Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1

The importance of herpes simplex viruses (HSV) as human pathogens and the e merging prospect of using mutant derivatives of HSV-1 as potential anti-can cer therapeutics have necessitated a thorough investigation into the molecu lar basis of host-cell permissiveness to HSV. Here we show that NIH-3T3 cel ls transformed with the oncogenes v-erbB, activated sos or activated ras be come significantly more permissive to HSV-1. Inhibitors of the Ras signalli ng pathway, such as farnesyl transferase inhibitor 1 and PD98069, effective ly suppressed HSV-1 infection of ras-transformed cells. Enhanced permissive ness of the transformed cells was linked to the inhibition of virus-induced activation (phosphorylation) of the double-stranded RNA-activated protein kinase (PKR), thereby allowing viral transcripts to be translated in these cells. An HSV-1-derived oncolytic mutant, R3616, was also found to infect p referentially both transformed cells and PKR-/- (but not PKR+/+) mouse embr yo fibroblasts. These observations suggest that HSV-1 specifically targets cells with an activated Ras signalling pathway, and have important ramifica tions in the use of engineered HSV in cancer therapy, the development of st rategies against HSV infections, and the controversial role of HSV in human cancers.