Abstract
Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.
Highlights
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide
The present study examined human leukocyte antigen (HLA), killer immunoglobulin-like receptor (KIR), and IL28B gene variant associations with an sustained virological response (SVR) following PEG-IFN and ribavirin therapy in Japanese patients with chronic hepatitis C
We found a significant association of HLA-Bw alleles with treatment outcome, the frequency of HLA-C alleles did not differ significantly between responders and nonresponders
Summary
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. Chronic HCV infection often develops into chronic hepatitis, which may progress to liver cirrhosis and/or hepatocellular carcinoma (HCC)[1]. Natural killer (NK) cells are key components of the innate antiviral immune response that are controlled by a balance of activation and inhibitory receptors. NK cell activation receptors include C-type lectin-like receptors (NKG2C, NKG2D, and NKG2E), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), and CD16, while known inhibitory receptors include killer cell immunoglobulin-like receptors (KIRs) and the CD94/ NKG2 family, which contains a C-type lectin-like receptor (NKG2A) [3,4]. KIR2DL2 and KIR2DL3 recognize HLA-B*4601 acquiring the-C1 epitope by gene conversion [6]. KIR3DL1 recognizes subsets of HLA-A and HLA-B allotypes having the Bw4 epitope determined by amino acid positions 77-83 [7]
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