title: Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines.
abstract: Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U986, Hôpital St-Vincent de Paul, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Sène
authors.forename: Franck
authors.initials: F
authors.lastname: Levasseur
authors.forename: Michal
authors.initials: M
authors.lastname: Abel
authors.forename: Marion
authors.initials: M
authors.lastname: Lambert
authors.forename: Xavier
authors.initials: X
authors.lastname: Camous
authors.forename: Céline
authors.initials: C
authors.lastname: Hernandez
authors.forename: Véronique
authors.initials: V
authors.lastname: Pène
authors.forename: Arielle R
authors.initials: AR
authors.lastname: Rosenberg
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jouvin-Marche
authors.forename: Patrice N
authors.initials: PN
authors.lastname: Marche
authors.forename: Patrice
authors.initials: P
authors.lastname: Cacoub
authors.forename: Sophie
authors.initials: S
authors.lastname: Caillat-Zucman
mesh_terms: D000328:Adult; D000368:Aged; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D018836:Inflammation Mediators / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D055655:NK Cell Lectin-Like Receptor Subfamily K; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase