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

• Published in: PloS one 2015-05, Vol.10 (5), p.e0125664
• Main Authors: Chu, Po-sung, Ebinuma, Hirotoshi, Nakamoto, Nobuhiro, Sugiyama, Kazuo, Usui, Shingo, Wakayama, Yuko, Taniki, Nobuhito, Yamaguchi, Akihiro, Shiba, Shunsuke, Yamagishi, Yoshiyuki, Wakita, Takaji, Hibi, Toshifumi, Saito, Hidetsugu, Kanai, Takanori
• Format: Article
• Language: English
• Subjects: Aged; Antiviral Agents - administration & dosage; Antiviral Agents - therapeutic use; Antiviral drugs; CD3 antigen; CD3 Complex - genetics; CD3 Complex - metabolism; CD56 antigen; CD56 Antigen - genetics; CD56 Antigen - metabolism; Chimeras; Chronic infection; Cytotoxicity; DNA methylation; Dosage and administration; Drug Combinations; Female; Gastroenterology; Gene expression; Genetic aspects; Genotype; Genotype & phenotype; Hepacivirus - genetics; Hepatitis; Hepatitis C; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Hepatology; Humans; Immune system; Immunology; Infections; Infectious diseases; Interferon; Interferon-alpha - administration & dosage; Interferon-alpha - therapeutic use; Interferons; Interleukins - genetics; Internal medicine; Leukocytes (mononuclear); Liver; Lymphocytes; Lymphocytes - metabolism; Male; Medicine; Middle Aged; Natural killer cells; NK Cell Lectin-Like Receptor Subfamily K - genetics; NK Cell Lectin-Like Receptor Subfamily K - metabolism; NKG2 antigen; Patients; Peripheral blood mononuclear cells; Physiological aspects; Polyethylene glycol; Polymorphism, Single Nucleotide; Proteins; Ribavirin; Ribavirin - administration & dosage; Ribavirin - therapeutic use; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Studies; T cell receptors; Therapy; Treatment Outcome; Virology; Viruses; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0125664

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-γ 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.