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Journal of Virology, February 2007, p. 1251-1260, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01408-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Oncolytic Virotherapy Synergism with Signaling Inhibitors: Rapamycin Increases Myxoma Virus Tropism for Human Tumor Cells{triangledown}

Marianne M. Stanford, John W. Barrett, Steven H. Nazarian, Steven Werden, and Grant McFadden*

Biotherapeutics Research Group, Robarts Research Institute, and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6G 2V4, Canada

Received 5 July 2006/ Accepted 9 November 2006

Myxoma virus is a rabbit-specific poxvirus pathogen that also exhibits a unique tropism for human tumor cells and is dramatically oncolytic for human cancer xenografts. Most tumor cell lines tested are permissive for myxoma infection in a fashion intimately tied to the activation state of Akt kinase. A host range factor of myxoma virus, M-T5, directly interacts with Akt and mediates myxoma virus tumor cell tropism. mTOR is a regulator of cell growth and metabolism downstream of Akt and is specifically inhibited by rapamycin. We report that treatment of nonpermissive human tumor cell lines, which normally restrict myxoma virus replication, with rapamycin dramatically increased virus tropism and spread in vitro. This increased myxoma replication is concomitant with global effects on mTOR signaling, specifically, an increase in Akt kinase. In contrast to the effects on human cancer cells, rapamycin does not increase myxoma virus replication in rabbit cell lines or permissive human tumor cell lines with constitutively active Akt. This indicates that rapamycin increases the oncolytic capacity of myxoma virus for human cancer cells by reconfiguring the internal cell signaling environment to one that is optimal for productive virus replication and suggests the possibility of a potentially therapeutic synergism between kinase signaling inhibitors and oncolytic poxviruses for cancer treatment.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Western Ontario, Siebens-Drake Building, Rm. 126, London, Ontario N6G 2V4, Canada. Phone: (519) 685-8300, ext. 34525. Fax: (519) 663-3715. E-mail: mcfadden{at}robarts.ca.

{triangledown} Published ahead of print on 15 November 2006.

Journal of Virology, February 2007, p. 1251-1260, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01408-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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