HSV-1-Induced SOCS-1 Expression in Keratinocytes: Use of a SOCS-1 Antagonist to Block a Novel Mechanism of Viral Immune Evasion

Abstract

Keratinocytes are important for the acute phase of HSV-1 infection and subsequent persistence in sensory nervous tissue. In this study, we showed that keratinocytes (HEL-30) were refractory to IFN-γ induction of an antiviral state to HSV-1 infection, while IFN-γ did induce an antiviral state in fibroblasts (L929). This led us to examine the possible role of suppressor of cytokine signaling-1 (SOCS-1) in this refractiveness. RT-PCR analysis of SOCS-1 mRNA expression in HSV-1-infected cells showed a 4-fold increase for keratinocytes while having a negligible effect on fibroblasts. A similar pattern was observed at the level of SOCS-1 protein induction. Activation of STAT1α in keratinocytes was inhibited by HSV-1 infection. A direct effect of HSV-1 on the SOCS-1 promoter was shown in a luciferase reporter gene assay. We have developed a small peptide antagonist of SOCS-1, pJAK2(1001–1013), that had both an antiviral effect in keratinocytes against HSV-1 as well as a synergistic effect on IFN-γ induction of an antiviral state. HSV-1 ICP0 mutant was inhibited by IFN-γ in HEL-30 cells and was less effective than wild-type virus in induction of SOCS-1 promoter. We conclude that SOCS-1 plays an important role in the inhibition of the antiviral effect of IFN-γ in keratinocytes infected with HSV-1. The use of SOCS-1 antagonist to abrogate this refractiveness could have a transformational effect on therapy against viral infections.

Human T Cell Leukemia Virus Type 1 Tax Inhibits Innate Antiviral Signaling via NF-κB-Dependent Induction of SOCS1

“…These findings have implications for HTLV-1-associated diseases, particularly HAM/ TSP which is associated with high Tax expression and a high proviral load. Small molecule antagonists of SOCS1 have been described (9) and may potentially be useful to reduce the proviral load in asymptomatic individuals who are at high risk for HAM/TSP. Since IFN-␣ is used in the clinic as a therapeutic for ATL and HAM/TSP patients (33), elevated SOCS1 may also confer resistance to antiviral drugs.…”

Viral Exploitation of Host SOCS Protein Functions

“…Importantly, type II IFNs are not sufficient to perform this function during the initial period of viral replication or during periodic outbreaks in keratinocytes. HSV-1 has been shown to induce the expression of SOCS1 specifically in HEL-30 keratinocytes but not in other cells such as L929 fibroblasts (18). HSV-1-induced SOCS1 expression correlates with inhibition of IFN-␥-induced STAT1 activation and enhanced viral replication in keratinocytes.…”

“…By binding the KIR of SOCS1 and preventing its function, pJAK2 has been shown to reverse the inhibition of SOCS1 overexpression on IL-6-induced STAT3 phosphorylation and to enhance reporter assay activity at the promoter of antiviral target genes in response to IFN-␥ (71). Keratinocytes, which are highly susceptible to HSV-1 infection due to virus-induced SOCS1 expression, are protected from HSV-1-induced death following pretreatment with pJAK2 (18). Treatment with pJAK2 alone enhances keratinocyte survival only modestly, while cotreatment with IFN-␥ results in complete protection.…”

Suppressor of cytokine signaling 1 expression in peripheral blood mononuclear cells of hepatitis C genotype 1 patients

“…Viral infections induce the expression of negative regulators of the IFN signaling pathway, such as SOCS1, which is associated with and inactivates JAK, inhibiting the phosphorylation of both IFN-a receptor and STAT proteins, 27,28 and downregulates the transcription of IFNstimulated genes. 29 Conversely, transfection of the HCV core protein in mouse liver silences SOCS-1 transcription, leading to permanent activation of the JAK/STAT signaling pathway.…”