title: Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C.
abstract: Natural killer (NK) cells constitute a first line of defense against viral infections; their function is governed by the integration of signals from multiple activating and inhibitory surface receptors. We hypothesized that because NKs become rapidly activated by cytokines, response to anti-hepatitis C virus (HCV) therapy would be predicted by the phenotype and function of NKs. We used a cohort of 101 patients (55 African, 46 Caucasian-American) who received pegylated-interferon (IFN) and ribavirin for 48 weeks. Multiparameter FACS analysis was used to examine relative expression of 14 different inhibitory/activating receptors. Interleukin (IL)-28B genotyping (rs12979860) was also performed. Pretreatment levels of inhibitory receptors CD158a, CD158b, and CD158e were higher in patients who demonstrated poor viral decline within the first 28 days of therapy. Higher expression levels of inhibitory receptors NKG2A, CD158b, and CD158e were demonstrable in patients who failed to achieve sustained virologic response (SVR). Patients carrying the IL-28B T allele had higher NKG2A expression on effector NKs. We created a mathematical regression model incorporating race, viral level, and two inhibitory receptors. The area-under-the curve was 0.88, which is highly predictive of SVR. Moreover, the model performed complementarily with IL-28B across the CC, CT, and TT genotypes. Purified NKG2A(neg) NKs treated with pegylated-IFN-α for 4 hours demonstrated higher levels of IFN-γ-inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) compared with their NKG2A(pos) counterparts.
  
  
  CONCLUSIONS
  These results provide novel insights into the associations of NK phenotype with IL-28B genotype and gene expression patterns, as well as the role of NKs in mediating IFN-induced viral clearance of chronic HCV infection.
authors: Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver & National Jewish Hospital, Denver, CO, USA.
authors: Lucy
authors: L
authors: Golden-Mason
authors: Kiran M
authors: KM
authors: Bambha
authors: Linling
authors: L
authors: Cheng
authors: Charles D
authors: CD
authors: Howell
authors: Milton W
authors: MW
authors: Taylor
authors: Paul J
authors: PJ
authors: Clark
authors: Nezam
authors: N
authors: Afdhal
authors: Hugo R
authors: HR
authors: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics / Q000276:immunology; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D054342:Receptors, KIR2DL1 / Q000378:metabolism; D054344:Receptors, KIR2DL3 / Q000378:metabolism; D054341:Receptors, KIR3DL1 / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000378:metabolism*; D017211:Treatment Failure; D055815:Young Adult; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D008565:Membrane Proteins; D055654:NK Cell Lectin-Like Receptor Subfamily C; D053633:Receptor, Interferon alpha-beta; D054342:Receptors, KIR2DL1; D054344:Receptors, KIR2DL3; D054341:Receptors, KIR3DL1; D055607:Receptors, Natural Killer Cell; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C093100:KIR2DL1 protein, human; C515078:KIR2DL3 protein, human; C515083:KIR3DL1 protein, human