Species‐specific inhibition of antiviral protein kinase R by capripoxviruses and vaccinia virus.

Double‐stranded RNA‐activated protein kinase R (PKR) is an important and rapidly evolving antiviral kinase. Most poxviruses contain two distinct PKR inhibitors, called E3 and K3 in vaccinia virus (VACV), the prototypic orthopoxvirus. E3 prevents PKR homodimerization by binding double‐stranded RNA, while K3 acts as a pseudosubstrate inhibitor by binding directly to activated PKR and thereby inhibiting interaction with its substrate eIF2α. In our study here, we analyzed E3 and K3 orthologs from the phylogenetically distinct capripoxviruses (CaPVs), which include lumpy skin disease virus, sheeppox virus, and goatpox virus. Whereas the sheeppox virus E3 ortholog did not substantially inhibit PKR, all three CaPV K3 orthologs showed species‐specific inhibition of PKR, with strong inhibition of sheep, goat, and human PKR but only weak inhibition of cow and mouse PKR. In contrast, VACV K3 strongly inhibited cow and mouse PKR but not sheep, goat, or human PKR. Infection of cell lines from the respective species with engineered VACV strains that contained different K3 orthologs showed a good correlation of PKR inhibition with virus replication and eIF2α phosphorylation. Our results show that K3 orthologs can have dramatically different effects on PKR of different species and indicate that effective PKR inhibition by K3 orthologs is crucial for virus replication. Even closely related viruses can display dramatic differences in their host range and virulence; however, the molecular mechanisms underlying these differences are poorly understood. This study shows that an antiviral host protein (PKR) is inhibited by poxvirus proteins in both a host‐ and virus‐specific fashion. Effective PKR inhibition correlated with virus replication in cell lines from many different species, including aberrant hosts such as humans. These data suggest that evolving resistance against one viral antagonist may come at the price of making PKR more sensitive to more distantly related PKR inhibitors in a so‐far‐unpredictable manner. [ABSTRACT FROM AUTHOR]