Molecular arms races at the virus-host splicing interface and their pathogenic implications

RNA splicing is a fundamental driver of eukaryotic transcriptomic and proteomic diversity. Constrained by compact genomes, diverse DNA and RNA viruses, including adenovirus, HIV-1, and influenza virus, have evolved to hijack the host splicing machinery. This exploitation not only maximizes viral coding capacity but also ensures the precise spatiotemporal regulation of viral infection. In this review, we summarize current advances in the molecular mechanisms of viral RNA splicing, illustrating how viruses co-opt the host spliceosome and reprogram global alternative splicing landscapes to support their infection cycle. Through representative viral models, we detail the convergent strategies of alternative splice site selection and the dynamic interplay between viral RNA elements and host trans-acting factors. Furthermore, we spotlight the emerging frontier of viral circular RNAs (vcircRNAs), highlighting their biogenesis via non-canonical back-splicing and their versatile roles in immune evasion. Finally, we summarize recent methodological breakthroughs, particularly long-read sequencing and single-cell analyses, that are rapidly charting the complex splicing landscape. Together, this review provides an integrated perspective on the virus-host splicing interface, exposing critical vulnerabilities that offer promising avenues for next-generation, broad-spectrum antiviral interventions.