Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
Clin Mol Hepatol. 2023 Jan;29(1):65-76. doi: 10.3350/cmh.2022.0032. Epub 2022 Aug 12.
Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.
丙型肝炎病毒 (HCV) 感染在建立病毒持续性方面非常有效，导致肝硬化和肝细胞癌 (HCC) 的发展。直接作用抗病毒药物 (DAA) 是清除病毒的有前途的 HCV 治疗方法。然而，最近的报告表明，在 DAA 治疗后，肝硬化的 HCV 患者 HCC 发展的风险可能会增加。CD8+T 细胞参与控制 HCV 感染。然而，在慢性丙型肝炎患者中，观察到严重的 CD4+和 CD8+T 细胞功能障碍。这表明 HCV 可能采用机制来对抗或抑制宿主 T 细胞反应。病毒复制的主要部位是肝细胞，感染可引发共刺激分子的表达和免疫调节细胞因子的分泌。许多研究表明，HCV 感染肝细胞通过调节免疫调节分子的表达来损害抗病毒宿主免疫。与不存在 HCV 基因组的肝细胞相比，表达完整 HCV 蛋白的肝细胞上调程序性细胞死亡蛋白 1 (PD-1)、程序性死亡配体 1 (PD-L1) 和转化生长因子 β (TGF-β) 的配体的合成。重要的是，HCV 感染的肝细胞能够诱导调节性 CD4+T 细胞，释放表面显示 TGF-β 的外泌体，并产生滤泡调节性 T 细胞。最近的研究报告称，外泌体 microRNAs 的表达谱为 HCV 感染和 HCV 相关慢性肝病提供了生物标志物。更好地了解与 HCV 感染相关的免疫调节机制和鉴定与 HCV 感染相关的生物标志物将有助于设计针对 HCV 的疫苗以绕过 HCV 诱导的免疫失调并预防 HCV 相关的慢性肝病的发展。
