title: Host cell responses induced by hepatitis C virus binding.
abstract: Initiation of hepatitis C virus (HCV) infection is mediated by docking of the viral envelope to the hepatocyte cell surface membrane followed by entry of the virus into the host cell. Aiming to elucidate the impact of this interaction on host cell biology, we performed a genomic analysis of the host cell response following binding of HCV to cell surface proteins. As ligands for HCV-host cell surface interaction, we used recombinant envelope glycoproteins and HCV-like particles (HCV-LPs) recently shown to bind or enter hepatocytes and human hepatoma cells. Gene expression profiling of HepG2 hepatoma cells following binding of E1/E2, HCV-LPs, and liver tissue samples from HCV-infected individuals was performed using a 7.5-kd human cDNA microarray. Cellular binding of HCV-LPs to hepatoma cells resulted in differential expression of 565 out of 7,419 host cell genes. Examination of transcriptional changes revealed a broad and complex transcriptional program induced by ligand binding to target cells. Expression of several genes important for innate immune responses and lipid metabolism was significantly modulated by ligand-cell surface interaction. To assess the functional relevance and biological significance of these findings for viral infection in vivo, transcriptional changes were compared with gene expression profiles in liver tissue samples from HCV-infected patients or controls. Side-by-side analysis revealed that the expression of 27 genes was similarly altered following HCV-LP binding in hepatoma cells and viral infection in vivo. In conclusion, HCV binding results in a cascade of intracellular signals modulating target gene expression and contributing to host cell responses in vivo. Reprogramming of cellular gene expression induced by HCV-cell surface interaction may be part of the viral strategy to condition viral entry and replication and escape from innate host cell responses.
authors.affiliation: Department of Medicine II, University of Freiburg, Freiburg, Germany.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Fang
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilpert
authors.forename: Bettina
authors.initials: B
authors.lastname: Gissler
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.forename: Clemens
authors.initials: C
authors.lastname: Kreutz
authors.forename: Thomas
authors.initials: T
authors.lastname: Maiwald
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.forename: Winfried V
authors.initials: WV
authors.lastname: Kern
authors.forename: Johannes
authors.initials: J
authors.lastname: Donauer
authors.forename: Marcel
authors.initials: M
authors.lastname: Geyer
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Erik
authors.initials: E
authors.lastname: Depla
authors.forename: Fritz
authors.initials: F
authors.lastname: von Weizsäcker
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
mesh_terms: D000956:Antigens, Viral / Q000378:metabolism; D001483:Base Sequence; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology*; D051863:Host Cell Factor C1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D040081:Protein Array Analysis; D012367:RNA, Viral / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D046509:Tissue Culture Techniques; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000956:Antigens, Viral; D002352:Carrier Proteins; D051863:Host Cell Factor C1; D012367:RNA, Viral; D014759:Viral Envelope Proteins