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Hepatitis C Virus Attenuates Interferon-Induced Major Histocompatibility Complex Class I Expression and Decreases CD8+ T Cell Effector Functions.
- Source :
- Gastroenterology (00165085); May2014, Vol. 146 Issue 5, p1351-1360.e4, 0p
- Publication Year :
- 2014
-
Abstract
- Background & Aims: Major histocompatibility complex (MHC) class I−restricted CD8<superscript>+</superscript> 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<superscript>+</superscript> 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<superscript>+</superscript> T cells and HCV-infected cells that expressed HLA-A2 demonstrated that HCV infection reduced the effector functions of HCV-specific CD8<superscript>+</superscript> 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<superscript>+</superscript> T cells. This appears to be an important mechanism by which HCV circumvents antiviral adaptive immune responses. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 00165085
- Volume :
- 146
- Issue :
- 5
- Database :
- Supplemental Index
- Journal :
- Gastroenterology (00165085)
- Publication Type :
- Academic Journal
- Accession number :
- 95583062
- Full Text :
- https://doi.org/10.1053/j.gastro.2014.01.054