IL1β signaling mediates the interaction between hepatitis B and C viruses

Hepatitis B virus (HBV) and hepatitis C virus (HCV) share transmission routes and often coinfect the liver, leading to accelerated liver disease progression. In the era of direct-acting antivirals (DAAs) for HCV, the clinical impact of coinfection is further complicated by reports of HBV reactivation following HCV cure. While HCV-induced interferon (IFN) responses are known to suppress HBV, the underlying mechanisms remain incompletely understood. This study aimed to investigate how HCV modulates HBV infection in the setting of coinfection and to identify strategies to prevent HBV reactivation post-HCV clearance.

We utilized a multicellular liver culture model composed of human-induced pluripotent stem cell (hiPSC)-derived hepatocytes, hepatic stellate cells, and macrophages, which supports productive HBV and HCV infection and recapitulates clinical coinfection dynamics. We found that IL1β derived from HCV-activated macrophage suppresses HBV replication independent of IFN signaling. Mechanistically, IL1β downregulated the HBV receptor SLC10A1 in hepatocytes via induction of a truncated C/EBPβ isoform that negatively regulates the full-length variant. Concurrently, IL1β induced ISG20 expression through USF1 phosphorylation, further inhibiting HBV replication. A combination treatment of DAAs and an HBV entry inhibitor effectively prevented HBV reactivation in the model.

Our findings reveal a macrophage-derived, IFN-independent mechanism by which HCV suppresses HBV infection, mediated through IL1β. These insights highlight the complex crosstalk between hepatotropic viruses during coinfection and suggest that targeting IL1β-regulated pathways may offer therapeutic potential to prevent HBV reactivation in DAA-treated patients.