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

摘要 在干扰素（IFN）-α加利巴韦林治疗的时代，丙型肝炎病毒（HCV）感染患者的一个亚群 他们的病毒被治愈，但一些患者仍然发展为肝细胞癌（HCC）。虽然直接行动 抗病毒（DAA）药物现在能够治愈大多数HCV感染，即使在晚期肝病患者中也是如此。 疾病，DAA诱导的病毒血症治愈后肝脏疾病发生的情况才刚刚开始出现。后 在既往接受过HCC治疗的患者中治愈HCV，已经明确表明HCC复发 不会增加。然而，就像IFN治疗时代一样，晚期肝病患者仍然停留在 即使最初的损伤，即病毒，被DAA消除，也有发生HCC的风险。 这项修订后的申请旨在确定肝脏疾病风险的分子基础， DAA治愈HCV感染。我们的指导思想是HCV DAA治愈后肝脏仍然异常。 事实上，我们最近发表的和新的初步数据表明，HCV诱导的表观遗传，信号传导和 HCV的DAA治愈后基因表达扰动持续存在。这些数据来自DAA-HCV-治愈研究， 细胞培养物、人肝切片培养物、小鼠和人。此外，这些表观遗传变化 在已知促进肝癌的肝基因表达和信号转导途径中。我们假设 在肝脏中，HCV的DAA治愈后，表观遗传变化的持续激活了 磷酸肌醇3激酶（PI3K）信号通路，以促进肝脏疾病的进展。的 假设将在三个特定目的中进行检验，这些特定目的将在人肝癌细胞上进行HCV感染性研究， HCV和饮食的组合诱导肝病的小鼠模型，在3D人肝切片培养物上， 和人类肝脏组织中。这种全面和互补的方法将用于定义1）HCV 2）HCV的DAA治疗促进PI3K信号通路，以及3） 通过体内HCV感染的DAA治愈来调节病毒和饮食诱导的HCC的组合。 该R01汇集了在HCV-宿主相互作用，临床HCV病毒学和肝脏方面具有经验的研究人员 免疫学它将为快速治愈HCV的新时代的临床重要问题提供及时的见解 感染潜在的结局包括在DAA方案中添加以通路为重点的（例如PI3K）治疗， 在DAA时代降低肝病的风险。这些药物已经在开发用于其他适应症， 我们研究的明确结果可能是临床可行的。

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.