(300d) Modulating the Lipoprotein-Dependent HCV Secretion

The hepatitis C virus (HCV) infects over 3% of the world population and is the leading cause of chronic liver disease world-wide. HCV has long been known to associate with circulating lipoproteins and its interactions with the cholesterol and lipid pathways have been recently described. In this work we demonstrate that HCV is actively secreted by infected cells through a Golgi-dependent mechanism, while bound to very low density lipoprotein (vLDL). Silencing apolipoprotein B (ApoB) mRNA in infected cells causes a 70% reduction in the secretion of both ApoB-100 and HCV. More importantly, we demonstrate that the grapefruit flavonoid naringenin, previously shown to inhibit vLDL secretion both in vivo and in vitro, inhibits the microsomal triglyceride transfer protein (MTP) activity as well as the transcription of HMG-Co Reductase and ACAT2 in infected cells. Stimulation with naringenin reduces HCV secretion in infected cells by 80%. Moreover, we find that naringenin is effective at concentrations that are an order of magnitude below the toxic threshold in primary human hepatocytes and in vivo in mice. These results suggest a novel therapeutic approach for the treatment of HCV infection