Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
J Clin Invest. 2020 Jun 1;130(6):3205-3220. doi: 10.1172/JCI135616.
In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons.
在 HBV 和 HCV 合并感染的患者中，已有报道称使用直接作用抗病毒药物（DAA）治疗 HCV 感染会导致 HBV 再激活，进而引发严重肝炎。在此，我们研究了这种病毒相互作用背后的分子机制。在合并感染的细胞培养和人源化小鼠中，HCV 合并感染抑制了 HBV 复制。体外实验中，当干扰素（IFN）信号通路被阻断时，HBV 抑制作用减弱。在体内，HBV 病毒血症在 HCV 超感染最初被抑制后，随着 DAA 治疗清除 HCV 而反弹，同时伴有肝内 IFN 反应降低。使用合并感染患者的血液样本，我们鉴定出包括 C-X-C 基元趋化因子 10（CXCL10）、C-C 基元趋化因子配体 5（CCL5）和丙氨酸氨基转移酶（ALT）在内的 IFN 刺激基因产物可预测 HCV 清除后 HBV 再激活。总之，我们的数据表明，HBV 再激活是 HCV 清除后肝内 IFN 反应减弱的结果，并确定了血清学标志物，可预测 DAA 治疗的 HBV-HCV 合并感染患者的 HBV 再激活。
