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The Green Tea Polyphenol, Epigallocatechin3gallate, Inhibits Hepatitis C Virus Entry

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The Green Tea Polyphenol, Epigallocatechin3gallate, Inhibits Hepatitis C Virus Entry The Green Tea Polyphenol, Epigallocatechin-3-Gallate, Inhibits Hepatitis C Virus Entry Sandra Ciesek,1,2 Thomas von Hahn,1 Che C. Colpitts,3 Luis M. Schang,3 Martina Friesland,2 Jo¨rg Steinmann,4 Michael P. Manns,1 Michael Ott,1 Heiner Wedemeyer,1 Philip Meuleman,5 Thomas Pietschmann,2 and Eike Steinmann2 Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Current antiviral therapy fails to clear infection in a substantial proportion of cases. Drug development is focused on nonstructural proteins required for RNA replication. Individu- als undergoing orthotopic liver transplantation face rapid, universal reinfection of the graft. Therefore, antiviral strategies targeting the early stages of infection are urgently needed for the prevention of HCV infection. In this study, we identified the polyphenol, epigallocatechin-3-gallate (EGCG), as an inhibitor of HCV entry. Green tea catechins, such as EGCG and its derivatives, epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC), have been previously found to exert antiviral and antioncogenic proper- ties. EGCG had no effect on HCV RNA replication, assembly, or release of progeny viri- ons. However, it potently inhibited Cell-culture–derived HCV (HCVcc) entry into hepatoma cell lines as well as primary human hepatocytes. The effect was independent of the HCV genotype, and both infection of cells by extracellular virions and cell-to-cell spread were blocked. Pretreatment of cells with EGCG before HCV inoculation did not reduce HCV infection, whereas the application of EGCG during inoculation strongly inhibited HCV infectivity. Moreover, treatment with EGCG directly during inoculation strongly inhibited HCV infectivity. Expression levels of all known HCV (co-)receptors were unaltered by EGCG. Finally, we showed that EGCG inhibits viral attachment to the cell, thus disrupting the initial step of HCV cell entry. Conclusion: The green tea molecule, EGCG, potently inhibits HCV entry and could be part of an antiviral strategy aimed at the prevention of HCV reinfection after liver transplantation. (HEPATOLOGY 2011;54:1947-1955) nfection with the hepatitis C virus (HCV) is a currently consisting of a combination of pegylated major cause of chronic liver disease and the major interferon-alpha (IFN-a) with ribavirin will soon also indication of liver transplantations worldwide. include an HCV nonstructural protein (NS)3/4A pro- I 2 Approximately 160 million people are chronically tease inhibitor. This addition is highly expected to infected with HCV, representing approximately 2% of improve response rates, especially in HCV genotype the world population, whereas in some countries up to 1–infected individuals. However, therapy will most 15%-20% of the population is infected.1 Chronic likely still remain expensive, fraught with side effects, HCV infection causes chronic hepatitis, cirrhosis, and and may still fail to clear infection in a substantial hepatocellular carcinoma (HCC). Standard therapy proportion of cases. Individuals undergoing orthotopic Abbreviations: INN, boceprevir; CD, cluster of differentiation; CLDN1, claudin-1; cpm, counts per minute; CyA, cyclosporine A; DMEM, Dulbecco’s modified Eagle’s medium; DMSO, dimethyl sulfoxide; EC, epicatechin; ECG, epicatechin gallate; EGC, epigallocatechin; EGCG, epigallocatechin-3-gallate; EGF-R, epidermal growth factor receptor; FACS, fluorescence-activated cell sorting; FBS, fetal bovine saerum; ffu, focus-forming units; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HCVcc, cell-culture–derived HCV; HCVpp, HCV pseudoparticles; HPM, hepatocyte plating media; IC50, half-maximal inhibitory concentration; IFN-a, interferon-alpha; JFH1, Japanese fulminant hepatitis 1; MLV, murine leukemia virus; MOI, multiplicity of infection; NS, nonstructural protein; NTRs, nontranslated regions; OCLN, occluding; OLT, orthotopic liver transplantation; oxLDL, oxidized low-density lipoprotein; PBS, phosphate-buffered saline; PHHs, primary human hepatocytes; RFP, red fluorescent protein; SR-BI, scavenger receptor class B type 1; VSV-G, vesicular stomatitis virus glycoprotein. From the 1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 2Division of Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Center for Infection Research (HZI), Hannover, Germany; 3Departments of Biochemistry and Medical Microbiology and Immunology and Li Ka Shing Insitute of Virology, University of Alberta, Edmonton, Alberta, Canada; 4Institute of Medical Microbiology, University Hospital Essen, Essen, Germany; and 5Center for Vaccinology, Ghent University and Hospital, Ghent, Belgium. Received June 20, 2011; accepted August 1, 2011. 1947 1948 CIESEK ET AL. HEPATOLOGY, December 2011 liver transplantation (OLT) for complications of HCV structural differences are attributed to the number of infection pose a particular clinical problem: Graft rein- hydroxyl groups on the B-ring and the presence or ab- fection with HCV occurs in nearly all cases, and long- sence of a galloyl moiety. For EGCG, a major compo- term outcomes are unsatisfactory.3 The pharmacologi- nent of green tea, inhibition of herpes simplex virus type cal repression of immune function after OLT results in 1 and 2, enterovirus 71, human immunodeficiency virus, enhanced viral replication. Moreover, some immuno- influenza A, and other viruses has been reported.10-14 suppressants have additional nonimmune-mediated The mechanism of the observed broad antiviral effect is proviral effects, as we have demonstrated for glucocor- not known, but has been suggested to differ between ticoids.4 Prevention of graft reinfection, as routinely viruses. This study was conducted to evaluate the effects achieved in the case of hepatitis B, is a major clinical of green tea catechins on HCV and to explore the mech- goal, but will likely require efficient pharmacological anism underlying their antiviral effects. means of preventing viral entry into hepatocytes. Such Our results reveal that EGCG, but not other green compounds are, so far, not available. tea catechins, is an inhibitor of HCVcc that does not HCV is a highly variable enveloped RNA virus of interfere with genome replication. Instead, EGCG the Flaviviridae family that infects hepatocytes and specifically targets viral cell entry (i.e., the NS3/4A- establishes a chronic infection in the majority of cases. independent initial stage of the viral replication cycle) The HCV genome, 9.6 kilobases in size, encodes for a into both hepatoma cell lines and primary human single polyprotein cleaved by cellular and viral pro- hepatocytes. Furthermore, we showed that EGCG teases into 10 different proteins: core, E1, E2 (struc- inhibits viral attachment to the target cell as well as tural proteins), p7, and the nonstructural proteins cell-to-cell transmission between adjacent cells. (NSs), NS2, NS3, NS4A, NS4B, NS5A, and NS5B. The single open reading frame (3,000 amino acids) encoded by the HCV genome is flanked by nontrans- Materials and Methods lated regions (NTRs) at the 50- and 30-end. Cell-culture–derived HCV particles (HCVcc), based on the Japanese fulminant hepatitis 1 (JFH1) strain of Compounds. EGCG, ECG, EC, and EGC were HCV genotype 2a, are infectious both in vitro and purchased from Sigma-Aldrich (Seelze, Germany). in vivo and, therefore, are a widely used model for the Cyclosprine A (CyA) was provided by Novartis (Basel, complete replication cycle of HCV.5-7 Unlike other Switzerland), and boceprevir (INN) was provided by HCV isolates, JFH1 replicates very efficiently in the Institute Pasteur Korea (Seongnam, Korea). Huh-7.5 cells in the absence of cell-culture–adaptive Plasmids and Viruses. Plasmids pFK-Jc1, pFK- mutations. Construction of chimeric virus genomes JFH1, and H77/JFH1 have been described recently.8,15 encoding JFH1-derived nonstructural proteins and The construct, Luc-Jc1, is a bicistronic firefly luciferase structural protein to form the J6/CF strain (genotype reporter virus that encodes a chimeric HCV polypro- 2a) has further improved the efficiency of the HCV tein consisting of codons 1-846 derived from J6/CF infection model.8 This system allows the assessment of combined with codons 847-3033 of JFH1.16 the impact of antiviral agents on HCV RNA replica- Cell Culture. Huh-7.5 cells were cultured in Dul- tion, virus production, and infectivity. becco’s modified Eagle’s medium (DMEM; Invitrogen, Green tea catechins, such as epigallocatechin-3-gallate Carlsbad, CA) with 10% fetal bovine serum (FBS), (EGCG), epigallocatechin (EGC), epicatechin gallate 1Â nonessential amino acids (Invitrogen), 100 lg/mL (ECG), and epicatechin (EC), have been found to have of streptomycin (Invitrogen), and 100 IU/mL of peni- antiviral and antioncogenic properties.9 Functional and cillin (DMEMcomplete; Invitrogen). This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (HA 4393/2-1; to T.V.H.) and (Ci 171/2-1; to S.C.) and from the CIHR and BWF (to L.M.S.). T.P. was supported by grants from the Helmholtz Association SO-024 and the DFG (PI 734/2-1 and SFB 900, Teilprojekt A6). E.S. was supported by an intramural young investigator award of the Helmholtz Center for Infection Research and the DFG (STE 1954/1-1). C.C.C. was supported by the NSERC and AHFMR. Address reprint requests to: Eike Steinmann, PhD, Division of Experimental Virology, TWINCORE, Center
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