Hepatitis C Virus Inhibits Cell Surface Expression of HLA-DR, Prevents Dendritic Cell Maturation, and Induces Interleukin-10 Production

Departments of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.
Journal of Virology (Impact Factor: 4.44). 05/2008; 82(7):3320-8. DOI: 10.1128/JVI.02547-07
Source: PubMed


Hepatitis C virus (HCV) chronic infection is characterized by low-level or undetectable cellular immune responses against HCV antigens. HCV proteins have been shown to affect various intracellular events and modulate immune responses, although the precise mechanisms used to mediate these effects are not fully understood. In this study, we have examined the effect of HCV proteins on the modulation of major histocompatibility complex (MHC) class II expression and other functions important for antigen presentation in humans. Expression of an HCV(1-2962) genomic clone (HCV-FL) in human fibrosarcoma cells (HT1080) inhibited gamma interferon (IFN-gamma)-induced upregulation of human leukocyte antigen-DR (HLA-DR) cell surface expression. Furthermore, inhibition of promoter activities of MHC class II transactivator (CIITA), IFN-gamma-activated site (GAS), and HLA-DR was observed in IFN-gamma-inducible HT1080 cells expressing HCV-FL by in vitro reporter assays. Exposure of human monocyte-derived dendritic cells (DCs) to cell culture-grown HCV (HCVcc) genotype 1a (clone H77) or 2a (clone JFH1) significantly inhibited DC maturation and was associated with the production of IL-10. Furthermore, DCs exposed to HCVcc were impaired in their functional ability to stimulate antigen-specific CD4-positive (CD4(+)) and CD8(+) T-cell responses. Taken together, our results indicated that HCV can have direct and/or indirect inhibitory effects on antigen-presenting cells, resulting in reduction of antigen-specific T-cell activation. These effects may account for or contribute to the low overall level of immunogenicity of HCV observed in chronically infected patients.

Download full-text


Available from: Getahun Abate, Feb 14, 2014
  • Source
    • "In vitro experiments have effectively shown that upon exposure of human mo-DCs to cell culture-grown HCV (HCVcc) genotype 1a or 2a, there was a significant inhibition of DC maturation and was associated with low HLA-DR expression and high production of IL-10. Furthermore, DCs exposed to HCVcc were impaired in their functional ability to stimulate antigen-specific CD4+ and CD8+ T cell responses69. DCs, upon exposure to HCV core protein, showed downregulation of major histocompatibility molecules (HLA-DR) and co-stimulatory molecules (CD80, CD86) and induction of IL-10 producing T cells70. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic hepatitis C infection poses a major global health predicament and appears to be potent threat to mankind. The treatment in wide use is interferon/ribavirin combination therapy which is generally effective in about 60-70 per cent of patients carrying genotype 3 and causes significant morbidity. The response to therapy is largely guided by limited number of factors such as genotype of virus, rapid virological response, ethnicity, pre-therapy viral load, etc. While involvement of host genetic factors has been a major focus of research in playing an important role in the outcome of disease, the role of immune system cannot be marginalized. Poor cellular trafficking and suboptimal T cell responses in liver, the hall marks of chronic hepatitis C virus infection, might be attributed to defective antigen presentation. Various immunological factors, both innate and adaptive, play role in the pathogenesis of the disease and become dysfunctional in active disease. Recent reports suggest the major impact of functional and numerical status of dendritic cells in deciding the fate of antiviral therapy. In this review we take a look at the involvement of dendritic cells in playing an important role in the response to therapy.
    Full-text · Article · Nov 2013 · The Indian Journal of Medical Research
  • Source
    • "In its role as a key regulatory cytokine, IL-10 is a crucial factor in the outcome of several viral diseases (reviewed by Blackburn and Wherry, 2007; Filippi and von Herrath, 2008). A number of viruses including lymphocytic choriomeningitis virus (Brooks et al., 2008; 2010), hepatitis C virus (Brady et al., 2003; Saito et al., 2008), hepatitis B virus (Hyodo, Nakamura, and Imawari, 2004), murine gammaherpesvirus 68 (Siegel, Herskowitz, and Speck, 2008), and HIV (Contreras, Bennasser, and Bahraoui, 2004; Gee et al., 2006; 2007; Granelli- Piperno et al., 2004; Gupta et al., 2008) induce elevated levels of IL-10 production during infection which correlate with the impairment of T-cell responses and the failure to control viral replication. Herpes simplex virus can stimulate infected T cells to selectively synthesize IL-10, and elevated levels of IL-10 have also been found in T cells of mice during acute infections with Sin Nombre virus (Schountz et al., 2007; Sloan and Jerome, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cowpox virus infection induces interleukin-10 (IL-10) production from mouse bone marrow-derived dendritic cells (BMDCs) or cells of the mouse macrophage line (RAW264.7) at about 1800 pg/ml, whereas infections with vaccinia virus (strains WR or MVA) induced much less IL-10. Similarly, in vivo, IL-10 levels in bronchoalveolar lavage fluids of mice infected with cowpox virus were significantly higher than those after vaccinia virus infection. However, after intranasal cowpox virus infection, although dendritic and T-cell accumulations in the lungs of IL-10 deficient mice were greater than those in wild-type mice, weight-loss and viral burdens were not significantly different. IL-10 deficient mice were more susceptible than wild-type mice to re-infection with cowpox virus even though titers of neutralizing antibodies and virus-specific CD8 T cells were similar between IL-10 deficient and wild-type mice. Greater bronchopneumonia in IL-10 deficient mice than wild-type mice suggests that IL-10 contributes to the suppression of immunopathology in the lungs.
    Full-text · Article · Jun 2011 · Virology
  • Source
    • "HCV also subverts cellular immunity by inducing IL-10, which in turn inhibits the activation of dendritic cells (DC) and development of Th-1 cells [111,112]. Similarly, there are reports of increased Th-1 cytokine in the setting of HCC [113]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today.
    Full-text · Article · Sep 2010 · Viruses
Show more