Systemically Administered Reovirus-Induced Downregulation of Hypoxia Inducible Factor-1α in Subcutaneous Tumors

Reovirus, which possesses a 10-segmented double-stranded RNA genome, mediates superior antitumor effects via not only virus replication in a tumor cell-specific manner but also other mechanisms distinct from virus replication. Several groups, including ours, reported the reovirus-mediated downregulation of hypoxia inducible factor-1 alpha (HIF-1 alpha) following infection in cultured tumor cells; however, it remained to be clarified whether reovirus downregulates the expression of HIF-1 alpha and its target genes in tumor-bearing hosts. We found that reovirus induced significant downregulation of protein levels of HIF-1 alpha and its target genes in the subcutaneous tumors at 120 h post-systemic administration. Expression of reovirus capsid protein sigma 3 was found in the pimonidazole-positive hypoxic area in the tumor. Significant levels of tumor cell apoptosis were not found in the tumors of reovirus-treated mice at this time point, suggesting that reovirus-mediated tumor cell killing did not largely contribute to the downregulation of HIF-1 alpha protein levels in the tumors. UV-inactivated reovirus did not induce downregulation of HIF-1 alpha expression in the tumors, indicating that virus replication was indispensable for downregulation of HIF-1 alpha expression in the subcutaneous tumors. This study provides important information for the development of reovirus-mediated virotherapy against various types of tumors.