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Article first published online: 15 FEB 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 5, pages 1716–1724, May 2013
How to Cite
Westhaus, S., Bankwitz, D., Ernst, S., Rohrmann, K., Wappler, I., Agné, C., Luchtefeld, M., Schieffer, B., Sarrazin, C., Manns, M. P., Pietschmann, T., Ciesek, S. and von Hahn, T. (2013), Characterization of the inhibition of hepatitis C virus entry by In vitro–generated and patient-derived oxidized low-density lipoprotein. Hepatology, 57: 1716–1724. doi: 10.1002/hep.26190
Potential conflict of interest: Dr. Manns is on the speakers' bureau of, consults for, and received grants from Roche, Gilead, Bristol-Myers Squibb, Merck, and Janssen. He is also on the speakers' bureau of GlaxoSmithKline. He consults for, and received grants from, Novartis and Boehringer-Ingelheim. He consults for Tibotec and Vertex. Dr. Pietschmann consults for Biotest and Janssen. Dr. Ciesek is on the speakers' bureau of MSD and received grants from Novartis.
This study was funded by the DFG Emmy Noether Program (grant no.: HA 4393/2-1; to T.v.H.) as well as SFB900 (project A6) and a grant from the Initiative and Networking Fund of the Helmholtz Association (grant no.: SO-024; to T.P.) and a DFG grant (no. Ci 171/2-1; to S.C.). The authors thank Jens Bukh (University of Copenhagen, Denmark), Alfredo Nicosia (Okairos, Basel, Switzerland), and Charlie Rice (The Rockefeller University, New York, NY) for providing reagents and Heiner Wedemeyer and the HepNet serum Bank for providing sera.
- Issue published online: 22 APR 2013
- Article first published online: 15 FEB 2013
- Accepted manuscript online: 5 DEC 2012 02:52AM EST
- Manuscript Accepted: 15 NOV 2012
- Manuscript Revised: 14 NOV 2012
- Manuscript Received: 25 JUN 2012
Oxidized low-density lipoprotein (oxLDL) has been reported as an inhibitor of hepatitis C virus (HCV) cell entry, making it the only known component of human lipid metabolism with an antiviral effect on HCV. However, several questions remain open, including its effect on full-length cell-culture–grown HCV (HCVcc) of different genotypes or on other steps of the viral replication cycle, its mechanism of action, and whether endogenous oxLDL shares the anti-HCV properties of in vitro–generated oxLDL. We combined molecular virology tools with oxLDL serum measurements in different patient cohorts to address these questions. We found that oxLDL inhibits HCVcc at least as potently as HCV pseudoparticles. There was moderate variation between genotypes, with genotype 4 appearing the most oxLDL sensitive. Intracellular RNA replication and assembly and release of new particles were unaffected. HCV particles entering target cells lost oxLDL sensitivity with time kinetics parallel to anti-SR-BI (scavenger receptor class B type I), but significantly earlier than anti-CD81, suggesting that oxLDL acts by perturbing interaction between HCV and SR-BI. Finally, in chronically HCV-infected individuals, endogenous serum oxLDL levels did not correlate with viral load, but in HCV-negative sera, high endogenous oxLDL had a negative effect on HCV infectivity in vitro. Conclusion: oxLDL is a potent pangenotype HCV entry inhibitor that maintains its activity in the context of human serum and targets an early step of HCV entry. (HEPATOLOGY 2013)