From CD163 to systems immunogenomics: genetic, epigenetic, and RNA-mediated antiviral resistance in pigs

Viral diseases remain major constraints on swine health, welfare, and productivity. Although vaccination, biosecurity, and herd management are essential, host-directed approaches offer complementary opportunities to improve disease resistance and resilience. CD163-edited pigs provide compelling evidence that modification of a host susceptibility factor can confer resistance to tested porcine reproductive and respiratory syndrome virus (PRRSV) strains. Beyond this established example, host genetic variation, innate immune pathways, epigenetic modifications, RNA methylation, and non-coding RNAs have been implicated in porcine antiviral responses. However, evidence ranges from experimentally demonstrated resistance to cell-based functional effects, molecular associations, and computational predictions. This review critically examines these mechanisms, emphasising their causal validation, pathogen specificity, and interactions across regulatory layers. We propose an evidence-weighted systems-immunogenomics framework that distinguishes validated regulatory relationships from hypothetical cross-talk and identifies priorities for mechanistic and whole-animal investigation. Translational opportunities in genomic selection, genome editing, and precision health management are considered alongside regulatory and commercial constraints. Advancing host-directed antiviral strategies will require reproducible resistance phenotypes and validation under biologically relevant production conditions.