title: Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti-MicroRNA-122, RG-101.
abstract: MicroRNA-122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG-101, an N-acetylgalactosamine-conjugated anti-microRNA-122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG-101 therapy on antiviral immunity. Thirty-two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG-101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells were collected at multiple time points, and comprehensive immunological analyses were performed. Following RG-101 administration, HCV RNA declined in all patients (mean decline at week 2, 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma interferon-γ-induced protein 10 (IP-10) levels declined significantly upon dosing with RG-101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon-γ production decreased after RG-101 dosing. Functional HCV-specific interferon-γ T-cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post-RG-101 injection. No increase in the magnitude of HCV-specific T-cell responses was observed at later time points, including 3 patients who were HCV RNA-negative 76 weeks postdosing.
  
  
  
  Dosing with RG-101 is associated with a restoration of NK-cell proportions and a decrease of NK cells expressing activation receptors; however, the magnitude and functionality of ex vivo HCV-specific T-cell responses did not increase following RG-101 injection, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG-101 therapy. (Hepatology 2017;66:57-68).
authors.affiliation: Departments of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.|Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Stelma
authors.affiliation: Departments of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.|Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Meike H
authors.initials: MH
authors.lastname: van der Ree
authors.affiliation: Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Marjan J
authors.initials: MJ
authors.lastname: Sinnige
authors.affiliation: Nuffield Department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brown
authors.affiliation: Nuffield Department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, UK.
authors.forename: Leo
authors.initials: L
authors.lastname: Swadling
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: J Marleen L
authors.initials: JML
authors.lastname: de Vree
authors.affiliation: Departments of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Sophie B
authors.initials: SB
authors.lastname: Willemse
authors.affiliation: Departments of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van der Valk
authors.affiliation: Regulus Therapeutics, San Diego, CA.
authors.forename: Paul
authors.initials: P
authors.lastname: Grint
authors.affiliation: Regulus Therapeutics, San Diego, CA.
authors.forename: Steven
authors.initials: S
authors.lastname: Neben
authors.affiliation: Nuffield Department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Nuffield Department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Barnes
authors.affiliation: Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
authors.affiliation: Departments of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
mesh_terms: D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D058501:Enzyme-Linked Immunospot Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D007279:Injections, Subcutaneous; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008297:Male; D035683:MicroRNAs / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009426:Netherlands; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D035683:MicroRNAs