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Apolipoprotein B100 is required for hepatitis C infectivity and Mipomersen inhibits hepatitis C

World Journal of Gastroenterology 2016年第45期22卷 9954-9965页

作者： Esperance AK Schaefer James Meixiong Christina Mark amy deik Daniel L Motola Dahlene Fusco Andrew Yang Cynthia Brisac Shadi Salloum Wenyu Lin Clary B Clish Lee F Peng Raymond T Chung Gastrointestinal Unit Massachusetts General Hospital Bossston MA 02114 United States Department of Medicine Harvard Medical School Bossston MA 02114 United States both of the Broad Institute of Harvard and M.I.T. Cambridge MA 02115 United States Temple University Health System Cambridge MA 02142 United States

AIM To characterize the role of apolipoprotein B100(apoB 100) in hepatitis C viral(HCV) infection. METHODS In this study, we utilize a gene editing tool, transcription activator-like effector nucleases(TALENs), to generate human hepatoma cells with a stable genetic deletion of APOB to assess of apoB in HCV. Using infectious cell culture-competent HCV, viral pseudoparticles, replicon models, and lipidomic analysis we determined the contribution of apoB to each step of the viral lifecycle. We further studied the effect of mipomersen, an FDAapproved antisense inhibitor of apoB 100, on HCV using in vitro cell-culture competent HCV and determined itsimpact on viral infectivity with the TCID50 method. RESULTS We found that apo B100 is indispensable for HCV infection. Using the JFH-1 fully infectious cell-culture competent virus in Huh 7 hepatoma cells with TALENmediated gene deletion of apoB(APOB KO), we found a significant reduction in HCV RNA and protein levels following infection. Pseudoparticle and replicon models demonstrated that apo B did not play a role in HCV entry or replication. However, the virus produced by APOB KO cells had significantly diminished infectivity as measured by the TCID-50 method compared to wildtype virus. Lipidomic analysis demonstrated that these virions have a fundamentally altered lipidome, with complete depletion of cholesterol esters. We further demonstrate that inhibition of apoB using mipomersen, an FDA-approved anti-sense oligonucleotide, results in a potent anti-HCV effect and significantly reduces the infectivity of the virus. CONCLUSION Apo B is required for the generation of fully infectious HCV virions, and inhibition of apo B with mipomersen blocks HCV. Targeting lipid metabolic pathways to impair viral infectivity represents a novel host targeted strategy to inhibit HCV.

关键词： Apolipoprotein Lipid Hepatitis C virus Gene silencing Viral replication

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