Identification of Mammalian Orthoreovirus Proteins That Are Responsible for Downregulation of Hif-1a

Tumor outgrowth from the blood supply leads to low oxygen condition, or hypoxia in micro regions of solid tumors. The transcription factor, Hypoxia Inducible Factor-1 (HIF-1), regulates these hypoxic cells, and is formed when one of its components, HIF-1a, is stabilized. We previously found that Mammalian Orthoreovirus (MRV), a potent oncolytic virus, causes the downregulation of HIF-1a in infected hypoxic cells. Here we report that MRV proteins, m1 and m2 induce the downregulation of HIF-1a independent of viral infection. The ability of m2 to downregulate HIF-1a was attributed to strain specific differences, where the T1L and T3DC strains induced more downregulation than the T3DF strain. By examining single amino-acid and deletion mutants, the region containing aa 188-380, and specifically amino-acid 208 of m2, and f domain of m1 were determined to be necessary for HIF-1a downregulation. These observations provide new insights into the effects of specific MRV proteins on HIF-1a when expressed in hypoxic cells