Viral host-range factor C7 or K1 is essential for modified vaccinia virus Ankara late gene expression in human and murine cells, irrespective of their capacity to inhibit protein kinase R-mediated phosphorylation of eukaryotic translation initiation factor 2α

Vaccinia virus (VACV) infection induces phosphorylation of eukaryotic translation initiation factor 2 alpha (elf2 alpha), which inhibits cellular and viral protein synthesis. In turn, VACV has evolved the capacity to antagonize this antiviral response by expressing the viral host-range proteins K3 and E3. This study revealed that the host-range genes K1L and C7L also prevent eIF2 alpha. phosphorylation in modified VACV Ankara (MVA) infection of several human and murine cell lines. Moreover, C7L-deleted MVA (MVA-Delta C7L) lacked late gene expression, which could be rescued by the function of host-range factor K1 or C7. It was demonstrated that viral gene expression was blocked after viral DNA replication and that it was independent of apoptosis induction. Furthermore, it was found that eIF2 alpha phosphorylation in MVA-Delta C7L-infected cells is mediated by protein kinase R (PKR) as shown in murine embryonic fibroblasts lacking PKR function, and it was shown that this was not due to reduced E3L gene expression. The block of eIF2 alpha phosphorylation by C7 could be complemented by K1 in cells infected with MVA-Delta C7L encoding a reinserted K1L gene (MVA-Delta C7L-K1L). Importantly, these data illustrated that eIF2 alpha phosphorylation by PKR is not responsible for the block of late viral gene expression. This suggests that other mechanisms targeted by C7 and K1 are essential for completing the VIVA gene expression cycle and probably also for VACV replication in a diverse set of cell types.