Figure 1.

Oncolytic mechanism of Herpes Simplex Virus. Viral RNA activates the double-stranded-RNA- (dsRNA-) dependent protein kinase (PKR) by phosphorylation, which causes eIF2α phosphorylation and inhibition of translation of the viral genes. HSV Υ-34.5 gene encodes the ICP34.5 protein that acts to dephosphorylate eIF2α allowing protein synthesis to continue. In many cancer cells with activated Ras, PKR is not phosphorylated. Deletion of the Υ-34.5 gene from HSV results in attenuation of viral replication in normal cells but allows a lytic infection in cancer cells that have defects in this signaling pathway.