Portal de Periódicos da CAPES

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

2010; National Academy of Sciences; Volume: 107; Issue: 4 Linguagem: Inglês

10.1073/pnas.0912344107

1091-6490

Tommy Alain, Xueqing Lun, Yvan Martineau, Polen Sean, Bali Pulendran, Emmanuel Petroulakis, Franz J. Zemp, Chantal G. Lemay, Dominic G. Roy, John C. Bell, George Thomas, Sara C. Kozma, Peter Forsyth, Mauro Costa‐Mattioli, Nahum Sonenberg,

Viral Infectious Diseases and Gene Expression in Insects

Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type I IFN greatly limits its clinical application. The kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that mouse embryonic fibroblasts and mice lacking S6K1 and S6K2 are more susceptible to vesicular stomatitis virus (VSV) infection than their WT counterparts as a result of an impaired type I IFN response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSV ΔM51 ), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV ΔM51 selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. These results demonstrate that reducing type I IFNs through inhibition of mTORC1 is an effective strategy to augment the therapeutic activity of VSV ΔM51 .