The virion host shut-off RNase plays a key role in blocking the activation of Protein kinase R in cells infected with Herpes Simplex Virus 1

Earlier studies have shown that active MEK blocks the activation of protein kinase R (PKR) a component of antiviral innate immune responses. In this report we show that the herpes simplex virus 1 virion host shutoff RNase (VHS) and MEK (mitogen-activated protein kinase kinase) act cooperatively in blocking the activation of PKR. This conclusion is based on the following: (a) In contrast to viral gene expression in parental cell line or a cell line expressing a constitutively active MEK, the replication of VHS mutant is particularly impaired in cells expressing dominant negative MEK. In this cell line PKR is activated by phosphorylation and the accumulation of several viral proteins is delayed. (b) In transfected cells wild-type VHS blocked the activation of PKR whereas PKR was activated in cells transfected with a mutant VHS or with plasmids encoding VHS, and VP16 and VP22, the two viral proteins that neutralize the RNase activity of VHS. The results suggest that early in infection VHS RNase degrades RNAs that activate PKR. Coupled with published data, the results suggest that inhibition of activation of PKR or its effect on viral replication is staged early in infection by VHS, post synthesis of VP16 and VP22 by γ(1)34.5 protein and very late in infection by the U(S)11 protein