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Journal of Virology, September 2004, p. 8960-8970, Vol. 78, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.17.8960-8970.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Replication and Cytopathic Effect of Oncolytic Vesicular Stomatitis Virus in Hypoxic Tumor Cells In Vitro and In Vivo

John H. Connor,1* Christine Naczki,2 Costas Koumenis,2 and Douglas S. Lyles1

Department of Biochemistry,1 Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina2

Received 26 November 2003/ Accepted 15 April 2004

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-2{alpha}) 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.

* Corresponding author. Present address: Wake Forest University School of Medicine, Department of Microbiology and Immunology, Medical Center Blvd., Winston-Salem, NC 27157. Phone: (336) 716-2270. Fax: (336) 716-9928. E-mail: jconnor{at}wfubmc.edu.

Journal of Virology, September 2004, p. 8960-8970, Vol. 78, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.17.8960-8970.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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