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Abstract
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 (CD56dim and CD56bright) 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+ CD56dim 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.
Highlights
Chronic hepatitis C virus (HCV) infection is associated with persistent liver inflammation, which progresses to cirrhosis in ∼10–20% of patients over a period of 20–30 years [1]
At baseline, HCV cirrhotic patients presented an altered distribution of natural killer (NK) subsets (CD56dim and CD56bright) with higher expression of NKp46, HLA-DR, NKp30, KIR2DL2/L3, NKG2A, and CD85j receptors compared to healthy controls
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)]
Summary
Chronic hepatitis C virus (HCV) infection is associated with persistent liver inflammation, which progresses to cirrhosis in ∼10–20% of patients over a period of 20–30 years [1]. In the wake of successful IFN-free therapies, three studies reported rapid ontreatment restoration (by weeks 8 and 12) of NK cell phenotype and function This consisted of normalization of (i) NK cell receptor expression (NKp30, NKp46, HLA-DR, CD85j, and NKG2A), (ii) effector function [expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)], and (iii) IFNα-induced response (expression of the degranulation indicator CD107a and phosphorylation of signal transducer and activator of transcription 1-alpha/beta, pSTAT1) [11,12,13]. Of note, these studies included patients with mild to severe fibrosis without analyzing the impact of liver disease severity on NK cell normalization. Whether restoration of NK cells occurs after successful interferon (IFN)-free therapies remains a controversial issue
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