Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA.
Digestive Disease Research Center, Medical University of South Carolina, Charleston, SC, USA.
J Viral Hepat. 2021 Nov;28(11):1614-1623. doi: 10.1111/jvh.13593. Epub 2021 Aug 19.
Treatment of chronic hepatitis C virus with direct-acting antivirals usually eradicates infection, but liver fibrosis does not resolve concurrently. In patients who develop cirrhosis prior to hepatitis C virus treatment, hepatic decompensation and hepatocellular carcinoma can still occur after viral elimination due to residual fibrosis. We hypothesized the liver proteome would exhibit meaningful changes in inflammatory and fibrinogenic pathways change upon hepatitis C virus eradication, which could impact subsequent fibrosis regression. We analysed the liver proteome and phosphoproteome of paired liver biopsies obtained from 8 hepatitis C virus-infected patients before or immediately after treatment with direct-acting antivirals. Proteins in interferon signalling and antiviral pathways decreased concurrent with hepatitis C virus treatment, consistent with prior transcriptomic analyses. Expression of extracellular matrix proteins associated with liver fibrosis did not change with treatment, but the phosphorylation pattern of proteins present within signalling pathways implicated in hepatic fibrinogenesis, including the ERK1/2 pathway, was altered concurrent with hepatitis C virus treatment. Hepatitis C virus treatment leads to reduced expression of hepatic proteins involved in interferon and antiviral signalling. Additionally, changes in fibrosis signalling pathways are detectable before alteration in extracellular matrix proteins, identifying a putative chronology for the dynamic processes involved in fibrosis reversal.
直接作用抗病毒药物治疗慢性丙型肝炎病毒通常可根除感染，但肝纤维化不会同时消退。在丙型肝炎病毒治疗前发生肝硬化的患者中，由于残留纤维化，病毒消除后仍可能发生肝失代偿和肝细胞癌。我们假设，在丙型肝炎病毒根除后，肝脏蛋白质组在炎症和纤维蛋白生成途径中会发生有意义的变化，这可能会影响随后的纤维化消退。我们分析了 8 例丙型肝炎病毒感染患者在接受直接作用抗病毒药物治疗前后或即刻获得的配对肝活检的肝脏蛋白质组和磷酸蛋白质组。与丙型肝炎病毒治疗同时，干扰素信号和抗病毒途径中的蛋白质表达下降，与先前的转录组分析一致。与肝纤维化相关的细胞外基质蛋白的表达在治疗过程中没有变化，但与肝纤维发生相关的信号通路中的蛋白质的磷酸化模式，包括 ERK1/2 通路，在丙型肝炎病毒治疗时发生了改变。丙型肝炎病毒治疗导致参与干扰素和抗病毒信号的肝脏蛋白质表达减少。此外，在细胞外基质蛋白发生变化之前，纤维化信号通路的变化是可检测到的，确定了纤维化逆转涉及的动态过程的潜在时间顺序。
