Department of Internal Medicine I, University of Bonn, Bonn, Germany, and the German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany.
Department of Internal Medicine I, University of Bonn, Bonn, Germany, and the German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany.
J Hepatol. 2017 May;66(5):888-896. doi: 10.1016/j.jhep.2016.12.019. Epub 2016 Dec 29.
BACKGROUND & AIMS: CD4 regulatory T cells (Tregs) expand during chronic hepatitis C virus (HCV) infection, inhibit antiviral immunity and promote fibrosis. Direct-acting antiviral agents (DAA) have revolutionized HCV therapy. However, it is unclear if Tregs are normalized after DAA-induced HCV elimination.
We analyzed Tregs before (baseline), at end of therapy (EOT), 12 and 24weeks (SVR12, SVR24) and long-term (51±14weeks) after EOT in 26 genotype-1-infected patients who were successfully treated with sofosbuvir (SOF) plus interferon (IFN)/ribavirin (n=12) and IFN-free DAA regimens (SOF plus daclatasvir or simeprevir; n=14). Frequency, phenotype and suppressor function of peripheral Foxp3 CD25 CD4 T cells were studied by multi-color flow cytometry and co-culture inhibition assays.
Frequencies and activation status of Foxp3 CD25 CD4 T cells remained elevated above those of normal controls in both treatment groups even long-term after HCV elimination. Co-culture assays indicated a dose-response relationship for functional inhibition of autologous CD4 effector T cells and confirmed that activation of Tregs remained largely unchanged over the observation period. Unlike IFN-free regimens, SOF plus IFN/ribavirin induced a transiently increased frequency of Foxp3 CD25 CD4 T cells at EOT (5.0% at baseline to 6.1% at EOT; p=0.001). These Foxp3 CD25 CD4 T cells co-expressed the activation markers glycoprotein A repetitions predominant (GARP; p=0.012) and tumor necrosis factor receptor superfamily, member 4 (OX-40; p=0.001) but showed unchanged in vitro inhibitory activity.
Although IFN-based DAA therapy induced transient expansion of activated Foxp3 CD25 CD4 T cells, neither IFN-based nor IFN-free DAA regimens normalized frequencies and activation status of Tregs one year after viral elimination. Persistence of immunosuppressive Tregs may thus contribute to complications of liver disease even long-term after HCV cure.
In chronic hepatitis C virus (HCV) infection, CD4 regulatory T cells (Tregs) can reduce antiviral immune responses, promote liver fibrosis and may increase the risk for liver cancer, because they gradually expand during disease. Modern direct-acting antiviral agents (DAA) can "cure" hepatitis C in almost all treated patients. However, our study shows that DAA do not normalize the increased frequency and activation status of Tregs even long-term after HCV elimination. Tregs may persistently modulate functions of the immune system even after "cure" of hepatitis C.
CD4 调节性 T 细胞（Tregs）在慢性丙型肝炎病毒（HCV）感染期间扩增，抑制抗病毒免疫并促进纤维化。直接作用抗病毒药物（DAA）彻底改变了 HCV 的治疗方法。然而，DAA 诱导 HCV 清除后 Tregs 是否恢复正常尚不清楚。
我们分析了 26 例基因型 1 感染患者在成功接受索非布韦（SOF）联合干扰素（IFN）/利巴韦林（n=12）和无 IFN 的 DAA 方案（SOF 联合达卡他韦或simeprevir；n=14）治疗后，在基线、治疗结束时（EOT）、12 周（SVR12）和 24 周（SVR24）以及 EOT 后 51±14 周时的 Tregs。通过多色流式细胞术和共培养抑制试验研究外周血 Foxp3 CD25 CD4 T 细胞的频率、表型和抑制功能。
即使在 HCV 清除后很长一段时间内，两组治疗中 Foxp3 CD25 CD4 T 细胞的频率和激活状态仍高于正常对照组。共培养试验表明，对自体 CD4 效应 T 细胞的功能抑制存在剂量反应关系，并证实 Tregs 的激活在整个观察期间基本保持不变。与无 IFN 的方案不同，SOF 联合 IFN/利巴韦林在 EOT 时会短暂增加 Foxp3 CD25 CD4 T 细胞的频率（基线时为 5.0%，EOT 时为 6.1%；p=0.001）。这些 Foxp3 CD25 CD4 T 细胞共表达激活标志物糖蛋白 A 重复为主（GARP；p=0.012）和肿瘤坏死因子受体超家族成员 4（OX-40；p=0.001），但体外抑制活性不变。
尽管 IFN 为基础的 DAA 治疗诱导了激活的 Foxp3 CD25 CD4 T 细胞的短暂扩增，但 IFN 为基础或无 IFN 的 DAA 方案均未能在病毒清除后 1 年内使 Tregs 的频率和激活状态正常化。因此，免疫抑制性 Tregs 的持续存在可能导致 HCV 治愈后长期发生肝脏疾病的并发症。
在慢性丙型肝炎病毒（HCV）感染中，CD4 调节性 T 细胞（Tregs）可以降低抗病毒免疫反应，促进肝纤维化，并可能增加肝癌的风险，因为它们在疾病过程中逐渐扩增。现代直接作用抗病毒药物（DAA）几乎可以治愈所有接受治疗的 HCV 患者。然而，我们的研究表明，即使在 HCV 清除后很长一段时间内，DAA 也不能使 Tregs 的增加频率和激活状态正常化。Tregs 甚至在 HCV 治愈后仍可能持续调节免疫系统的功能。
