Accessory Gene Products of Influenza A Virus

Pinto, Rute Maria; Lycett, Samantha; Gaunt, Eleanor; Digard, Paul

doi:10.1101/cshperspect.a038380

Cited by 15 publications

(17 citation statements)

References 122 publications

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“…Influenza A viruses (IAV) have segmented negative-sense RNA genomes encoding 10 core proteins and a variable number of strain-specific accessory proteins [1,2]. Due to its small genome size and nuclear replication, IAV has evolved a number of ways to increase its protein coding capacity including the use of splice variants (M2, NEP and the more recently discovered M42, PB2-S1 and NS3 proteins), encoding multiple open reading frames (ORFs), both nested and overlapping on a single gene segment (e.g.…”

Section: Introductionmentioning

confidence: 99%

PA-X is an avian virulence factor in H9N2 avian influenza virus

Clements

Peacock

Sealy

et al. 2021

Journal of General Virology

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Influenza A viruses encode several accessory proteins that have host- and strain-specific effects on virulence and replication. The accessory protein PA-X is expressed due to a ribosomal frameshift during translation of the PA gene. Depending on the particular combination of virus strain and host species, PA-X has been described as either acting to reduce or increase virulence and/or virus replication. In this study, we set out to investigate the role PA-X plays in H9N2 avian influenza viruses, focusing on the natural avian host, chickens. We found that the G1 lineage A/chicken/Pakistan/UDL-01/2008 (H9N2) PA-X induced robust host shutoff in both mammalian and avian cells and increased virus replication in mammalian, but not avian cells. We further showed that PA-X affected embryonic lethality in ovo and led to more rapid viral shedding and widespread organ dissemination in vivo in chickens. Overall, we conclude PA-X may act as a virulence factor for H9N2 viruses in chickens, allowing faster replication and wider organ tropism.

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Section: Introductionmentioning

confidence: 99%

PA-X is an avian virulence factor in H9N2 avian influenza virus

Clements

Peacock

Sealy

et al. 2021

Journal of General Virology

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“…4a). Segment 5 is monocistronic and encodes for the viral nucleoprotein (NP) 33 . To identify the amino acid residue/s in NP determining the sensitivity or resistance to BTN3A3, we compared the NP sequences of the five human and five avian IAVs tested in Fig.…”

Section: Main Textmentioning

confidence: 99%

Zoonotic avian influenza viruses evade human BTN3A3 restriction

Pinto

Bakshi

Lytras

et al. 2022

Preprint

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Cross-species transmission of avian influenza A viruses (IAVs) into humans could represent the first step of a future pandemic1. Multiple factors limiting the spillover and adaptation of avian IAVs in humans have been identified, but they are not sufficient to explain which virus lineages are more likely to cross the species barrier1,2. Here, we identified human BTN3A33 (butyrophilin subfamily 3 member A3) as a potent inhibitor of avian but not human IAVs. We determined that BTN3A3 is constitutively expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts at the early stages of virus replication by inhibiting avian IAV vRNA transcription. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F, or rarely 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, several serotypes of avian IAVs that spilled over into humans in recent decades evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure4. Importantly, we identified more than 150 avian IAV lineages with a BTN3A3-resistant genotype. In conclusion, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.

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“…The IAV genome is (relatively) straightforward to recode (i.e., synonymously alter the genetic sequence of) due to the facile reverse genetics system (29,30), in which the 8 segments of negative sense RNA genome are encoded on plasmids that upon co-transfection into permissive cells yield infectious virus. The IAV genome itself is thoroughly characterised, with well-defined packaging signals (31)(32)(33) and gene annotation (including accessory proteins, reviewed in (34)), providing comparative clarity about which genome regions may be suitable for recoding and those that must remain unaltered. Furthermore, prior to the discovery of ZAPS as a CpG sensor (6), we found that synonymous addition of CpGs to IAV genome segment 5 (encoding nucleoprotein (NP)) significantly attenuated the virus but that antibody and T cell responses to infection were equivalent in mice, thereby demonstrating that attenuation mediated by CpG enrichment need not impair development of adaptive immunity (35).…”

Section: Introductionmentioning

confidence: 99%

CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy

Thompson

Nash

Thorley

et al. 2022

Preprint

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Synonymous recoding of RNA virus genomes is a promising approach for generating attenuated viruses to use as vaccines. However, such recoding typically hinders virus growth. A potential solution to this is CpG dinucleotide enrichment. CpGs are recognised by cellular zinc-finger antiviral protein (ZAP), leading to viral RNA degradation and/or type I interferon stimulation and consequently reduced viral yields. Therefore, in principle, removing the ZAP CpG sensor from a virus propagation system will reverse attenuation of a CpG-enriched virus. Using influenza A viruses (IAVs) engineered for increased CpG content in different genome regions, we show that ZAP mediated virus attenuation is dependent on the viral segment to which CpGs are added. In ZAP-expressing human cells, CpG introduction invariably impaired transcript and protein production, but ZAP-sensitivity did not convey type I interferon activation. Importantly for vaccine development, CpG-enriched viruses were genetically stable during serial passage. Furthermore, the ZAP-sensitive virus was fully replication competent in MDCK cells and in embryonated hens’ eggs, both of which are used to propagate live attenuated influenza vaccines. Thus, ZAP-sensitive CpG enriched viruses that are defective in human systems can yield high titre in vaccine propagation systems, providing a realistic, economically viable platform for live attenuated vaccine development.

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Accessory Gene Products of Influenza A Virus

Cited by 15 publications

References 122 publications

PA-X is an avian virulence factor in H9N2 avian influenza virus

PA-X is an avian virulence factor in H9N2 avian influenza virus

Zoonotic avian influenza viruses evade human BTN3A3 restriction

CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy

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