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Persistence of HCV-Induced Perturbations of Cellular Pathways Post DAA Cure in Advanced Liver Disease

In the era of interferon (IFN)-alpha plus ribavirin therapy, a subset of Hepatitis C Virus (HCV) infected patients were cured of their virus but some patients still went on to develop hepatocellular carcinoma (HCC). While Directly Acting Antiviral (DAA) drugs are now able to cure the majority of HCV infections, even in subjects with advanced liver disease, what happens to liver disease upon DAA-induced cure of viremia is only beginning to emerge. In a very recent study of DAA cure of HCV in subjects with pre-existing liver cancer, the cancer appeared to undergo accelerated growth. This issue is controversial and currently a hotly debated topic because several studies have refuted this claim. 

What is apparent is that even if HCV is cured, we are only beginning to understand the issues that remain for the cured patient in regards to progression of liver disease and how such a rapid, DAA-induced uncoupling of a long-entrenched virus-host interaction affects cellular signaling pathways involved in liver disease. Our guiding idea is that the liver remains abnormal after DAA cure of HCV. Indeed, our preliminary data indicate that HCV-induced epigenetic marks persist after DAA cure of HCV, both in cell culture models and in human liver tissue, and that these epigenetic changes confer changes in liver gene expression and signal transduction pathways that promote liver cancer. More specifically, we hypothesize that in the liver, following DAA cure of HCV, persistence of epigenetic changes activates the phosphoinositol 3 kinase (PI3K) signaling pathway to promote progression of liver disease. The hypothesis will be tested in three Specific Aims that will deploy HCV-infectivity studies on human hepatoma, 3D human liver slice cultures, and an HCV-infectable mouse model of diet-induced HCC to define the mechanisms by which 1) HCV engages the epigenetic machinery, 2) DAA cure of HCV promotes PI3K signaling pathway, and 3) How diet-induced HCC is modulated by DAA cure of HCV infection in vivo. 

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