The importance of herpes simplex viruses (HSV) as human pathogens and the emerging prospect of using mutant derivatives of HSV-1 as potential anti-cancer therapeutics have necessitated a thorough investigation into the molecular basis of host-cell permissiveness to HSV. Here we show that NIH-3T3 cells transformed with the oncogenes v-erbB, activated sos or activated ras become significantly more permissive to HSV-1. Inhibitors of the Ras signalling pathway, such as farnesyl transferase inhibitor 1 and PD98059, effectively suppressed HSV-1 infection of ras-transformed cells. Enhanced permissiveness 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 preferentially both transformed cells and PKR−/− (but not PKR+/+) mouse embryo fibroblasts. These observations suggest that HSV-1 specifically targets cells with an activated Ras signalling pathway, and have important ramifications in the use of engineered HSV in cancer therapy, the development of strategies against HSV infections, and the controversial role of HSV in human cancers.
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We thank B. Roizman for the HSV-1 (strain F) and mutant R3616; D. Faller for the NIH-3T3 and H-ras-transformed cells; M. Karin for sos-transformed cells (TNIH#5); H.-J. Kung for THC-11 cells; B. Williams for the PKR−/− and PKR+/+ mouse embryo fibroblasts; R. N. Johnston for NIH3T3 c-myc cells; C. P. Webb for Ras effector domain mutant cell lines; P. Olivo for the anti-ICP8 antibody; K. M. Lee and K. Fonseca for assistance with immunofluorescence studies; and W. Yong, F. Yong, M. Schultz and D. Bazett-Jones for assistance with microscopy. This work was supported by the Canadian Institutes of Health Research (P.W.K.L.). F.F. is a recipient of a Studentship from the Canadian Institutes of Health Research.
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