The green tea polyphenol, epigallocatechin-3-gallate, inhibits hepatitis C virus entry

Abstract

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. Individuals 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 properties. EGCG had no effect on HCV RNA replication, assembly, or release of progeny virions. 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.

Entry and replication of recombinant hepatitis C viruses in cell culture

“…Also, virus internalization can be efficiently demonstrated by resistance to protease digestion (proteinase K [146,167] or trypsine [168][169][170]). The efficiency of virus adsorption onto the cell surface can be evaluated by detection of the cell-associated viral RNA by reverse transcription and quantitative PCR [168,171] or with 35 S-labelled HCV virions [172]. How the virus triggers a cellular response leading to its internalization and delivery to a compartment favourable for fusion remains incompletely understood and requires systematic studies of the signalling cascades regulated after virus attachment onto the cell surface.…”

Characterization of the inhibition of hepatitis C virus entry by In vitro –generated and patient-derived oxidized low-density lipoprotein

“…Firefly reporter (CSFlucW2) lentiviral pseudoparticles were generated as previously described. 30 Production of HCVcc was performed by electroporation of Huh-7.5 cells with 5 lg of RNA of a full-length HCV genome, as previously described. 31 Supernatant was harvested 48 hours post-transfection.…”

Limited Sampling Estimates of Epigallocatechin Gallate Exposures in Cirrhotic and Noncirrhotic Patients With Hepatitis C After Single Oral Doses of Green Tea Extract

“…8,22 EGCG has been found to be a potent inhibitor of HCV entry in hepatoma cell lines as well as primary human hepatocytes. 23,24 Beyond its antiviral effect on HCV, Since 1966, 216 case reports of toxicity with green tea extracts were identified by the United States Pharmacopeia, of which 34 were concerning for liver toxicity. 13 The majority of cases present with an acute hepatocellular injury pattern and most recover with cessation of use.…”