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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1351-1360.e4
JournalGastroenterology
Volume146
Issue number5
DOIs
Publication statusPublished - 2014 May

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'Hepatitis C virus attenuates interferon-induced major histocompatibility complex class i expression and decreases CD8<sup>+</sup> T cell effector functions'. Together they form a unique fingerprint.

  • Cite this

    Kang, W., Sung, P. S., Park, S. H., Yoon, S., Chang, D. Y., Kim, S., Han, K. H., Kim, J. K., Rehermann, B., Chwae, Y. J., & Shin, E. C. (2014). Hepatitis C virus attenuates interferon-induced major histocompatibility complex class i expression and decreases CD8+ T cell effector functions. Gastroenterology, 146(5), 1351-1360.e4. https://doi.org/10.1053/j.gastro.2014.01.054