The Herpes Simplex Virus 1 vhs Protein Enhances Translation of Viral True Late mRNAs and Virus Production in a Cell Type-Dependent Manner

Abstract

ABSTRACT The herpes simplex virus 1 (HSV-1) virion host shutoff protein (vhs) degrades viral and cellular mRNAs. Here, we demonstrate for the first time that vhs also boosts translation of viral true late mRNAs in a cell type-dependent manner and that this effect determines the viral growth phenotype in the respective cell type. Our study was prompted by the detection of stress granules, indicators of stalled translation initiation, in cells infected with vhs mutants but not in wild-type-virus-infected cells. Accumulation of true late-gene products gC and US11 was strongly reduced in the absence of vhs in HeLa cells and several other restrictive cell lines but not in Vero and other permissive cells and was independent of phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Polysome analysis showed that gC and US11 transcripts were poorly translated in vhs-null-virus-infected HeLa cells, while translation of a cellular mRNA was not affected. Interestingly, hippuristanol, an eIF4A inhibitor, produced a similar phenotype in HeLa cells infected with wild-type HSV-1, while Vero cells were much more resistant to the inhibitor. These results suggest that translation of true late-gene transcripts is particularly sensitive to conditions of limited access to translation factors and that vhs is able either to prevent the limiting conditions or to facilitate translation initiation under these conditions. The varied permissivity of cell lines to vhs-null infection may stem from differences in the resilience of the translation machinery or the ability to control the accumulation of mRNAs.