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

点击翻译按钮获取中文摘要

ABSTRACT 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 developed 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. After curing HCV in patients who had previously treated HCC, it has been conclusively shown that HCC recurrence does not increase. However, just like the IFN treatment era, patients with advanced liver disease still remain at risk for developing HCC even when the original insult, the virus, is eliminated by DAAs. This revised application seeks to define the molecular underpinnings for the liver disease risk that persists after DAA cure of HCV infection. Our guiding idea is that the liver remains abnormal after DAA cure of HCV. Indeed, our recently published and new preliminary data indicate that HCV-induced epigenetic, signaling and gene expression perturbations persist after DAA cure of HCV. The data derive from DAA-HCV-cure studies in cell culture, human liver slice cultures, mice, and humans. Moreover, these epigenetic changes confer changes in hepatic gene expression and signal transduction pathways known to promote liver cancer. 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 cells, a mouse model where the combination of HCV and diet induce liver disease, on 3D human liver slice cultures, and in human liver tissue. This comprehensive and complementary approach will be used to define how 1) HCV engages the epigenetic machinery, 2) DAA cure of HCV promotes PI3K signaling pathway, and 3) How the combination of virus and diet induced HCC is modulated by DAA cure of HCV infection in vivo. This R01 brings together investigators with experience in HCV-host interactions, clinical HCV virology, and liver immunology. It will provide timely insight into a clinically important issue in the new era of rapid cure of HCV infection. Potential outcomes include the addition of pathway-focused (e.g. PI3K) therapies to DAA regimens to reduce the risk of liver disease in the DAA era. Such drugs are already in development for other indications, so a clear outcome from our research may be clinically actionable.