Background: Chronic hepatitis C virus (HCV) infection impairs natural killer (NK) cell phenotype and function. Whether restoration of NK cells occurs after successful interferon (IFN)-free therapies remains a controversial issue.

Aim: To analyze how HCV-related liver cirrhosis impacts changes in NK cells prior and post-IFN-free therapies.

Methods: NK cell analysis by multicolor flow cytometry was performed in HCV-infected patients with (n = 17) and without (n = 14) cirrhosis at baseline, week 4 during therapy, and weeks 12 and 48 after the end of therapy (FU12 and FU48, respectively). Non-HCV cirrhotic patients (n = 12) and healthy individuals (n = 12) served as controls.

Results: At baseline, HCV cirrhotic patients presented an altered distribution of NK subsets (CD56^dim and CD56^bright) with higher expression of NKp46, HLA-DR, NKp30, KIR2DL2/L3, NKG2A, and CD85j receptors compared to healthy controls. All frequencies normalized by FU48, except for CD85j⁺ cells. Likewise, substantial alterations were detected in NK cell function assessed by (i) signal transducer and activator of transcription 1 (STAT1) and phosphorylated levels of STAT1 and STAT4, (ii) degranulation (CD107a), (iii) cytotoxicity [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)], and (iv) cytokine production [IFN-γ and tumor necrosis factor-α (TNF-α)]. Of note, NK cell function at FU48 remained partially impaired. In contrast, non-cirrhotics showed normal baseline frequencies of HLA-DR-, NKG2A-, and CD85j-expressing NK cells. Importantly, altered baseline frequencies of NK cell subsets and NKp46⁺ CD56^dim cells, as well as NK cell function, were rapidly and completely restored.

Conclusions: NK cell phenotype alterations persist after HCV eradication in cirrhotic patients, while their function is only partially restored, compromising immune restoration and immunosurveillance.

背景：慢性丙型肝炎病毒 (HCV) 感染会损害自然杀伤 (NK) 细胞表型和功能。成功的无干扰素 (IFN) 治疗后 NK 细胞是否会恢复仍然是一个有争议的问题。

目的：分析 HCV 相关肝硬化如何影响无干扰素治疗前后 NK 细胞的变化。

方法：通过多色流式细胞术对 HCV 感染患者进行 NK 细胞分析（n= 17) 且没有 (n= 14) 基线、治疗期间第 4 周以及治疗结束后第 12 周和第 48 周出现肝硬化（分别为 FU12 和 FU48）。非 HCV 肝硬化患者（n= 12) 和健康个体 (n= 12) 作为对照。

结果：在基线时，与健康对照相比， HCV 肝硬化患者的 NK 亚群（CD56^暗淡和 CD56^亮）分布发生改变， NKp46、HLA-DR、NKp30、KIR2DL2/L3、NKG2A 和 CD85j 受体表达较高。除 CD85j ⁺细胞外，所有频率均由 FU48 归一化。同样，通过（i）信号转导器和转录激活剂1（STAT1）以及STAT1和STAT4的磷酸化水平，（ii）脱颗粒（CD107a），（iii）细胞毒性[肿瘤坏死因子-相关的凋亡诱导配体 (TRAIL)]，以及 (iv) 细胞因子的产生 [IFN-γ 和肿瘤坏死因子-α (TNF-α)]。值得注意的是，FU48 的 NK 细胞功能仍然部分受损。相比之下，非肝硬化患者表达 HLA-DR、NKG2A 和 CD85j 的 NK 细胞的基线频率正常。^{重要的是，NK 细胞亚群和 NKp46 +} CD56^暗细胞的基线频率改变以及 NK 细胞功能都得到了快速、完全的恢复。

结论：肝硬化患者的 HCV 根除后，NK 细胞表型改变持续存在，但其功能仅部分恢复，损害了免疫恢复和免疫监视。