Reovirus double-stranded RNA genomes and polyI:C induce down-regulation of hypoxia-inducible factor 1α

Reovirus has genomes consisting of 10-segmented double-stranded RNAs, and have received much attention as an oncolytic virus. A previous study reported that reovirus down-regulates hypoxia-inducible factor 1α (HIF-1α) protein levels following infection in tumor cells, which contributes to the antitumor effects of reovirus; however, the mechanism remains to be elucidated. In this study, we examined which virus component was involved in reovirus-mediated down-regulation of HIF-1α. Reovirus induced significant down-regulation of HIF-1α protein levels in not only reovirus-permissive tumor cells but also reovirus-resistant tumor cells. UV-inactivated reovirus also induced a reduction in HIF-1α protein levels. These data indicate that reovirus induces HIF-1α down-regulation independently of virus replication. Furthermore, transfection with not only reovirus genomes but also polyI:C efficiently induced HIF-1α down-regulation in a manner similar to reovirus, indicating that double-stranded reovirus RNA genomes are a key component for HIF-1α down-regulation. Reovirus-mediated HIF-1α down-regulation was inhibited when tumor cells were pretreated with inhibitors of cathepsins B and L, which play a crucial role in endo-lysosomal escape of virions to the cytoplasm. These data suggest that endo-lysosomal escape of reovirus genome into the cytoplasm is crucial for HIF-1α down-regulation; however, the retinoic acid-inducible gene-I (RIG-I) or interferon-β promoter stimulator-1 (IPS-1), which are involved in reovirus genome-induced innate immunity in the cytoplasm, did not play a crucial role in reovirus-mediated HIF-1α reduction.