HERV-K10 as a mediator of immune modulation in hepatitis infections

The human genome contains ~8% of endogenous retroviruses (HERVs), which are implicated in diseases such as cancer and autoimmune disorders. Among these, HERV-K10 has attracted attention for its potential role in immune modulation and viral infections. This study investigates HERV-K10 expression in hepatitis virus infections, focusing on its impact on host gene expression and immune responses. We analysed HERV-K10 in PBMCs from patients chronically infected with hepatitis C virus (HCV) and in HBV-infected liver cell models. Our results show a significant upregulation of HERV-K10 in HBV-infected HepG2-NTCP cells, HCV-infected PBMCs and a trend in HBV-infected primary hepatocytes. HERV-K10 activation was specific to hepatitis infection, as no effect was seen with HBV entry inhibitors or adenovirus 5. RNA sequencing of HBV-infected HepG2-NTCP cells revealed distinct clustering based on HERV expression profiles, including HERV-K10 encoding the MAG1 domain, an immune response target. To investigate the potential immunomodulatory role of HERV-K10 MAG1, we vaccinated mice with the MAG1 peptide, which resulted in activation of CD4+ and CD8+ T-cell responses and higher levels of MAG1-specific antibodies. Furthermore, chronic HBV patients exhibited an immune response to MAG1 characterized by elevated levels of IL-6 and IL-1ß cytokines. Taken together, our data suggest that HERV-K10 plays an important role in immune modulation during viral hepatitis infection and may contribute to the pathogenesis of autoimmune diseases. Overall design: RNA-seq profiling of HBV-wt infected HepG2-NTCP cells two days post infection