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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 
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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
강원석(Kang, Won Suk)
김승택(Kim, Seung Taek)
김자경(Kim, Ja Kyung) ORCID logo https://orcid.org/0000-0001-5025-6846
한광협(Han, Kwang-Hyub) ORCID logo https://orcid.org/0000-0003-3960-6539
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