Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct-acting antivirals.

Chronic hepatitis C virus (HCV) infections compromise NK cell immunity. Direct-acting antivirals (DAA) effectively eliminate HCV, but the long-term effects on NK cells in cured patients are debated. We conducted a proteomic study on CD56 + NK cells of chronic HCV-infected patients before, and one year after DAA therapy. Donor-variation was observed in NK cell proteomes of HCV-infected patients, with 46 dysregulated proteins restored after DAA therapy. However, 30% of the CD56 + NK cell proteome remained altered one year post-therapy, indicating a phenotypic shift with low donor-variation. NK cells from virus-negative cured patients exhibited global regulation of RNA-processing and pathways related to "stimuli response", "chemokine signaling", and "cytotoxicity regulation". Proteomics identified down-regulation of vesicle transport components (CD107a, COP I/II complexes) and altered receptor expression profiles, indicating an inhibited NK cell phenotype. Yet, activated NK cells from HCV patients before and after therapy effectively upregulated IFN-γ and recruited CD107a. Conversely, reduced surface expression levels of Tim-3 and 2B4 were observed before and after therapy. In conclusion, this study reveals long-term effects on the CD56 + NK cell compartment in convalescent HCV patients one year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK cell phenotype. This article is protected by copyright. All rights reserved.