The Intrinsic Innate Immunity of Hepatocytes Suppresses HBV Replication and Is Antagonized by HBx.

(1) Background: Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of viruses that interact with hepatocytes. HBV infection is a major global health problem. Most adults clear the infection quickly after being infected with HBV, while a few people develop chronic HBV infection. It is well-known that the early innate immune response of host cells plays an important role in the fight against virus infection. However, the interactions between HBV and the intrinsic innate immune system of hepatocytes are still not fully understood. The aim of this study was to confirm the interaction between HBV and hepatocytes, and to identify the interferon-stimulated genes (ISGs) regulated by HBx and their expression in association with HBV-associated HCC (HBV-HCC), so that we can refine our understanding of the interaction between HBV and ISGs and its potential influence on HBV-HCC. (2) Methods: We analyzed data concerning the stimulation of IFN-dependent genes in primary human hepatocytes (PHHs) transfected with pathogen DNA mimetics or infected with HBV in the GSE69590 database. Bioinformatic methods, such as GSEA, GO, and KEGG, were used to analyze the differentially expressed innate immunity genes and their related pathways to identify candidate intrinsic innate immune factors. qPCR on HepG2 and Huh7 cells, which highly express HBx, was used to detect relevant intrinsic innate immune factors. qPCR, RNAi, and Elisa methods were used to identify intrinsic innate immune factors in HBV-integrated HepG2.2.15 cells, and bioinformatics analysis was conducted on the HBV-infected tissues and cells in the GEO database. (3) Results: Inhibition of the JAK-STAT pathway enhanced HBV replication in HepG2 cells transfected with HBV plasmid and HepG2-NTCP cells infected with HBV. GSEA analysis of the GSE69590 data revealed significant changes in intrinsic innate immune pathways during HBV infection with PHH for 40 h. A total of 84 differentially expressed, candidate innate immunity genes were identified in GSE69590. Validation showed that and were down-regulated when HBx was expressed. Consistently, and were up-regulated following inhibition of HBx by transfection of HBx siRNA into HepG2.2.15 cells, and HBV pgRNA was up-regulated following down-regulated expression of and in HEK293 cells. Receiver operating characteristics (ROC) and overall survival (OS) analysis of 204 HBV-HCC patients showed that expression of was closely associated with HBV-HCC, and high expression of was associated with longer survival. (4) Conclusions: Innate immunity genes and are regulated by HBx, and higher expression of is closely related to longer survival of HBV-HCC patients.