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

World journal of gastroenterology
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Abstract

AIM: To characterize the role of apolipoprotein B100 (apoB100) 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 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 FDA-approved antisense inhibitor of apoB100, on HCV using cell-culture competent HCV and determined its impact on viral infectivity with the TCID50 method.RESULTS: We found that apoB100 is indispensable for HCV infection. Using the JFH-1 fully infectious cell-culture competent virus in Huh 7 hepatoma cells with TALEN-mediated gene deletion of apoB (), we found a significant reduction in HCV RNA and protein levels following infection. Pseudoparticle and replicon models demonstrated that apoB did not play a role in HCV entry or replication. However, the virus produced by cells had significantly diminished infectivity as measured by the TCID-50 method compared to wild-type 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: ApoB is required for the generation of fully infectious HCV virions, and inhibition of apoB with mipomersen blocks HCV. Targeting lipid metabolic pathways to impair viral infectivity represents a novel host targeted strategy to inhibit HCV.

Year of Publication
2016
Journal
World journal of gastroenterology
Volume
22
Issue
45
Pages
9954-9965
Date Published
12/2016
ISSN
2219-2840
DOI
10.3748/wjg.v22.i45.9954
PubMed ID
28018102
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