Second-Site Mutation Outside of the U S 10-12 Domain of Δγ 1 34.5 Herpes Simplex Virus 1 Recombinant Blocks the Shutoff of Protein Synthesis Induced by Activated Protein Kinase R and Partially Restores Neurovirulence

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Abstract
Earlier studies have shown that herpes simplex virus type 1 (HSV-1) activated protein kinase R (PKR) but that the product of the product of the γ 1 34.5 gene binds and redirects the host phosphatase 1 to dephosphorylate the α subunit of eukaryotic translation initiation factor 2 (eIF-2α). In consequence, the γ 1 34.5 gene product averts the threatened shutoff of protein synthesis caused by activated PKR. Serial passages of Δγ 1 34.5 mutants in human cells led to isolation of two classes of second-site, compensatory mutants. The first, reported earlier, resulted from the juxtaposition of the α promoter of the U S 12 gene to the coding sequence of the U S 11 gene. The mutant blocks the phosphorylation of eIF-2α but does not restore the virulence phenotype of the wild-type virus. We report another class of second-site, compensatory mutants that do not map to the U S 10-12 domain of the HSV-1 genome. All mutants in this series exhibit sustained late protein synthesis, higher yields in human cells, and reduced phosphorylation of PKR that appears to be phosphatase dependent. Specific dephosphorylation of eIF-2α was not demonstrable. At least one mutant in this series exhibited a partial restoration of the virulence phenotype characteristic of the wild-type virus phenotype. The results suggest that the second-site mutations reflect activation of fossilized functions designed to block the interferon response pathways in cells infected with the progenitor of present HSV.

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