The relevance of translational control in the gene expression and oncotropism of the autonomous parvoviruses was investigated with MVMp, the prototype strain of minute virus of mice (MVM), infecting normal and transformed rodent and human cells of different tissue origins. Mouse embryo fibroblasts (MEFs) and NIH 3T3 fibroblasts were resistant to MVMp
infection, but 3T3 fibroblasts derived from
double-stranded RNA (dsRNA)-dependent
protein kinase R (PKR) knockout mice (PKR(o/o)) behaved in a manner that was highly permissive to productive MVMp replication. NIH 3T3 resistance correlated with significant phosphorylation of eukaryotic translation
initiation factor 2 (
eIF2) occurring at early time points after
infection. Permissive PKR(o/o) cells were converted to MVMp-restrictive cells after reintroduction of the PKR gene by transfection. Conversely, regulated expression of the vaccinia virus E3
protein, a PKR inhibitor, in MEFs prevented eIF2alpha phosphorylation and increased MVMp
protein synthesis. In vitro-synthesized genome-length R1
mRNA of MVMp was a potent activator of PKR. Virus-resistant primary MEFs and NIH 3T3 cells responded to MVMp
infection with significant increases in eIF2alpha phosphorylation. In contrast, virus-permissive mouse (PKR(o/o), BHK21, and A9) and human transformed (NB324K fibroblast, U373
glioma, and HepG2
hepatoma) cells consistently showed no significant increase in the level of eIF2alpha phosphorylation following MVMp
infection. The synthesis of the viral NS1
protein was inversely correlated with the steady-state PKR levels. Our results show that the PKR-mediated
antiviral response is an important mechanism for control of productive MVMp
infection, and its impairment in human transformed cells allowed efficient MVMp gene expression. PKR translational control may therefore contribute to the oncolysis of MVMp and other autonomous parvoviruses.