Insights into molecular mechanisms of poxvirus evolution and host range through studies of poxvirus inhibitors of protein kinase R

Protein kinase R (PKR) acts both as a sensor for virus infections, by detecting double-stranded (ds) RNA, and as an antiviral effector by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). Consequently, viruses have evolved many mechanisms to evade this potent antiviral protein, which in turn led to the fast evolution of PKR. There is an emerging understanding that these molecular arms races have important implications for the virulence and host range of viruses, which was in part propelled by research on PKR and poxvirus PKR inhibitors. At least four direct PKR pathway inhibitors, which either prevent PKR activation, inhibit interaction with eIF2α, or reverse eIF2α phosphorylation, evolved independently in different poxvirus clades, while poxvirus decapping enzymes provide another mechanism to subdue PKR activation via the reduction of dsRNA formation. In addition to discussing the functions and distributions of poxvirus PKR pathway inhibitors, we focus on host species-specific PKR-inhibitor interactions and their consequences for virus host range and virulence, including differential NF-κB pathway activation. We further highlight how research with PKR inhibitor-deficient poxviruses led to seminal discoveries elucidating molecular mechanisms for virus evolution, including gene amplification and horizontal gene transfer.