Abstract
Abstract: :
Purpose: All viruses have one or more mechanisms to avoid the antiviral effects of the host interferon–inducible kinase PKR. HSV–1 mutants defective for expression of the PKR antagonist ICP34.5 display profound reductions in neurovirulence and do not replicate efficiently in certain cell types in culture. The relative roles of other HSV–encoded PKR antagonists, such as US11, however, have not been studied. The purpose of this study is to determine the role of US11 in viral replication, autophagy, neurovirulence, and pathogenesis, and to assess its contribution relative to ICP34.5. Methods: Recombinant viruses were generated that fail to express either US11 (Δ11) or both US11 and ICP34.5 (Δ11Δ34.5). Viruses were tested for their abilities to activate PKR, for replication in cell culture, for neurovirulence, and for pathogenesis in vivo using the mouse ocular model. Results: In cell culture Δ11 grew comparably to wild type virus, but the Δ11Δ34.5 showed an additional defect compared to a Δ34.5 mutant. Growth of all viruses were normalized in the presence of the autophagy inhibitor 3MA and in cells lacking PKR. The additional effect of mutating US11 was also seen in vivo following corneal infection of mice with significant changes in growth in corneas, periocular skin and brains. Conclusions: While ICP34.5 is essential for neurovirulence, US11 clearly acts to inhibit PKR function in vivo and in vitro. US11 is therefore a virulence determinant which serves to supplement the function of ICP34.5 and may play an independent role in the promotion of anterograde spread in vivo. US11 and ICP34.5 also likely serve to promote viral growth through suppression of the autophagy pathway.
Keywords: herpes simplex virus • immunomodulation/immunoregulation • cytokines/chemokines