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Review
. 2023 Feb;38(1):1-8.
doi: 10.1016/j.virs.2022.10.005. Epub 2022 Oct 27.

Revisiting influenza A virus life cycle from a perspective of genome balance

Ruikun Du  1 , Qinghua Cui  2 , Zinuo Chen  3 , Xiujuan Zhao  4 , Xiaojing Lin  3 , Lijun Rong  5
Affiliations
Review

Revisiting influenza A virus life cycle from a perspective of genome balance

Ruikun Du et al. Virol Sin. 2023 Feb.

Abstract

Influenza A virus (IAV) genome comprises eight negative-sense RNA segments, of which the replication is well orchestrated and the delicate balance of multiple segments are dynamically regulated throughout IAV life cycle. However, previous studies seldom discuss these balances except for functional hemagglutinin-neuraminidase balance that is pivotal for both virus entry and release. Therefore, we attempt to revisit IAV life cycle by highlighting the critical role of "genome balance". Moreover, we raise a "balance regression" model of IAV evolution that the virus evolves to rebalance its genome after reassortment or interspecies transmission, and direct a "balance compensation" strategy to rectify the "genome imbalance" as a result of artificial modifications during creation of recombinant IAVs. This review not only improves our understanding of IAV life cycle, but also facilitates both basic and applied research of IAV in future.

Keywords: Balance compensation; Balance regression; Genome balance; Influenza A virus (IAV); Segmented genome.

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Figures

Fig. 1
Fig. 1
Influenza A virus (IAV) life cycle. The virus entry into host cell is initiated by hemagglutinin (HA) mediated receptor binding followed by endocytosis and membrane fusion, releasing internal genetic contents into the cytoplasm (1). The incoming viral RNAs (vRNPs) are then transported into nucleus (2), where genome transcription occurs (3). After export of viral mRNAs from nucleus to cytoplasm, viral proteins are expressed (4) and the newly synthesized RdRp constituents and NPs are imported into nucleus, facilitating vRNA replication and vRNP formation (5). Progeny vRNPs are then transported into cytoplasm, assemble (6) and bud at plasma membrane (7). Eventually, progeny virions are released from host cell surface via viral neuraminidase (NA) mediated receptor destroying.
Fig. 2
Fig. 2
Alternative configurations of influenza polymerase and viral RNA (vRNA) promoters. A The peripheral domains (PA-N endonuclease, PB2 cap-binding domain and PB2–C domains) of influenza polymerase complex are flexible and rearrange upon binding to template vRNA and cRNA. The apo form (PDB ID: 5d98) and cRNA binding form (PDB ID: 5epi) of influenza polymerase represent transcription inactive states, while the vRNA binding form (PDB ID: 4wsa) could initiate “cap-snatching” which is critical for transcription. B Different vRNA promoter structure models proposed over time. Unpaired nucleotides are shown in brown, while paired nucleotides are shown in green. The segment specific duplex extensions are highlighted in grey.
Fig. 3
Fig. 3
Diagrams of the proposed models of influenza A virus (IAV) genome packaging. A Conflicting hypothesis of the genome packaging model. The viral genome replication takes place in the nucleus. The viral RNA (vRNA) segments, in the form of RNPs, are transported to the plasma membrane, followed by packaging and budding. In the selective packaging model (i), eight unique vRNA segments are consistently packaged into every progeny virus particle. The random packaging model (ii) proposes that vRNA segments are arbitrarily packaged into virus particles, and the progeny virus particles are infectious only when at least one copy of each segment is incorporated. B A compromised model that accommodates the “selective” and “random” packaging models. After transport from nucleus, a highly selective sub-bundle of vRNPs comprising of at least PB2, PA, NP and M segments is formed initially. Although the core sub-bundle is sufficient for virus budding, a more stabilized “1 ​+ ​7” configuration is prone to form by recruiting more vRNPs. This process occurs at random and contaminants like ribosomal RNAs might be incorporated by chance.
Fig. 4
Fig. 4
Schematic representation of hemagglutinin (HA)-neuraminidase (NA) balance regression during influenza A virus (IAV) evolution. HA-NA mismatch usually occurs when new coupled HA-NA subtypes emerge via reassortment or after interspecies transmission, resulting in either overwhelmed receptor binding affinity of HA by receptor destroying activity of NA, or vice versa. Both kinds of HA-NA mismatch would threaten the viral viability by interfering with virus entry into and release from host cells, compelling directed virus evolution to achieve HA-NA rebalance. SA, sialic acid.
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