Figure 2

Strategy and mechanism for oncolytic gene therapy. (A); Oncolytic gene therapy employs replication-competent virus vectors capable of selective replication in target tumor cells. Spreading to new adjacent progeny cells occurs as the host cell is lysed and progeny virus is released. (B); Most viruses can replicate poorly in normal cells by a defense mechanism as follows. In response to viral infection, Protein Kinase R (PKR) in the host cells shut off protein synthesis by which PKR dimerizes and is inactivated by autophosphorylation resulting in the conversion of eukaryotic initiation factor-2 alpha (EIF-2α) into its inactive state following phosphorylation, which is required for translation initiation. Consequently, translation is arrested in the infected host cells as an anti-viral protective mechanism. However, the ICP34.5 in HSV-1 can overcome this defense by recruiting protein phosphatase-1α to dephosphorylate EIF-2α allowing protein synthesis to proceed. Therefore, when a deletion of γ34.5 gene is engineered, the HSV-1 mutant can no longer successfully proliferate in non-replicating cells. HSV-1 lacking ICP34.5 activity can only infect cells with defective PKR pathway. In tumor cells, PKR autophosphorylation is blocked due to Ras activation, permitting replication of viruses lacking the γ34.5 gene in tumor cells with hyper-activated Ras.