IL1β signaling mediates the interaction between hepatitis B and C viruses

作者：Fan Zhang, Yuanyuan Zhao, Lu Bian, Xinjia Wang, Eun‐Hee Ha, Lei Wang, Zhuoying Feng, Egan Sanchez, Andrew C. Kwong, Kyle O’Shaughnessy, Weibo Chen, Shuyang Chen, Suan‐Sin Foo, Weiqiang Chen, Liqun Ning, Yingpu Yu, Yujie Zhang, Viet Loan Dao Thi, Jianjun Wu, Xianfang Wu · 发表于：Hepatology · 年份：2025 · DOI：10.1097/hep.0000000000001525 · 被引用次数：3 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Hepatitis Viruses Studies and Epidemiology

BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: Our findings reveal a macrophage-derived, IFN-indepen...