RIG-I and MDA-5 Detection of Viral RNA-dependent RNA Polymerase Activity Restricts Positive-Strand RNA Virus Replication

Type i interferons (ifn) are important for antiviral responses. melanoma differentiation-associated gene 5 (mda-5) and retinoic acid-induced gene i (rig-i) proteins detect cytosolic double-stranded rna (dsrna) or 5′-triphosphate (5′-ppp) rna and mediate ifn production. cytosolic 5′-ppp rna and dsrna are generated during viral rna replication and transcription by viral rna replicases [rna-dependent rna polymerases (rdrp)]. here,we show that the semliki forest virus (sfv) rna replicase can induce ifn-β independently of viral rna replication and transcription. the sfv replicase converts host cell rna into 5′-ppp dsrna and induces ifn-β through the rig-i and mda-5 pathways. inactivation of the sfv replicase rdrp activity prevents ifn-β induction. these ifn-inducing modified host cell rnas are abundantly produced during both wild-type sfv and its non-pathogenic mutant infection. furthermore,in contrast to the wild-type sfv replicase a non-pathogenic mutant replicase triggers increased ifn-β production,which leads to a shutdown of virus replication. these results suggest that host cells can restrict rna virus replication by detecting the products of unspecific viral replicase rdrp activity. © 2013 nikonov et al.