title: Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons.
abstract: Hepatitis C virus (HCV)-specific impairments in host immunity have been described at multiple levels of the innate and adaptive response, which may lead to viral persistence in the majority of infections. Understanding of HCV-associated immune defects could lead to novel therapeutic advances. Natural killer (NK) cells, the major effector cells of the innate immune system, are functionally impaired in chronic HCV infection. It has been suggested that this phenotype is a result of virus-specific defects in antigen-presenting cells (APCs) that regulate NK cell activity, as normal NK function is restored when they are stimulated ex vivo. In this study, we used human NK cell cytotoxicity assays to evaluate the activation-induced effects of NK cells on the HCV replicon-containing hepatic cells. We found that cytokine-activated NK cells were capable of inducing an HCV-associated, perforin/granzyme-dependent lysis of human hepatoma cells and that this required direct cellular contact and was independent of MHC class I expression levels. In contrast, on removal of cytokine stimulation, NK cells failed to exert any direct cytolytic effect on replicon targets. These findings suggest an important underlying mechanism by which NK cells control HCV infection and, with appropriate understanding of HCV-associated immune defects, could lead to novel therapeutic advances.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. jonathan.2.larkin@gsk.com
authors.forename: Jonathan
authors.initials: J
authors.lastname: Larkin
authors.forename: Anne
authors.initials: A
authors.lastname: Bost
authors.forename: John I
authors.initials: JI
authors.lastname: Glass
authors.forename: Seng-Lai
authors.initials: SL
authors.lastname: Tan
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D006528:Carcinoma, Hepatocellular; D016207:Cytokines / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D012093:Replicon; D060225:Tetraspanin 28; D014407:Tumor Cells, Cultured; D014779:Virus Replication
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; D016207:Cytokines; D060225:Tetraspanin 28