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Journal of Virology, June 2008, p. 5735-5749, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02601-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Vesicular Stomatitis Virus Oncolysis of T Lymphocytes Requires Cell Cycle Entry and Translation Initiation ^,

Stephanie Oliere,^1,2 Meztli Arguello,^1,2 Thibault Mesplede,^1,2 Vanessa Tumilasci,^1,2 Peyman Nakhaei,^1,2 David Stojdl,³ Nahum Sonenberg,⁴ John Bell,⁵ and John Hiscott^1,2*

Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada H3T 1E2,¹ Departments of Microbiology & Immunology and Medicine, McGill University, Montreal, Canada H3A 2T8,² Apoptosis Research Centre, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada KIH 8L1,³ Department of Biochemistry and McGill Cancer Centre, McGill University, Montreal, Quebec, Canada H3G 1Y6,⁴ Ottawa Regional Cancer Centre, University of Ottawa, Ottawa, Canada K1Y 4E9⁵

Received 6 December 2007/ Accepted 4 April 2008

Vesicular stomatitis virus (VSV) is a candidate oncolytic virus that replicates and induces cell death in cancer cells while sparing normal cells. Although defects in the interferon antiviral response facilitate VSV oncolysis, other host factors, including translational and growth regulatory mechanisms, also appear to influence oncolytic virus activity. We previously demonstrated that VSV infection induces apoptosis in proliferating CD4⁺ T lymphocytes from adult T-cell leukemia samples but not in resting T lymphocytes or primary chronic lymphocytic leukemia cells that remain arrested in G₀. Activation of primary CD4⁺ T lymphocytes with anti-CD3/CD28 is sufficient to induce VSV replication and cell death in a manner dependent on activation of the MEK1/2, c-Jun NH₂-terminal kinase, or phosphatidylinositol 3-kinase pathway but not p38. VSV replication is specifically impaired by the cell cycle inhibitor olomoucine or rapamycin, which induces early G₁ arrest, but not by aphidicolin or Taxol, which blocks at the G₁1S or G₂1M phase, respectively; this result suggests a requirement for cell cycle entry for efficient VSV replication. The relationship between increased protein translation following G₀/G₁ transition and VSV permissiveness is highlighted by the absence of mTOR and/or eIF4E phosphorylation whenever VSV replication is impaired. Furthermore, VSV protein production in activated T cells is diminished by small interfering RNA-mediated eIF4E knockdown. These results demonstrate that VSV replication in primary T lymphocytes relies on cell cycle transition from the G₀ phase to the G₁ phase, which is characterized by a sharp increase in ribogenesis and protein synthesis.

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* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T 1E2. Phone: (514) 340-8222, ext. 5265. Fax: (514) 340-7576. E-mail: john.hiscott{at}mcgill.ca

Published ahead of print on 16 April 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, June 2008, p. 5735-5749, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02601-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.