title: Hepatitis C virus-induced NK cell activation causes metzincin-mediated CD16 cleavage and impaired antibody-dependent cytotoxicity.
abstract: The Fc receptor family for immunoglobulin (Ig)G type III (FcγRIII, CD16) is an activating receptor on natural killer (NK) cells and an essential mediator of antibody-dependent cellular cytotoxicity (ADCC). There is only limited information on its role during chronic hepatitis C virus (HCV) infection. We studied CD16 expression in relation to NK cell functional activity in HCV-infected patients and sought mechanistic insights into virus-induced modulation.
  
  
  
  NK cell CD16 expression and activation status were evaluated ex vivo by flow cytometry in HCV-infected patients and healthy controls (HC) as well as in vitro after co-culture with HCV-infected HuH7.5 cells. Rituximab-mediated ADCC was assessed in HC and HCV-infected patients using Daudi cells as a target. The role of metzincins in CD16 down-modulation was assessed using specific inhibitory molecules and by evaluating intracellular mRNA levels.
  
  
  
  HCV-infected patients exhibited increased frequencies of ex vivo activated NK cells and a concomitantly decreased NK CD16 expression, which resulted in impaired ADCC activity. Moreover, exposure of NK cells to culture-derived HCV recapitulated the ex vivo findings of decreased CD16 expression and increased NK cell activation. Importantly, blockade of metzincin-mediated shedding activity, including selective a disintegrin and metalloproteinase 17 (ADAM-17) inhibition, restored NK CD16 expression. Successful treatment with direct-acting antivirals partially improved NK ADCC function despite delayed CD16 reconstitution.
  
  
  
  Chronic HCV infection induces NK cell activation resulting in ADAM-17-dependent CD16 shedding and consequent impaired ADCC function. Altered ADCC may contribute to failure to eradicate HCV-infected hepatocytes.
  
  
  
  We show here that hepatitis C virus (HCV) activates natural killer (NK) lymphocytes which, as a consequence, loose their Fc receptor for IgG (CD16), an essential molecule for antibody binding. We show that this occurs through the action of enzymes named metzincins, resulting in altered NK-mediated antibody-dependent killing (ADCC) of target cells. This mechanism may contribute to HCV persistence and may represent a general phenomenon whereby some viruses can escape host's immune responses.
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Oliviero
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mantovani
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Varchetta
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy.
authors.forename: Dalila
authors.initials: D
authors.lastname: Mele
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Grossi
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ludovisi
authors.affiliation: Department of Pharmacy, University of Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.affiliation: Department of Pharmacy, University of Pisa, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy; Department of Internal Medicine and Therapeutics, University of Pavia, Italy. Electronic address: mario.mondelli@unipv.it.
authors.forename: Mario U
authors.initials: MU
authors.lastname: Mondelli
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity; D000998:Antiviral Agents / Q000627:therapeutic use; D002460:Cell Line; D018920:Coculture Techniques; D058851:GPI-Linked Proteins / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D006801:Humans; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D008213:Lymphocyte Activation; D045726:Metalloproteases / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D000072230:Sustained Virologic Response
chemical_list: D000998:Antiviral Agents; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG; D045726:Metalloproteases
keywords: ADAM-17; Anti-viral agents; Antibody-dependent cell cytotoxicity; CD69; DAAs; Disintegrins; FcγRIII; HCV; MMP9; Natural killer