title: Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B.
abstract: OBJECTIVE
  Natural killer (NK) cells play a major role in anti-viral immunity as first line defense and regulation of virus-specific T cell responses. This study aimed to investigate phenotype and function of NK cells in patients with chronic hepatitis B virus (HBV) infection and to study the effect of anti-viral therapy.
  
  
  METHODS
  Peripheral blood NK cells from 40 chronic HBV patients were compared to NK cells of 25 healthy controls. The effect of entecavir-induced viral load reduction on NK cell phenotype and function was investigated in 15 chronic HBV patients.
  
  
  RESULTS
  NK cell numbers and subset distribution did not differ between HBV patients and normal subjects. In chronic HBV patients, the cytotoxic capacity was retained, but NK cell activation and subsequent IFNγ and TNFα production, especially of the CD56(dim) subset, were strongly hampered. This functional dichotomy was paralleled by an altered activation state, elevated expression of NKG2A, and downregulated expression of CD16 and NKp30, which correlated with serum HBV-DNA load. Anti-viral therapy partially restored NK cell phenotype, as shown by NKG2A downregulation. Moreover, viral replication inhibition improved IFNγ production as a result of an increased ability of CD56(dim) NK cells to become activated de novo. This improved NK cell activation and function which correlated with therapy-induced reduction in serum ALT levels, but not HBV-DNA load.
  
  
  CONCLUSIONS
  The specific defect in CD56(dim) NK cell activation and the reduced capacity to produce anti-viral and Th1-skewing cytokines may play a role in HBV persistence. Restoration of this NK cell cytokine-producing capacity, as achieved by viral load reduction, could therefore contribute to definite clearance of the virus.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Eric T T L
authors.initials: ET
authors.lastname: Tjwa
authors.forename: Gertine W
authors.initials: GW
authors.lastname: van Oord
authors.forename: Joost P
authors.initials: JP
authors.lastname: Hegmans
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Woltman
mesh_terms: D000328:Adult; D019002:CD56 Antigen / Q000032:analysis; D003430:Cross-Sectional Studies; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000032:analysis; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006684:HLA-DR Antigens / Q000032:analysis; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000032:analysis; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000032:analysis; D017452:Receptors, IgG / Q000032:analysis; D019562:Viral Load
chemical_list: D019002:CD56 Antigen; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D006684:HLA-DR Antigens; C522918:NCAM1 protein, human; C431710:NCR3 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055628:Natural Cytotoxicity Triggering Receptor 3; D017452:Receptors, IgG; C413685:entecavir; D006147:Guanine; D007371:Interferon-gamma