Tumor hypoxia presents an obstacle to the effectiveness of most antitumor
therapies, including treatment with oncolytic viruses. In particular, an oncolytic virus must be resistant to the inhibition of
DNA,
RNA, and
protein synthesis that occurs during hypoxic stress. Here we show that
vesicular stomatitis virus (VSV), an oncolytic RNA virus, is capable of replication under hypoxic conditions. In cells undergoing hypoxic stress, VSV
infection produced larger amounts of
mRNA than under normoxic conditions. However, translation of these mRNAs was reduced at earlier times postinfection in
hypoxia-adapted cells than in normoxic cells. At later times postinfection, VSV overcame a
hypoxia-associated increase in alpha subunit of
eukaryotic initiation factor 2 (eIF-2alpha) phosphorylation and initial suppression of
viral protein synthesis in hypoxic cells to produce large amounts of
viral protein. VSV
infection caused the dephosphorylation of the translation
initiation factor eIF-4E and inhibited host translation similarly under both normoxic and hypoxic conditions. VSV produced progeny virus to similar levels in hypoxic and normoxic cells and showed the ability to expand from an initial
infection of 1% of hypoxic cells to spread through an entire population. In all cases,
virus infection induced classical cytopathic effects and apoptotic cell death. When VSV was used to treat
tumors established in nude mice, we found VSV replication in hypoxic areas of these
tumors. This occurred whether the virus was administered intratumorally or intravenously. These results show for the first time that VSV has an inherent capacity for infecting and killing hypoxic
cancer cells. This ability could represent a critical advantage over existing
therapies in treating established
tumors.