Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals

• Published in: PLoS genetics Vol. 15; no. 6; p. e1008181
• Main Authors: Perez, Shira, Kaspi, Antony, Domovitz, Tom, Davidovich, Ateret, Lavi-Itzkovitz, Anat, Meirson, Tomer, Alison Holmes, Jacinta, Dai, Chia-Yen, Huang, Chung-Feng, Chung, Raymond T, Nimer, Assy, El-Osta, Assam, Yaari, Gur, Stemmer, Salomon M, Yu, Ming-Lung, Haviv, Izhak, Gal-Tanamy, Meital
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.06.2019; Public Library of Science (PLoS)
• Subjects: Aged; Antiviral agents; Antiviral Agents - administration & dosage; Bioengineering; Bioinformatics; Biological response modifiers; Biology and Life Sciences; Biopsy; Cancer; Carcinoma; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - virology; Cell cycle; Chemotherapy; Chromatin; Chromatin - genetics; Diabetes; DNA methylation; Dosage and administration; Drug therapy; Enzymes; Epidemiology; Epidermal growth factor receptors; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; Epigenetic inheritance; Epigenetics; ErbB Receptors - antagonists & inhibitors; Erlotinib; Erlotinib Hydrochloride; Female; Funding; Gastroenterology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Genomes; Genomics; Health aspects; Hepacivirus - genetics; Hepacivirus - pathogenicity; Hepatitis; Hepatitis C; Hepatitis C - drug therapy; Hepatitis C - genetics; Hepatitis C - pathology; Hepatitis C - virology; Hepatitis C virus; Hepatocellular carcinoma; Histone Code - genetics; Histones - genetics; Hospitals; Host-Pathogen Interactions - genetics; Humans; Immunoprecipitation; Infection; Infections; Interferon; Interferons - administration & dosage; Internal medicine; Laboratories; Life cycles; Liver; Liver - drug effects; Liver - pathology; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - virology; Male; Medical prognosis; Medical research; Medicine and health sciences; Middle Aged; Mortality; Next-generation sequencing; Novels; Patient outcomes; Post-translation; Precision medicine; Proteins; Ribonucleic acid; Risk Factors; RNA; Signal Transduction - drug effects; Software; Sorafenib; Supervision; Sustained Virologic Response; Tumors; Viral proteins; Virology; Israel; United States > US; Massachusetts; Taiwan; Hong Kong China; Melbourne Victoria Australia; Tel Aviv Israel; Australia
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008181

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.