Abstract
Hepatocytes are the main source of hepatitis C virus (HCV) replication and contain the maximum viral load in an infected person. Chronic HCV infection is characterized by weak cellular immune responses to viral proteins. Cathepsin S is a lysosomal cysteine protease and controls HLA-DR-antigen complex presentation through the degradation of the invariant chain. In this study, we examined the effect of HCV proteins on cathepsin S expression and found it to be markedly decreased in dendritic cells (DCs) exposed to HCV or in hepatocytes expressing HCV proteins. The downregulation of cathepsin S was mediated by HCV core and NS5A proteins involving inhibition of the transcription factors interferon regulatory factor 1 (IRF-1) and upstream stimulatory factor 1 (USF-1) in gamma interferon (IFN-γ)-treated hepatocytes. Inhibition of cathepsin S by HCV proteins increased cell surface expression of the invariant chain. In addition, hepatocytes stably transfected with HCV core or NS5A inhibited HLA-DR expression. Together, these results suggested that HCV has an inhibitory role on cathepsin S-mediated major histocompatibility complex (MHC) class II maturation, which may contribute to weak immunogenicity of viral antigens in chronically infected humans.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antigen Presentation
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Antigens, Differentiation, B-Lymphocyte / metabolism*
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Cathepsins / antagonists & inhibitors*
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Cathepsins / genetics
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Cell Differentiation
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Cell Line
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Cell Membrane / immunology
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Dendritic Cells / immunology
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Dendritic Cells / pathology
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Dendritic Cells / virology
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Down-Regulation
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HLA-DR Antigens / metabolism
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Hepacivirus / genetics
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Hepacivirus / immunology
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Hepacivirus / pathogenicity*
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Hepatitis C, Chronic / immunology
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Hepatitis C, Chronic / pathology
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Hepatitis C, Chronic / virology
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Hepatocytes / immunology*
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Hepatocytes / virology*
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Histocompatibility Antigens Class II / metabolism*
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Host-Pathogen Interactions / genetics
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Host-Pathogen Interactions / immunology
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Humans
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Interferon Regulatory Factor-1 / genetics
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Interferon Regulatory Factor-1 / metabolism
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Transfection
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Upstream Stimulatory Factors / genetics
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Upstream Stimulatory Factors / metabolism
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Viral Core Proteins / genetics
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Viral Core Proteins / immunology
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / immunology
Substances
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Antigens, Differentiation, B-Lymphocyte
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HLA-DR Antigens
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Histocompatibility Antigens Class II
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IRF1 protein, human
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Interferon Regulatory Factor-1
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USF1 protein, human
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Upstream Stimulatory Factors
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Viral Core Proteins
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Viral Nonstructural Proteins
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invariant chain
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NS-5 protein, hepatitis C virus
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Cathepsins
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cathepsin S