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.

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Available from: Getahun Abate, Feb 14, 2014
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    • "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. "
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    • "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). "
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    • "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]. "
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