RNA silencing provides protection against RNA viruses by targeting both the helper virus and its satellite RNA (satRNA). Virus-derived small interfering RNAs (vsiRNAs) bound with Argonaute (AGO) proteins are presumed participants in the silencing process. Here, we show that a vsiRNA targeted to virus RNAs triggers the host RNA-dependent RNA polymerase 6 (RDR6)-mediated degradation of viral RNAs. We confirmed that satRNA-derived small interfering RNAs (satsiRNAs) could be associated with different AGO proteins in planta. Diverse RNA silencing processes exist in plants, including silencing by microRNAs (miRNAs) and several classes of endogenous small interfering RNAs (siRNAs) involved in pathways with multiple Dicer-like proteins (DCLs) and Argonaute proteins (AGOs) (3, 4). There are four specialized DCLs (DCL1 to DCL4) that produce different kinds of small RNAs (sRNAs; 21 to 25 nucleotides [nt] in length) from doublestranded RNAs or stem-loop precursors in Arabidopsis thaliana. The resulting sRNAs bind to an AGO protein to form effector complexes, termed RNA-induced silencing complexes (RISCs), to target the cleavage or translational suppression of cRNA based on sequence complementarity (1). There are three clades of AGOs, including 10 subfamily members in Arabidopsis (50). Recent studies reveal distinct binding affinities of sRNAs with different 5Ј-terminal nucleotides targeted to AGO proteins (31). AGO1 displays a strong bias for sRNAs with a 5Ј-terminal uridine, while AGO2 and AGO4 are associated mainly with sRNA sequences that are initiated with a 5Ј adenosine, and AGO5 is highly enriched for sRNA sequences that are initiated with a 5Ј cytosine (31).RNA silencing also provides protection against diverse RNA viruses in many eukaryotic organisms (28,38,52). Two classes of viral siRNAs are generated in virus infections: the primary siRNAs, derived from the DCL-mediated cleavage of a viral RNA precursor, and the secondary siRNAs, whose biogenesis requires host RNA-dependent RNA polymerases (RDRs) (12,16,20,52) in a process likely resembling the production of secondary siRNAs in plants, which is triggered by an AGO1-containing 22-nt miRNA or siRNA (7,9,42). To counter or escape from host antiviral silencing, many viruses have evolved viral suppressors of RNA silencing (VSR) to interfere with host RNA silencing at different stages (11,14,27). For example, the 2b protein, a VSR encoded by a Cucumber mosaic virus (CMV) (5, 21, 29), perturbs RNA silencing by directly interacting with AGO1, which results in a block of the loading of sRNAs into the AGO1 RISC and, thereby, interferes with the Slicer activity of AGO1 (55).CMV is one of the best-characterized tripartite positivesense single-stranded RNA viruses, with genes encoding five proteins distributed on three genomic and two subgenomic RNAs. The 1a and 2a proteins encoded by genomic RNA1 and RNA2, respectively, are RDRs involved in viral replication (24,35,36). Genomic RNA3 encodes the 3a protein, or movement