EPIGENETIC MODIFIER INHIBITORS INHIBIT HCV LIFE CYCLE AND REPLICATION, AND REVERSE THE "EPIGENETIC SIGNATURE" THAT IS IMPRINTED BY HCV

Shira Perez ^1,2 Anat Lavi-Itzkovitz ^1,3 Antony Kaspi ⁴ Ateret Davidovich ¹ Assam El-Osta ⁴ Gur Yaari ³ Izhak Haviv ² Meital Gal-Tanamy ¹

¹Molecular Virology Lab, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed
²Cancer Personalized Medicine and Diagnostic Genomics Lab, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed
³Systems Computational Biology, Faculty of Engineering, Bar-Ilan University, Ramat-Gan
⁴Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne

Hepatitis C virus (HCV) is a leading cause of hepatocellular carcinoma (HCC). While direct acting antivirals (DAAs) therapy efficiently eradicate HCV infection, epidemiological studies show that sustained virological response following anti-HCV treatment does not eliminate the risk for HCC.

We hypothesize that HCV infection promotes epigenetic alternations that affect host gene expression involved in cellular networks essential to HCV life cycle. Moreover HCV leaves an "epigenetic signature" on the host chromatin that can be reverted by epigenetic modifier drugs.

To evaluate the role of HCV-induced epigenetic alterations on viral life cycle we measured HCV infection and replication in epigenetic inhibitors treated cells. To inhibit H3K9Ac we used histone acetyl transferase inhibitor C646, HDAC inhibitors to inhibit deacetylation of H3K9, and EZH2 inhibitor EPZ-6438 to inhibit H3K27Me3. To evaluate whether epigenetic drugs inhibit virus entry and replication, we treated cells with epigenetic inhibitors prior or following HCV infection respectively. The results demonstrate inhibition of HCV by all tested inhibitors, with complete eradication of HCV in all-drugs combination. Moreover C646 treatment following DAA therapy shows reversibility of the epigenetic signature.

These results demonstrate that HCV-induced epigenetic missregulation are essential for the HCV life cycle. Moreover, since epigenetic changes are potentially reversible, this research may open new avenues to epigenetic modifying drugs utilization to revert the oncogenic effects of HCV infection to prevent HCC.