The increasing worldwide prevalence of Hepatocellular carcinoma (HCC), characterized by resistance to conventional chemotherapy, poor prognosis and eventually mortality, place it as a prime target for new modes of prevention and treatment. Hepatitis C Virus (HCV) is the predominant risk factor for HCC in the US and Europe. Multiple epidemiological studies showed that sustained virological responses (SVR) following treatment with the powerful direct acting antivirals (DAAs), which have replaced interferon-based regimes, do not eliminate tumor development. We aimed to identify an HCV-specific pathogenic mechanism that persists post SVR following DAAs treatment. We demonstrate that HCV infection induces genome-wide epigenetic changes by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) for histone post-translational modifications that are epigenetic markers for active and repressed chromatin. The changes in histone modifications correlate with reprogramed host gene expression and alter signaling pathways known to be associated with HCV life cycle and HCC. These epigenetic alterations require the presence of HCV RNA or/and expression of the viral proteins in the cells. Importantly, the epigenetic changes induced following infection persist as an "epigenetic signature" after virus eradication by DAAs treatment, as detected using in vitro HCV infection models. These observations led to the identification of an 8 gene signature that is associated with HCC development and demonstrate persistent epigenetic alterations in HCV infected and post SVR liver biopsy samples. The epigenetic signature was reverted in vitro by drugs that inhibit epigenetic modifying enzyme and by the EGFR inhibitor, Erlotinib. This epigenetic “scarring” of the genome, persisting following HCV eradication, suggest a novel mechanism for the persistent pathogenesis of HCV after its eradication by DAAs. Our study offers new avenues for prevention of the persistent oncogenic effects of chronic hepatitis infections using specific drugs to revert the epigenetic changes to the genome. Hepatitis C virus (HCV) is a leading cause of hepatocellular carcinoma (HCC) in western countries. While direct acting antivirals (DAAs) therapy for HCV efficiently eradicates the infection, sustained virological response (SVR) following anti-HCV treatment does not eliminate the risk for HCC development. With the 3–4 million newly infected cases each year, it is estimated that HCV-associated disease burden remains high in the next decade and the population of post-DAA-based SVR patients is expected to grow exponentially in the near future. Therefore, Post-SVR HCC is an emerging problem with an urgent unmet need for the elucidation of its molecular mechanisms for therapeutic target and biomarker discovery. We demonstrate that HCV-induce epigenetic missregulation. These HCV-induced epigenetic changes reprogram host gene expression and persist as an "epigenetic signature" following virus eradication. Treatment of HCV-cured cells with specific inhibitors reverted the epigenetic signature. These results suggest a "hit and run" scenario that may explain why some chronic HCV infected patients do proceed to develop HCC after HCV eradication. Our discoveries provide an insight into the outcomes of HCV infection and HCC development, also following SVR, and novel approaches for its prevention.

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