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Hepatitis C Virus Attenuates Interferon-Induced Major Histocompatibility Complex Class I Expression and Decreases CD8+ T Cell Effector Functions

 Wonseok Kang  ;  Pil Soo Sung  ;  Su-Hyung Park  ;  Sarah Yoon  ;  Dong-Yeop Chang  ;  Seungtaek Kim  ;  Kwang Hyub Han  ;  Ja Kyung Kim  ;  Barbara Rehermann  ;  Yong-Joon Chwae  ;  Eui-Cheol Shin 
 GASTROENTEROLOGY, Vol.146(5) : 1351-1360, 2014 
Journal Title
Issue Date
Adaptive Immunity* ; CD8-Positive T-Lymphocytes/immunology* ; CD8-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/virology ; Cell Line, Tumor ; Coculture Techniques ; DNA Replication ; DNA, Viral/biosynthesis ; Down-Regulation ; Enzyme Activation ; Eukaryotic Initiation Factor-2/metabolism ; Genotype ; Hepacivirus/genetics ; Hepacivirus/growth & development ; Hepacivirus/immunology* ; Hepacivirus/metabolism ; Hepacivirus/pathogenicity ; Hepatocytes/immunology* ; Hepatocytes/metabolism ; Hepatocytes/virology ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/metabolism* ; Host-Pathogen Interactions ; Humans ; Interferons/metabolism* ; Phosphorylation ; RNA Interference ; Signal Transduction ; Transfection ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
Adaptive Immune Response ; Antigen Presentation ; Immune Evasion ; JFH-1
BACKGROUND & AIMS: Major histocompatibility complex (MHC) class I-restricted CD8(+) T cells are required for clearance of hepatitis C virus (HCV) infection. MHC class I expression is up-regulated by type I and II interferons (IFNs). However, little is known about the effects of HCV infection on IFN-induced expression of MHC class I.
METHODS:We used the HCV cell culture system (HCVcc) with the genotype 2a Japanese fulminant hepatitis-1 strain to investigate IFN-induced expression of MHC class I and its regulatory mechanisms. HCVcc-infected Huh-7.5 cells were analyzed by flow cytometry, metabolic labeling, immunoprecipitation, and immunoblotting analyses. Protein kinase R (PKR) was knocked down with lentiviruses that express small hairpin RNAs. The functional effects of MHC class I regulation by HCV were demonstrated in co-culture studies, using HCV-specific CD8(+) T cells.
RESULTS:Although the baseline level of MHC class I was not affected by HCV infection, IFN-induced expression of MHC class I was notably attenuated in HCV-infected cells. This was associated with replicating HCV RNA, not with viral protein. HCV infection reduced IFN-induced synthesis of MHC class I protein and induced phosphorylation of PKR and eIF2α. IFN-induced MHC class I expression was restored by small hairpin RNA-mediated knockdown of PKR in HCV-infected cells. Co-culture of HCV-specific CD8(+) T cells and HCV-infected cells that expressed HLA-A2 demonstrated that HCV infection reduced the effector functions of HCV-specific CD8(+) T cells; these functions were restored by small hairpin RNA-mediated knockdown of PKR.
CONCLUSIONS:IFN-induced expression of MHC class I is attenuated in HCV-infected cells by activation of PKR, which reduces the effector functions of HCV-specific CD8(+) T cells. This appears to be an important mechanism by which HCV circumvents antiviral adaptive immune responses.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Won Suk(강원석)
Kim, Seung Taek(김승택)
Kim, Ja Kyung(김자경) ORCID logo https://orcid.org/0000-0001-5025-6846
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
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