)(33)(34)(35)(36)(37). Importantly, these efforts have revealed high levels of mixed infection and point to two ways that such infections arise.…”

mentioning

confidence: 99%

Influenza A Virus Coinfection through Transmission Can Support High Levels of Reassortment

Tao

White

et al. 2015

J Virol

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The reassortment of gene segments between influenza viruses increases genomic diversity and plays an important role in viral evolution. We have shown previously that this process is highly efficient within a coinfected cell and, given synchronous coinfection at moderate or high doses, can give rise to ϳ60 to 70% of progeny shed from an animal host. Conversely, reassortment in vivo can be rendered undetectable by lowering viral doses or extending the time between infections. One might also predict that seeding of transmitted viruses into different sites within the target tissue could limit subsequent reassortment. Given the potential for stochastic factors to restrict reassortment during natural infection, we sought to determine its efficiency in a host coinfected through transmission. Two scenarios were tested in a guinea pig model, using influenza A/Panama/2007/99 (H3N2) virus (wt) and a silently mutated variant (var) thereof as parental virus strains. In the first, coinfection was achieved by exposing a naive guinea pig to two cagemates, one infected with wt and the other with var virus. When such exposure led to coinfection, robust reassortment was typically seen, with 50 to 100% of isolates carrying reassortant genomes at one or more time points. In the second scenario, naive guinea pigs were exposed to a cagemate that had been coinoculated with wt and var viruses. Here, reassortment occurred in the coinoculated donor host, multiple variants were transmitted, and reassortants were prevalent in the recipient host. Together, these results demonstrate the immense potential for reassortment to generate viral diversity in nature. IMPORTANCE Influenza viruses evolve rapidly under selection due to the generation of viral diversity through two mechanisms. The first is the introduction of random errors into the genome by the viral polymerase, which occurs with a frequency of approximately 10؊5 errors/nucleotide replicated. The second is reassortment, or the exchange of gene segments between viruses. Reassortment is known to occur readily under well-controlled laboratory conditions, but its frequency in nature is not clear. Here, we tested the hypothesis that reassortment efficiency following coinfection through transmission would be reduced compared to that seen with coinoculation. Contrary to this hypothesis, our results indicate that coinfection achieved through transmission supports high levels of reassortment. These results suggest that reassortment is not exquisitely sensitive to stochastic effects associated with transmission and likely occurs in nature whenever a host is infected productively with more than one influenza A virus.T he segmented nature of the influenza virus genome allows for ready exchange of genetic material between two viruses that coinfect one cell (1). If the parental viruses differ in all eight gene segments, 256 different progeny viruses can be produced in a single reassortment event. Reassortment between two very distinct strains is typically associated with marked genotypic and ...

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Evolution of Equine Influenza Virus in Vaccinated Horses

Cited by 36 publications

References 16 publications

Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans

Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans

Genome plasticity of triple-reassortant H1N1 influenza A virus during infection of vaccinated pigs

Influenza A Virus Coinfection through Transmission Can Support High Levels of Reassortment

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