The Herpes Simplex Virus Neurovirulence Factor γ34.5: Revealing Virus–Host Interactions
Fig 2
Reversal of the host shutoff of protein synthesis mediated by HSV γ34.5.
During viral infection, the host cell detects type I IFNs through the IFN receptor, activating the JAK-STAT pathway and up-regulating several interferon-stimulated genes (ISGs), one of which is the kinase PKR. Once activated by one of its ligands (dsRNA or PACT), a major function of PKR is to phosphorylate the host translation initiation factor eIF2α to cause translational arrest and global inhibition of both viral and host protein synthesis. However, the HSV γ34.5 protein binds the host phosphatase PP1α and retargets it to eIF2α for dephosphorylation and restoration of mRNA translation. Viruses mutant in only the two amino acids required for PP1α-binding are significantly attenuated for disease in models of encephalitis, disseminated disease, and HSV keratitis.