Nipah virus (NiV) and Hendra virus (HeV) are recently emerged zoonotic paramyxoviruses exclusively grouped within a new genus, Henipavirus. These viruses cause fatal disease in a wide range of species, including humans. Both NiV and HeV have continued to re-emerge sporadically in Bangladesh and Australia, respectively. There are currently no
therapeutics or
vaccines available to treat
Henipavirus infection and both are classified as BSL4 pathogens. RNA interference (RNAi) is a process by which
double-stranded RNA directs sequence-specific degradation of
messenger RNA in animal and plant cells. Small interfering RNAs (siRNAs) mediate RNAi by inhibiting gene expression of homologous
mRNA and our preliminary studies suggest RNAi may be a useful approach to developing novel
therapies for these highly lethal pathogens. Eight NiV
siRNA molecules (four L and four N gene specific), two HeV N gene specific, and two non-specific control
siRNA molecules were designed and tested for their ability to inhibit a henipavirus minigenome replication system (which does not require the use of live virus) in addition to live
virus infections in vitro. In the minigenome assay three out of the four siRNAs that targeted the L gene of NiV effectively inhibited replication. In contrast, only NiV N gene siRNAs were effective in reducing live NiV replication, suggesting inhibition of early, abundantly expressed gene transcripts may be more effective than later, less abundant transcripts. Additionally, some of the siRNAs effective against
NiV infection were only partially effective inhibitors of HeV
infection. An inverse correlation between the number of
nucleotide mismatches and the efficacy of
siRNA inhibition was observed. The demonstration that RNAi effectively inhibits henipavirus replication in vitro, is a novel approach and may provide an effective
therapy for these highly lethal, zoonotic pathogens.