Hepatitis B virus hijacks CTHRC1 to evade host immunity and maintain replication

Abstract

HepatitisBvirus (HBV) infection causes acuteand chronic liver diseases, but is not directly cytopathic. Liver injury results fromrepeated attempts of the cellular immune response system to control the viral infection. Here, we investigate the roles of cellular factors and signaling pathways involved in the regulation of HBV replication to reveal the mechanism underlying HBV infection and pathogenesis. Weshowthat collagen triple helix repeat containing 1(CTHRC1) expression is elevated in HBV-infected patients andin HBV-transfected cells through epigenetic modification and transcriptional regulation. CTHRC1 facilitates HBV replication in cultured cells and BALB/c mice by activating the PKCα/ERK/JNK/c-Jun cascade to repress the IFN/JAK/STAT pathway. HBV-activated CTHRC1 downregulates the activityof typeI interferon(IFN), theproductionof IFN-stimulatedgenes (ISGs),andthephosphorylationof signal transducerandactivator of transcription 1/2 (STAT1/2), whereas it upregulates the phosphorylation and ubiquitination of type I IFN receptors (IFNARα/β). Thus, our results showthat HBV uses a novelmechanismto hijack cellular factors and signal cascades in order to evade host antiviral immunity and maintain persistent infection.We also demonstrate that CTHRC1 has a novel role in viral infection.