title: Hepatitis C virus-mediated inhibition of cathepsin S increases invariant-chain expression on hepatocyte surface.
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.
authors: Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA.
authors: Hangeun
authors: H
authors: Kim
authors: Budhaditya
authors: B
authors: Mazumdar
authors: Sandip K
authors: SK
authors: Bose
authors: Keith
authors: K
authors: Meyer
authors: Adrian M
authors: AM
authors: Di Bisceglie
authors: Daniel F
authors: DF
authors: Hoft
authors: Ranjit
authors: R
authors: Ray
mesh_terms: D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D015536:Down-Regulation; D006684:HLA-DR Antigens / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D002403:Cathepsins; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D050856:Interferon Regulatory Factor-1; D051720:Upstream Stimulatory Factors; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C494257:IRF1 protein, human; C497181:USF1 protein, human; C045084:invariant chain; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C028217:cathepsin S