Convergent Transcription of Interferon-Stimulated Genes by TNF-A and IFN-A Augments Antiviral Activity against HCV and HEV

Abstract

IFN- has been used for decades to treat chronic hepatitis B and C, and as an off-label treatment for some cases of hepatitis E virus (HEV) infection. TNF- is another important cytokine involved in inflammatory disease, which can interact with interferon signaling. Because interferon-stimulated genes (ISGs) are the ultimate antiviral effectors of the interferon signaling, this study aimed to understand the regulation of ISG transcription and the antiviral activity by IFN- and TNF-. In this study, treatment of TNF- inhibited replication of HCV by 71 2.4% and HEV by 41 4.9%. Interestingly, TNF- induced the expression of a panel of antiviral ISGs (2-11 fold). Blocking the TNF- signaling by Humira abrogated ISG induction and its antiviral activity. Chip-seq data analysis and mutagenesis assay further revealed that the NF-B protein complex, a key downstream element of TNF- signaling, directly binds to the ISRE motif in the ISG promoters and thereby drives their transcription. This process is independent of interferons and JAK-STAT cascade. Importantly, when combined with IFN-, TNF- works cooperatively on ISG induction, explaining their additive antiviral effects. Thus, our study reveals a novel mechanism of convergent transcription of ISGs by TNF- and IFN-, which augments their antiviral activity against HCV and HEV.