The inhibition of type I interferon signaling by herpes simplex virus 1

Viruses and their hosts are involved in an ongoing arms race, whereby host cells must protect themselves to survive and viruses must get past host defenses to successfully replicate. Type I interferon (IFNα/β) is an important non-specific antiviral cytokine that is induced by viral infection in many cell types. Pretreatment of cells with interferon inhibits replication of a number of viruses, including herpes simplex virus 1 (HSV-1). HSV-1 has evolved several mechanisms that antagonize type I IFN signaling. The HSV-1 ICP27 protein is necessary and sufficient to inhibit IFNαa-induced Stat-1 phosphorylation and nuclear accumulation. However, ICP27 is not necessary to inhibit interferon stimulated gene 15 (ISG15) expression, arguing that HSV-1 encodes at least two mechanisms of inhibition of the IFNα signaling pathway. Types I and II IFN signaling share Jak-1 and Stat-1 in their respective pathways, and though type I IFN signaling is inhibited by HSV-1, type II signaling is not. There is also ICP27-dependent inhibition of Jak-1 activation but no induction of the Jak-1 inhibitor, SOCS3. Though the IFNα receptor subunits IFNAR1 and IFNAR2 are stable during HSV-1 infection, there is internalization of IFNAR1 in some cells. These data suggest that ICP27-dependent inhibtion of IFNα signaling occurs at or before Jak-1 activation. Finally, HSV-1 infection and ICP27 expression alone stimulate the secretion of an IFNα-antagonizing factor. Preliminary characterization of this factor showed that it is heat-stable, protease-sensitive, and between 10-50 kDa. Because of the previously described roles of ICP27 in RNA processing, we hypothesized that this factor might be the secreted splice variant of IFNAR2. However, HSV-1 does not appear to alter the splicing or nuclear export of IFNAR2 mRNAs. Our data are consistent with at least two models of inhibition of IFNα-induced Stat-1 phosphorylation by HSV-1. The first is that ICP27 causes the internalization of the IFNα receptors, desensitizing cells to the effects of IFN treatment. The second is that ICP27 causes the secretion of a factor that competes for binding between IFNα and IFNAR. These studies have important implications for viral spread and may lead to the production of more effective vaccines and antiviral treatments.