Viruses and RNA interference in mammalian cells

4. RNA interference in mammals
The problem, whether there is mammalian antiviral RNAi counterpart, is the subject of
many studies. It was supposed, that RNA silencing machinery is not typical for mammalian
cells. This skepticism was derived from the fact that mammalian cells respond to the
presence of dsRNA with activation of IFN system. Plants and invertebrates do not possess
this system; hence it might functionally replace the RNA interference (Gitlin and Andino,
2003). Then scientists discovered that siRNAs themselves are not able to induce IFN
system. (Elbashir et al., 2001). This finding entailed other question whether siRNAs could
target mammalian virus and whether viruses would have means to avoid such an onset
(Schütz and Sarnow, 2006).
It was considered, that mammalian cells might not need to interfere with the RNAi pathway,
because they have an effective IFN, which responds to the accumulation of viral dsRNAs by
inducing the synthesis of a large group of genes which exert inhibitory effects on viral gene
expression (Gale et al., 2000; Katze et al., 2002).
Viruses have evolved highly sophisticated mechanisms for interacting with the host cell
machinery, and recent evidence indicates that these interactions also involve RNAi
pathways. Last years the evidences that RNAi functions as an antiviral defense mechanism
in mammalian cells are accumulating. To the present time, there are only few papers
describing the mechanism of antiviral action of RNAi in mammalian cells.
Artificially triggered RNAi
The mammalian cellular RNAi machinery can inhibit virus replication, when the formation
of siRNAs is experimentally induced (Li et al., 2004). To attest this supposition, the
experiment with poliovirus replication, sense ssRNA virus, in the presence of siRNAs was
performed. The poliovirus’ genome is identical to mRNA, therefore can immediately initiate
translation of virus-encoded proteins. In one-step growth curves artificial siRNAs resulted in
a 100-fold reduction of the progeny titer (Gitlin et al., 2002). But the first RNAi-mediated
suppression of mammalian virus replication in tissue culture has been shown on
Coxsackievirus B3 (CVB3), which is the most common causal agent of viral myocarditis.
CVB3 belongs to the Picornaviridae family and has a ss(+)RNA genome (Yuan et al.,
2004).
Also the down regulating viral gene expression and replication of negative- and positivestrand
RNA viruses were demonstrated by the examples of influenza A and West Nile virus
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