AUTHOR=Perpiñán Elena , Pérez-Del-Pulgar Sofía , Londoño María-Carlota , Mariño Zoe , Bartres Concepción , González Patricia , García-López Mireia , Pose Elisa , Lens Sabela , Maini Mala K. , Forns Xavier , Koutsoudakis George 

TITLE=Cirrhosis Hampers Early and Rapid Normalization of Natural Killer Cell Phenotype and Function in Hepatitis C Patients Undergoing Interferon-Free Therapy

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00129

DOI=10.3389/fimmu.2020.00129

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Aim:</bold> To analyze how HCV-related liver cirrhosis impacts changes in NK cells prior and post-IFN-free therapies.</p><p><bold>Methods:</bold> NK cell analysis by multicolor flow cytometry was performed in HCV-infected patients with (<italic>n</italic> = 17) and without (<italic>n</italic> = 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 (<italic>n</italic> = 12) and healthy individuals (<italic>n</italic> = 12) served as controls.</p><p><bold>Results:</bold> At baseline, HCV cirrhotic patients presented an altered distribution of NK subsets (CD56<sup>dim</sup> and CD56<sup>bright</sup>) 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<sup>+</sup> 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<sup>+</sup> CD56<sup>dim</sup> cells, as well as NK cell function, were rapidly and completely restored.</p><p><bold>Conclusions:</bold> NK cell phenotype alterations persist after HCV eradication in cirrhotic patients, while their function is only partially restored, compromising immune restoration and immunosurveillance.</p>