Fig. 1

Viral proteins and small molecule compounds may inhibit signaling in synergy to promote viral replication, and improve elicited inflammation, ICD and antitumor immune responses. We use RAS, IFN and dsRNA-dependent protein kinase (PKR) pathways as an example. Most viruses replicate poorly in cells that produce active PKR. In response to viral infection, PKR activates the transcription factor NF-κB by inducing degradation of IκBβ. NF-κB activates transcription of proinflammatory genes that induce an immune response against viruses. RAS activation by EGFR, v-Erb2, or platelet-derived growth-factor receptor (PDGFR) signaling inhibits PKR activity. RAS activation therefore allows viral oncolytic activity in cancer cells. PKR activity is also activated by interferon (IFN)-α/β signaling through the IFN receptor (IFNR). Tumor cells with defects in this signaling pathway allow a higher degree of viral replication than normal cells. Several viral proteins and RNAs (adenoviral VA RNA128, VV’s E3L and K3L, the hepatitis CE2 protein and influenza virus NS1 protein) inhibit PKR. Interfering with the different steps of signaling pathways using different classes of compounds have resulted in increased viral replication and subsequent efficacy. PKR shuts off protein synthesis by phosphorylating eIF2α. The protein phosphatase-1α is activated by the protein ICP34.5, which is expressed by HSV-1. ICP34.5 dephosphorylates eIF2α to allow protein synthesis to continue. An HSV1 strain that expresses a mutant form of ICP34.5 can therefore only replicate in cells with inactive PKR. Targeting this process by means of different small molecule inhibitors increased OV spread and efficacy. Note: Viral genes are shown in red, small molecule inhibitors are shown in green, whereas cellular proteins are shown in blue