title: Immunological Analysis During Interferon-Free Therapy for Chronic Hepatitis C Virus Infection Reveals Modulation of the Natural Killer Cell Compartment.
abstract: BACKGROUND
  Chronic hepatitis C virus (HCV) infection is a global health problem, resulting in liver failure, hepatocellular carcinoma, and liver-related death. Natural killer (NK) cells are innate immune cells, and their activity is known to correlate to viral treatment response of HCV. In this study, we investigate the immune effects of viral load decline with direct-acting antivirals (DAAs) in blood.
  
  
  METHODS
  Twelve patients with chronic HCV were treated with asunaprevir and daclatasvir, and peripheral blood was analyzed at various time points during therapy.
  
  
  RESULTS
  In line with previous studies, we confirmed restoration of HCV-specific T-cell frequency upon viral load decline. In addition, we show that serum interferon (IFN)-γ inducible-protein 10, interleukin (IL)-12p40, and IL-18 levels decreased early after start of therapy. Surface expression of activation receptors NKp30, NKp46, and inhibitory receptor NKG2A on blood NK cells reduced during therapy. In addition, the expression of TRAIL on NK cells was reduced during IFN-free therapy, suggesting a decrease in TRAIL-mediated killing by NK cells.
  
  
  CONCLUSIONS
  We show that viral load decline as a consequence of treatment with novel DAAs in chronic HCV patients reduces serum levels of NK cell-stimulating cytokines and causes correction of the altered NK cell phenotype observed in chronic HCV patients.
  
  
  BACKGROUND
  NCT02282709.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: Spaan
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Gertine
authors.initials: G
authors.lastname: van Oord
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Kreefft
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Jun
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands Division of Gastroenterology, Liver Clinic University Health Network, University of Toronto, Ontario, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Andre
authors.initials: A
authors.lastname: Boonstra
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use; D002219:Carbamates; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007546:Isoquinolines / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D011759:Pyrrolidines; D012367:RNA, Viral; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000502:physiology; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D016207:Cytokines; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D012367:RNA, Viral; D011971:Receptors, Immunologic; D013449:Sulfonamides; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir
keywords: DAA therapy; HCV-specific T cells; TNF-related apoptosis-induced ligand (TRAIL); interferon-stimulated genes (ISGs); viral hepatitis