VSV oncolysis of T lymphocytes requires cell cycle entry and translation initiation

Oliere S, Arguello M, Mesplede T, Tumilasci V, Nakhaei P, Stojdl D, Sonenberg N, Bell J, Hiscott J
Source: J Virol
Publication Date: (2008)
Issue: 82(12): 5735-49
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human stim.
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
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 (IFN) 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 MEK1/2, JNK, or PI3K pathways, but not p38. VSV replication is specifically impaired by the cell cycle inhibitors oloumicine or rapamycin, which induce early G1 arrest, but not by aphidicolin or taxol, which block at G1-S and G2-M 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 siRNA-mediated eIF4E knockdown. These results demonstrate that VSV replication in primary T lymphocytes relies on cell cycle transition from the G0 to G1 phase - which is characterized by a sharp increase in ribogenesis and protein synthesis.