Frequency and patterns of reassortment in natural influenza A virus infection in a reservoir host

Wille, Michelle; Tolf, Conny; Avril, Alexis; Latorre‐Margalef, Neus; Wallerström, Sofie; Olsén, Björn; Waldenström, Jonas

doi:10.1016/j.virol.2013.05.004

Cited by 56 publications

(62 citation statements)

References 50 publications

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“…The vast majority of reassortment events have negligible effects on AIV fitness and are presumably limited only by the rate at which multiple infections occur in host species (8). However, while it was not observed here, multiple studies have found persistence of entire AIV constellations across migratory seasons, suggesting the possible persistence of a virus in the environment until opportunistic exposure to some naive host species (62)(63)(64), although environmental conditions likely influence this persistence (65). Influenza A virus similarity.…”

Section: Discussionmentioning

confidence: 53%

“…Therefore, any nucleotide differences observed between two viruses likely represent mutations that have passed through several selective "sieves." Recently, Reeves et al (42) showed that a 99% nucleotide identity was a natural cutoff for determining virus similarity among AIVs collected from waterfowl in Alaska, and multiple other studies have built off this work, even exploring nucleotide identity values as low as 97% (63,64,69). However, due to the large number of isolates included in this study and the variability among regions, we did not observe a natural cutoff and instead selected the top 1% of all pairwise comparisons within an AIV gene segment to define virus identity (Table 3).…”

Section: Discussionmentioning

confidence: 99%

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Spread and Persistence of Influenza A Viruses in Waterfowl Hosts in the North American Mississippi Migratory Flyway

Fries

Nolting

Bowman

et al. 2015

J Virol

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While geographic distance often restricts the spread of pathogens via hosts, this barrier may be compromised when host species are mobile. Migratory waterfowl in the order Anseriformes are important reservoir hosts for diverse populations of avian-origin influenza A viruses (AIVs) and are assumed to spread AIVs during their annual continental-scale migrations. However, support for this hypothesis is limited, and it is rarely tested using data from comprehensive surveillance efforts incorporating both the temporal and spatial aspects of host migratory patterns. We conducted intensive AIV surveillance of waterfowl using the North American Mississippi Migratory Flyway (MMF) over three autumn migratory seasons. Viral isolates (n ‫؍‬ 297) from multiple host species were sequenced and analyzed for patterns of gene dispersal between northern staging and southern wintering locations. Using a phylogenetic and nucleotide identity framework, we observed a larger amount of gene dispersal within this flyway rather than between the other three longitudinally identified North American flyways. Across seasons, we observed patterns of regional persistence of diversity for each genomic segment, along with limited survival of dispersed AIV gene lineages. Reassortment increased with both time and distance, resulting in transient AIV constellations. This study shows that within the MMF, AIV gene flow favors spread along the migratory corridor within a season, and also that intensive surveillance during bird migration is important for identifying virus dispersal on time scales relevant to pandemic responsiveness. In addition, this study indicates that comprehensive monitoring programs to capture AIV diversity are critical for providing insight into AIV evolution and ecology in a major natural reservoir. IMPORTANCEMigratory birds are a reservoir for antigenic and genetic diversity of influenza A viruses (AIVs) and are implicated in the spread of virus diversity that has contributed to previous pandemic events. Evidence for dispersal of avian-origin AIVs by migratory birds is rarely examined on temporal scales relevant to pandemic or panzootic threats. Therefore, characterizing AIV movement by hosts within a migratory season is important for implementing effective surveillance strategies. We conducted surveillance following birds along a major North American migratory route and observed that within a migratory season, AIVs rapidly reassorted and gene lineages were dispersed primarily within the migratory corridor. Patterns of regional persistence were observed across seasons for each gene segment. We show that dispersal of AIV gene lineages by migratory birds occurs quickly along migratory routes and that surveillance for AIVs threatening human and animal health should focus attention on these routes.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Spread and Persistence of Influenza A Viruses in Waterfowl Hosts in the North American Mississippi Migratory Flyway

Fries

Nolting

Bowman

et al. 2015

J Virol

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“…Efficient IAV replication is linked to optimal activities and interactions of the viral polymerase complex (and its subunits and co-factors) (Ngai et al, 2013;Wille et al, 2013). Previous studies of HYR-IVSs produced by natural reassortment between circulating strains and PR8 have shown that the PB1 segment of many HYR-IVSs was derived from the circulating strain and, apparently, provided a significant growth advantage over IVSs that contained the PR8 PB1 segment (PB1 PR8 ) (Fulvini et al, 2011;Ramanunninair et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…In many cases, however, PR8-based reassortants containing HA and NA segments from circulating strains fail to grow efficiently in embryonated eggs and/ or cell culture, providing a significant obstacle to efficient large-scale vaccine production (Abt et al, 2011;Compans et al, 1972;Wanitchang et al, 2010). Efficient IAV replication is linked to optimal activities and interactions of the viral polymerase complex (and its subunits and co-factors) (Ngai et al, 2013;Wille et al, 2013). Previous studies of HYR-IVSs produced by natural reassortment between circulating strains and PR8 have shown that the PB1 segment of many HYR-IVSs was derived from the circulating strain and, apparently, provided a significant growth advantage over IVSs that contained the PR8 PB1 segment (PB1 PR8 ) (Fulvini et al, 2011;Ramanunninair et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The PB1 segment of an influenza A virus H1N1 2009pdm isolate enhances the replication efficiency of specific influenza vaccine strains in cell culture and embryonated eggs

Mostafa

Kanrai

Ziebuhr

et al. 2016

Journal of General Virology

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Influenza vaccine strains (IVSs) contain the haemagglutinin (HA) and neuraminidase (NA) genome segments of relevant circulating strains in the genetic background of influenza A/ PR/8/1934 virus (PR8). Previous work has shown that the nature of the PB1 segment may be a limiting factor for the efficient production of IVSs. Here, we showed that the PB1 segment (PB1 Gi ) from the 2009 pandemic influenza A virus (IAV) A/Giessen/06/2009 (Gi wt, H1N1pdm) may help to resolve (some of) these limitations. We produced a set of recombinant PR8-derived viruses that contained (i) the HA and NA segments from representative IAV strains (H3N2, H5N1, H7N9, H9N2); (ii) the PB1 segment from PR8 or Gi wt, respectively; and (iii) the remaining five genome segments from PR8. Viruses containing the PB1 Gi segment, together with the heterologous HA/NA segments and five PR8 segments (5+2+1), replicated to higher titres compared with their 6+2 counterparts containing six PR8 segments and the equivalent heterologous HA/NA segments. Compared with PB1 PR8 -containing IVSs, viruses with the PB1 Gi segment replicated to higher or similar titres in both cell culture and embryonated eggs, most profoundly IVSs of the H5N1 and H7N9 subtype, which are known to grow poorly in these systems. IVSs containing either the PB1 Gi or the cognate PB1 segment of the respective specific HA/NA donor strain showed enhanced or similar virus replication levels. This study suggests that substitution of PB1 PR8 with the PB1 Gi segment may greatly improve the large-scale production of PR8-derived IVSs, especially of those known to replicate poorly in vitro. INTRODUCTIONInfluenza viruses belong to the family Orthomyxoviridae and are classified into three genera termed Influenza virus A, B and C. Among these, influenza A viruses (IAVs) pose the greatest threat to human and animal health. They contain eight segments of negative-sense ssRNA (Ritchey et al., 1976;Shaw & Palese, 2013). The eight genomic segments encode at least 10 viral proteins, comprising the three subunits of the viral RNA polymerase complex [polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1) and polymerase acidic protein (PA)], the surface glycoproteins [haemagglutinin (HA) and neuraminidase (NA)], the nucleoprotein (NP), the matrix protein (M1), the ion channel protein (M2), the non-structural protein 1 (NS1) and the nuclear export protein (NEP). IAVs are genetically diverse, with new strains rapidly emerging by point mutations introduced by the low-fidelity viral RNA replicase (potentially resulting in antigenic drift if changes occur in the HA and/or NA coding sequences and affect important antigenic epitopes) or by genetic reassortment of genomic segments (potentially leading to antigenic shift if antigenically distant HA and NA segments are incorporated). Minor and major antigenic changes in the HA and NA proteins of circulating IAV are important driving forces for the emergence of new strains causing epidemics or even major pandemics (Neumann et al., 2009;Peng et al., 2014;Smith...

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“…PB1 from a seasonal strain or with targeted mutations has been shown to improve growth or HA yield of H3 reassortants (Cobbin et al, 2013;Plant et al, 2012); however, mixed results have been observed for H5 reassortants (Abt et al, 2011;Rudneva et al, 2007;Wanitchang et al, 2010). All three polymerase segments reassort together more frequently in experimental settings than natural reassortment, suggesting gene constellation effects (Macken et al, 2006;Varich et al, 2008;Wille et al, 2013). Here, we examined the growth of H5 reassortants with the PB1 m5 allele with or without a chimeric NA.…”

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confidence: 99%

Chimeric neuraminidase and mutant PB1 gene constellation improves growth and yield of H5N1 vaccine candidate virus

Plant

2015

Journal of General Virology

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We previously showed that a mutated PB1 gene improved the growth kinetics of a H3N2 influenza reassortant. Here, we showed that the same mutations improved the growth kinetics of a virus containing the A/Vietnam/1203/2004 (H5N1) haemagglutinin and neuraminidase (NA). Total protein yield and NA activity were increased when a chimeric NA was included. These increases indicated that the synergistic effect was due to the gene constellation containing both the altered PB1 gene and the chimeric NA gene.The object of this work was to improve the genomic backbone segments used in vaccine candidate viruses whilst avoiding detrimental gene constellation effects. It is not known what attributes from each segment affect the gene constellation or reassortment, but it is desirable that vaccine seed strains containing contemporary haemagglutinin (HA) and neuraminidase (NA) segments in the context of known backbone segments can be recovered. It is also desirable that those strains replicate well and that satisfactory protein yields can be harvested. We have previously shown that five mutations to the PB1 gene of the high-growth backbone virus PR/8 improved the growth kinetics of a reassortant containing the HA and NA segments from an H3N2 virus (Plant et al., 2012). These mutations (G180E, S216G, S361R, Q621R and N654S) were not selected based on any structural or functional information. The five mutations made to the PB1 gene (PB1 m5 ) were based on sequence variations found in vaccine strain reassortants. We have also described the improved growth and protein yield of a reassortant (Table 1) and all the viruses produced large plaques on MDCK cells (Fig. 1a). The longer stalk region of the H5N1 NA has been shown to contribute to pathogenicity (Zhou et al., 2009). Here, we confirmed that removing this region reduced pathogenicity, with or without the PB1 M5 allele, by determining mean death time (MDT). Virus particles (10 6 ) were inoculated into the allantoic fluid of eight eggs, which were then incubated at 35 u C and candled at 12 h intervals. Eggs were scored as alive or dead and the time of death recorded. MDT was obtained by multiplying the number of embryos dead at each interval post-inoculation by the hours post-inoculation and dividing by the total number of embryos inoculated. The MDT range was similar for all viruses (Table 1).Optimal polymerase activity is required for efficient replication (Giesendorf et al., 1986;Li et al., 2009;Ngai et al., 2013). PB1 from a seasonal strain or with targeted mutations has been shown to improve growth or HA yield of H3 reassortants (Cobbin et al., 2013;Plant et al., 2012); however, mixed results have been observed for H5 reassortants (Abt et al., 2011;Rudneva et al., 2007;Wanitchang et al., 2010). All three polymerase segments reassort together more frequently in experimental settings than natural reassortment, suggesting gene constellation effects (Macken et al., 2006;Varich et al., 2008;Wille et al., 2013). Here, we examined the growth of H5 reassortants with the PB1 m5 allele w...

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Frequency and patterns of reassortment in natural influenza A virus infection in a reservoir host

Cited by 56 publications

References 50 publications

Spread and Persistence of Influenza A Viruses in Waterfowl Hosts in the North American Mississippi Migratory Flyway

Spread and Persistence of Influenza A Viruses in Waterfowl Hosts in the North American Mississippi Migratory Flyway

The PB1 segment of an influenza A virus H1N1 2009pdm isolate enhances the replication efficiency of specific influenza vaccine strains in cell culture and embryonated eggs

Chimeric neuraminidase and mutant PB1 gene constellation improves growth and yield of H5N1 vaccine candidate virus

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