Antiviral RNA silencing in mammals: no news is not good news.

In plants, fungi, and invertebrates, antiviral RNAi is activated by processing viral doublestranded RNA (dsRNA) replication intermediates into virus-derived small interfering RNAs (vsiRNAs). Typically of a discrete length of ~22 nt, vsiRNAs form perfect duplexes, with 2 nt 3′ overhangs diagnostic of the Dicer-like RNase III activities that generate them across kingdoms. vsiRNAs are loaded into and guide Argonaute (AGO) nucleases in order to subsequently suppress virus accumulation (Ding and Voinnet, 2007). Attesting to the importance of antiviral RNAi, the virulence of plant and invertebrate viruses requires production of virus-encoded suppressors of RNAi (VSRs) that become dispensable for infection in RNAi-defective hosts (Ding and Voinnet, 2007). Comparatively, antiviral RNAi in mammals remains a hotly debated issue: virus-derived small RNAs (vsRNAs, unlike the vsiRNAs evoked above) isolated in numerous infections of mammalian differentiated cell lines do not conform to the definition of siRNAs; their random size-distribution and strong strand bias usually reflect the unspecific degradation of a single, abundant viral RNA strand (Parameswaran et al., 2010). Perhaps unsurprisingly, therefore, the replication of many viruses is unchanged in differentiated cells in which Dicer function is genetically disabled (Bogerd et al. 2014). This overall uncertainty has led to a hypothesis that the interferon response, which also detects viral dsRNA, may prevent dsRNA recognition by RNAi in mammals.