HSV-1 is proficient at counteracting innate immune responses through the expression of several accessory proteins. The viral endoribonuclease virion host shutoff protein (VHS) is proposed to counteract the protein kinase R (PKR) pathway by inducing the degradation of viral transcripts that form dsRNA; infection with an HSV-1 mutant lacking VHS (DVHS) has been shown to induce PKR and eIF2α phosphorylation, translational shutoff and stress granule (SG) formation. However, VHS is also proposed to antagonise the interferon (IFN) system by inducing degradation of host interferon stimulated gene (ISG) transcripts. Here we have utilised a panel of five DVHS viruses in different HSV-1 strains of different provenance, including a novel clinical isolate, to explore the relationship between these two key innate immune pathways. Intriguingly, these viruses have very different phenotypes depending on their background, exhibiting a wide range of PKR activation, SG formation and ability to spread on primary human fibroblasts. Furthermore, RNAseq has revealed that activated PKR levels correlate with 10 to 20-fold higher levels of ISG transcripts. We are now using this panel of DVHS viruses to dissect the IFN pathway and determine at which stage DVHS induces ISGs. In addition, we are using a range of strategies to block specific steps in the PKR pathway - including SG formation – to determine if inhibition of this pathway also inhibits the IFN pathway. In this way, we aim to establish if there is crosstalk between the PKR and IFN pathways that might explain the complex downstream effects of deleting VHS from HSV1.