Antiviral RNA silencing in mammals: the importance of selecting the appropriate experimental model

The role of RNA interference (RNAi) in mammalian antiviral immunity remains debated, partly due to variations in experimental models. Here, we critically examine key factors inffuencing the detection and interpretation of antiviral RNAi, including virus selection, infection efffciency, and small RNA proffling. We highlight the limitations of certain viral models and the need for rigorous methodologies to distinguish canonical virus-derived small interfering RNAs from degradation products. Additionally, we discuss the challenges of using transgenic mouse models to study Dicer-mediated antiviral responses. Standardizing experimental approaches will be essential for clarifying the role of RNAi in mammalian antiviral defense.