An immunocompetent murine model of virus-elicited liver fibrosis and hepatocellular carcinoma.

[BACKGROUND & AIMS] Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Over 75% of HCC cases are associated with chronic viral infections. Mechanistic studies and preclinical therapeutic development for virus-associated HCC have been limited by a paucity of small animal models of chronic hepatotropic virus infection that faithfully recapitulate human disease.

[METHODS] We investigated chronic viral infection with Norway rat hepacivirus (NrHV) - a virus closely related to HCV - in immunocompetent laboratory mice. We assessed the development of chronic hepatitis, progressive liver fibrosis, and HCC. Liver tumors were histologically and molecularly characterized, and liver transcriptomes were analyzed to compare NrHV-induced changes with those observed in human HCV-associated disease.

[RESULTS] Chronic NrHV infection induced persistent hepatitis, progressive liver fibrosis, and HCC in immunocompetent mice. NrHV-elicited tumors closely resembled HCV-associated tumors. Transcriptome analyses revealed numerous similarities between chronic NrHV infection in mice and HCV infection in humans, including changes in pathways associated with fibrosis, inflammation, and oncogenesis.

[CONCLUSIONS] These findings establish an experimentally tractable, physiologically relevant, and immunocompetent mouse model of virus-elicited progressive liver fibrosis and oncogenesis.

[IMPACT AND IMPLICATIONS] The Norway rat hepacivirus-induced hepatocellular carcinoma model represents the first immunocompetent infectious system that faithfully recapitulates the multistage progression from chronic viral hepatitis to spontaneous hepatocellular carcinoma, bridging a long-standing translational gap between mechanistic mouse studies and human liver cancer. By mirroring the immunopathological, molecular, and sex-associated features of chronic HCV infection, this model provides an unparalleled platform to investigate virus-host interactions underlying fibrosis and oncogenesis. High hepatocellular carcinoma incidence and the genetically tractable C57BL/6 background further enhance experimental utility, enabling precise mechanistic dissection and genetic manipulation in a physiologically relevant setting. The capacity to study spontaneous tumor development in the context of natural infection allows for rigorous testing of antifibrotic and anti-cancer strategies, while the persistence of oncogenic potential after viral clearance raises important questions about irreversible disease reprogramming and elevated cancer risk following viral cure - issues of direct relevance to patients cured of HCV.