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Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct-acting antivirals |
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| Authors: | Wenjie Bi Anke Kraft Sophie Engelskircher Jasmin Mischke Moana Witte Frank Klawonn Marco van Ham Markus Cornberg Heiner Wedemeyer Julia Hengst Lothar Jänsch |
| Affiliation: | 1. Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany;2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany TWINCORE, A Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany;3. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany;4. Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany Department of Computer Science, Ostfalia University, Wolfenbüttel, Germany;5. Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany;6. Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany Cluster of Excellence Resolving Infection Susceptibility (RESIST;7. EXC 2155), Hannover Medical School, Hannover, Germany These authors contributed equally.;8. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany These authors contributed equally. |
| Abstract: | Chronic hepatitis C virus (HCV) infections compromise natural killer (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 1 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 1 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 downregulation of vesicle transport components (CD107a, COPI/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 1 year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK-cell phenotype. |
| Keywords: | Direct-acting antivirals HCV NK cells NK-cell memory Proteomics |