Vesicular stomatitis virus oncolysis of T lymphocytes requires cell cycle entry and translation initiation.
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 G(0). 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 NH(2)-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 G(1) arrest, but not by aphidicolin or Taxol, which blocks at the G(1)1S or G(2)1M phase, respectively; this result suggests a requirement for cell cycle entry for efficient VSV replication. The relationship between increased protein translation following G(0)/G(1) 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 G(0) phase to the G(1) phase, which is characterized by a sharp increase in ribogenesis and protein synthesis.
Oliere
Stephanie
S
Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada H3T 1E2.
Arguello
Meztli
M
Mesplede
Thibault
T
Tumilasci
Vanessa
V
Nakhaei
Peyman
P
Stojdl
David
D
Sonenberg
Nahum
N
Bell
John
J
Hiscott
John
J
D001402:B-Lymphocytes / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002453:Cell Cycle; D016923:Cell Death; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology*; D010948:Viral Plaque Assay; D014779:Virus Replication
D034741:RNA, Small Interfering