Influenza A virus RNA localisation and the interceding trafficking pathways of the host cell

Viruses have evolved to efficiently navigate host cells to deliver, express, and replicate their genetic material. Understanding the mechanisms underlying viral RNA localisation is paramount to designing new antivirals. In this review, we discuss Influenza A Virus (IAV) as a model system to highlight some of the ways in which RNA viruses can hijack the endomembrane systems, as well as nuclear transporters, to achieve the correct localisation of their transcripts. IAV exemplifies a nuclear-replicating RNA virus with a complex and highly regulated RNA localisation and trafficking system within host cells. The virus subverts various vesicular transport systems and nuclear transporters, altering normal cellular functions. IAV RNA trafficking begins during entry; after clathrin-mediated endocytosis, the viral genome (vRNPs) is released into the cytosol after fusion with the endosomal membrane, and it is subsequently imported into the nucleus via the importin system. There, vRNPs engage with most major subnuclear structures and exploit host chromatin, the transcription machinery and splicing apparatus to achieve efficient viral mRNA synthesis and export. Subsequently, newly synthesised vRNPs are rapidly exported from the nucleus and contact the host's recycling endosome network for transport to the plasma membrane. We discuss the critical viral remodelling of the entire endomembrane system, particularly the Rab11 recycling endosome and the endoplasmic reticulum. Lastly, replicated genomes come together into bundles to be inserted in budding virions, and we discuss the current models being proposed and the evidence behind them. Despite advances in understanding these processes, several knowledge gaps remain, particularly regarding the specific export of unspliced IAV transcripts, the remodelling of the endomembrane system, and segment bundling.