Alphavirus-Based Vaccines

Lundstrom, Kenneth

The relatively recent discovery of the commonly occurring phenomenon of gene silencing has also made its impact on vaccine development. In this context, small interfering RNAs (siRNAs) were engineered against two conserved regions of the nsP3 and E1 genes of CHIK [119] . A significant reduction of virus titer was observed in Vero cells after 24 h (99%) and 48 h (65%), suggesting a potential new therapeutic approach. In another approach, microRNA (miRNA)-specific target sequences for replicon particle production were introduced into alphavirus helper RNAs [120] . In the presence of miRNA-specific inhibitors, CHIK particles were efficiently generated, whereas in their absence, cellular miRNAs downregulated helper RNA replication. When mice were inoculated with replicon RNA carrying engineered miRNA sequences, cellular miRNAs prevented the replication of replicon RNA, which opens the feasibility of using miRNAs as a therapeutic approach for the inhibition of viral replication. Moreover, the VEE RNA-dependent RNA polymerase (RdRp) was targeted by artificial miRNAs in attempts to inhibit VEE replication [124] . Of five miRNAs that were evaluated in BHK cells, three showed significant inhibition of VEE replication.