Viral Escape From RNAi in Mammalian Cells

Background: Fire, Mello, and coworkers first discovered that introducing long double-stranded RNA (dsRNA) into the nematode Caenorhabditis elegans led to the targeted degradation of homologous messenger (m)RNA. This discovery revealed the existence of a fundamental mechanism for gene expression regulation, now known as RNA interference (RNAi) (Fire et al., 1998). Later, Elbashir et al. showed that RNAi also occurs in mammalians cells (Elbashir et al., 2001). Importantly, they performed the extraordinary demonstration by cell transfection that synthetic, short, 21 base-pair (bp) duplexes of interfering RNA (siRNA) could mediate RNAi in a sequence-specific manner. This finding enabled the specific regulation of gene expression in a variety of biological systems, including diseased cells. Recent studies regarding the utility of RNAi to specifically inhibit virus replication have opened new possibilities for the development of novel therapies against viral infection. However, viruses appear to be capable of escaping RNAi inhibition in mammalian cells. Viral mechanisms for escaping RNAi may include suppression of RNAi, mutational escape from RNAi, and modulation of the cell's microRNA (miRNA) /RNAi profile. Here, we summarize these viral mechanisms and discuss potential strategies for neutralizing viral escape from RNAi.