title: Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα.
abstract: Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy.
  
  
  
  Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα.
  
  
  
  The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα.
  
  
  
  IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries.
  
  
  
  NCT01888900 and NCT00718172.
authors.affiliation: Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.|Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Serti
authors.affiliation: Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.|Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
authors.forename: Heiyoung
authors.initials: H
authors.lastname: Park
authors.affiliation: Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.|Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Keane
authors.affiliation: Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.|Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
authors.forename: Ashley C
authors.initials: AC
authors.lastname: O'Keefe
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
authors.forename: Elenita
authors.initials: E
authors.lastname: Rivera
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ghany
authors.affiliation: Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.|Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rehermann
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D007546:Isoquinolines / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011759:Pyrrolidines; D019233:Retreatment; D012254:Ribavirin / Q000627:therapeutic use; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000627:therapeutic use*; D000072230:Sustained Virologic Response; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D016898:Interferon-alpha; D007546:Isoquinolines; D011759:Pyrrolidines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir
keywords: HEPATITIS C; IMMUNE RESPONSE; IMMUNOLOGY; IMMUNOLOGY IN HEPATOLOGY