title: Hepatitis B viral replication influences the expression of natural killer cell ligands.
abstract: BACKGROUND
  Hepatitis B virus (HBV) is accounting for over one million deaths annually due to immune-mediated chronic liver damage. Natural killer (NK) cells are abundant in the liver and contribute in HBV persistence. NK cytotoxic effects are controlled by signals from activating and inhibitory receptors. HBV may circumvent host antiviral immunity via the regulation of NK receptors and their ligands. We investigated the effect of viral replication and HBeAg mutations on NK mediators expression in the livers of chronic HBV (CHB) patients and in cell cultures.
  
  
  METHODS
  HBV monomers bearing hotspot mutations in the basal core promoter and precore region were transfected into HepG2 cells using a plasmid-free assay. Serum viremia and liver HBV RNA were measured in 19 CHB patients. The expression of HBV RNA and of NKG2D ligands, B7H6, DNAX accessory molecule-1, lectin-like transcript 1 (LLT1), LFA-1 and TRAIL was measured in the livers of CHB patients and transfected cells.
  
  
  RESULTS
  In general, high HBV replication in CHB patients and cell lines upregulated the mRNA of all NK cell ligands and particularly the inhibitory NK cell ligand, LLT1. The exception was the NKG2D ligand, MICA, that was significantly decreased in patients with high serum viremia and intrahepatic HBV RNA levels.
  
  
  CONCLUSIONS
  HBV replication has differential effects on NK cell ligands suggesting a potential escape mechanisms through up-regulation of LLT1 and down-regulation of MICA. A general trend towards upregulating NK cell ligands can be counteracted by decreasing MICA and hence weakening NK surveillance.
authors.affiliation: Department of Medicine, Hepatology and Gastroenterology Section, Imperial College, St. Mary's Campus, London, UK (Lemonia Koumbi, Naveenta Kumar).
authors.forename: Lemonica
authors.initials: L
authors.lastname: Koumbi
authors.affiliation: Department of Pediatric, Gynecologic, Microbiologic, and Biomedical Sciences, University Hospital of Messina, Messina, Italy (Teresa Pollicino).
authors.forename: Teresa
authors.initials: T
authors.lastname: Pollicino
authors.affiliation: Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy (Giovanni Raimondo).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Raimondo
authors.affiliation: Department of Medicine, Hepatology and Gastroenterology Section, Imperial College, St. Mary's Campus, London, UK (Lemonia Koumbi, Naveenta Kumar).
authors.forename: Naveenta
authors.initials: N
authors.lastname: Kumar
authors.affiliation: University of Nicosia Medical School, Nicosia, Cyprus (Peter Karayiannis).
authors.forename: Peter
authors.initials: P
authors.lastname: Karayiannis
authors.affiliation: Henry Welcome Laboratories, Southampton General Hospital, Southampton, UK (Salim I. Khakoo).
authors.forename: Salim I
authors.initials: SI
authors.lastname: Khakoo
keywords: Hepatitis B virus; LLT1; NK cells; NKG2D; mutations; precore; viral replication; virus