Hepatitis C virus attenuates interferon-induced major histocompatibility complex class I expression and decreases CD8+ T cell effector functions.
OBJECTIVE
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.
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Wonseok
W
Kang
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
Pil Soo
PS
Sung
Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Su-Hyung
SH
Park
Department of Microbiology, Ajou University School of Medicine, Suwon, Korea.
Sarah
S
Yoon
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
Dong-Yeop
DY
Chang
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Seungtaek
S
Kim
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Kwang Hyub
KH
Han
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Ja Kyung
JK
Kim
Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Barbara
B
Rehermann
Department of Microbiology, Ajou University School of Medicine, Suwon, Korea.
Yong-Joon
YJ
Chwae
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea. Electronic address: ecshin@kaist.ac.kr.
Eui-Cheol
EC
Shin
D056704:Adaptive Immunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis; D015536:Down-Regulation; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D004279:DNA, Viral; D015852:Eukaryotic Initiation Factor-2; D015395:Histocompatibility Antigens Class I; D007372:Interferons; D019892:eIF-2 Kinase
Adaptive Immune Response; Antigen Presentation; Immune Evasion; JFH-1