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Genotype-Associated Differential NKG2D Expression on CD56+CD3+ Lymphocytes Predicts Response to Pegylated-Interferon/Ribavirin Therapy in Chronic Hepatitis C.

ABSTRACT: Hepatitis C virus (HCV) genotype 1 infections are significantly more difficult to eradicate with PEG-IFN/ribavirin therapy, compared to HCV genotype 2. The aim of this work is to investigate the difference of immunological impairments underlying this phenomenon. Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes and CD56+CD3- NK cells from cases of chronic hepatitis C were analyzed and assessed by treatment effect. Two strains of HCV were used to co-incubate with immune cells in vitro. NKG2D expression on peripheral CD56+CD3+ lymphocytes, but not NK cells, was significantly impaired in genotype 1 infection, compared to genotype 2. When peripheral blood mononuclear cells from healthy donors were co-incubated with TNS2J1, a genotype 1b/2a chimera strain, or with JFH1, a genotype 2a strain, genotype-specific decrease of NKG2D on CD56+CD3+ lymphocytes, but not NK cells, was observed.?Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes significantly correlated with reduction in serum HCV RNA levels from week 0 to week 4, and predicted treatment response. Ex vivo stimulation of peripheral CD56+CD3+ lymphocytes showed NKG2D expression-correlated IFN-? production. In conclusion, Decreased NKG2D expression on CD56+CD3+ lymphocytes in chronic HCV genotype 1 infection predicts inferior treatment response to PEG-IFN/ribavirin therapy compared to genotype 2.

SUBMITTER: Chu PS

PROVIDER: S-EPMC4428701 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genotype-Associated Differential NKG2D Expression on CD56+CD3+ Lymphocytes Predicts Response to Pegylated-Interferon/Ribavirin Therapy in Chronic Hepatitis C.

Chu Po-sung PS Ebinuma Hirotoshi H Nakamoto Nobuhiro N Sugiyama Kazuo K Usui Shingo S Wakayama Yuko Y Taniki Nobuhito N Yamaguchi Akihiro A Shiba Shunsuke S Yamagishi Yoshiyuki Y Wakita Takaji T Hibi Toshifumi T Saito Hidetsugu H Kanai Takanori T

PloS one 20150512 5

Hepatitis C virus (HCV) genotype 1 infections are significantly more difficult to eradicate with PEG-IFN/ribavirin therapy, compared to HCV genotype 2. The aim of this work is to investigate the difference of immunological impairments underlying this phenomenon. Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes and CD56+CD3- NK cells from cases of chronic hepatitis C were analyzed and assessed by treatment effect. Two strains of HCV were used to co-incubate with immune cells in ...[more]

PMID: 25965701

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Project description:Background and aim: Conventional hepatitis C treatment using pegylated interferon (PEG-IFN) and ribavirin is associated with significant side effects. IL28B polymorphism can predict response to treatment, with CC genotype having a better response. ITPA gene deficiency protects against clinically significant anaemia induced by treatment. The purpose of this study was to determine IL28B polymorphism and ITPA variation among hepatitis C genotype 1 patients who have undergone therapy with PEG-IFN and ribavirin and their association with sustained viral response (SVR). Methods: All hepatitis C genotype 1 patients who had been treated with PEG-IFN and ribavirin over the past 10 years were identified by available medical records and were contacted by letter of invitation to participate in the study. Blood samples for IL28B and ITPA genotyping were obtained. Medical records were reviewed for verification of treatment response, development of anaemia and if treatment reduction was required during the treatment. Results: A total of 61 patients with hepatitis C genotype 1 were treated with PEG-IFN and ribavirin, of whom 42 agreed to participate in the study. Mean age was 45.6±12.9 years at time of treatment, and 83.3% of patients were males. Thirty-three (78.6%) had IL28B CC genotype, of whom 25 (75.8%) obtained SVR compared with only 3 of 9 (33.3%) non C/C genotype patients who achieved SVR (P=0.041). Eleven (26.1%) patients had ITPA AC genotype, and 30 (71.4%) had CC genotype. There was no statistically significant difference between ITPA AC and CC genotypes in predicting clinically significant anaemia (45.5% vs 63.3%, P=0.302). Even among patients who developed anaemia, 70.8% still managed to achieve SVR. Treatment reduction also had no impact on SVR. Conclusion: Hepatitis C genotype 1 patients should be informed of the response rate for treatment with PEG-IFN and ribavirin in a population with favourable IL28B genotype before consideration of newer therapeutic options.

Project description:BACKGROUND:The standard treatment for patients with chronic hepatitis C (CHC), pegylated interferon-? (PEG-IFN) plus ribavirin (RBV) does not provide a sustained virological response (SVR) in all patients. Genetic variations at the interleukin 28B (IL-28B) locus are important in predicting outcome following therapy in CHC patients. RESULTS:We investigated the role of IL28B variations (rs8099917) in response to PEG-IFN-?/RBV treatment and evaluated its association with the risk of the null virological response (NVR) and relapse (REL) in different viral genotypes. We found that the overall distributions of the genotype among the SVR, NVR, and REL groups were significantly different (P < 0.001). Patients with the TG genotype had an increased risk of NVR and REL (OR = 6.45 95% CI = 2.88-14.47, P < 0.001 for NVR; OR = 2.51, 95% CI = 1.29-4.86, P = 0.006 for REL, respectively), and patients with the GG genotype had a further increased risk of NVR and REL (OR = 12.04, 95% CI = 3.21-45.13, P < 0.001 for NVR; ,OR = 4.30, 95% CI = 1.21-15.13, P = 0.017 for REL, respectively). G variant genotypes (TG+GG) also had an increased risk of NVR and REL, and there was a significant trend for a dose-effect of G allele on the risk of NVR and REL (P < 0.05). The SVR rate in TT higher than in TG+GG was more pronounced in those patients infected with non-G1 compared to the patients infected with G1. The treatment response did differ based on the rs8099917 genotype in patients with different viral genotypes, compared with patients infected with the non-G1, the G1 infected patients had an increased risk of NVR and REL (OR = 2.03 95% CI = 1.03-4.01, P = 0.04 for NVR and OR = 2.58, 95% CI = 1.35-4.94, P = 0.004 for REL, respectively). Moreover, multivariate regression analysis show that the rs8099917 G allele was the only independent factor significantly associated with a NVR and REL. CONCLUSION:This study suggests that host genetic polymorphisms rs8099917 in the vicinity of IL-28B is the most important predictor of treatment response of PEG-IFN-?/RBV for HCV patients in China.

Dataset Information

Genotype-Associated Differential NKG2D Expression on CD56+CD3+ Lymphocytes Predicts Response to Pegylated-Interferon/Ribavirin Therapy in Chronic Hepatitis C.

Publications

Genotype-Associated Differential NKG2D Expression on CD56+CD3+ Lymphocytes Predicts Response to Pegylated-Interferon/Ribavirin Therapy in Chronic Hepatitis C.

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