title: Oxidized Low-Density Lipoprotein Is a Novel Predictor of Interferon Responsiveness in Chronic Hepatitis C Infection.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) cell entry is mediated by several cell surface receptors, including scavenger receptor class B type I (SR-BI). Oxidized low density lipoprotein (oxLDL) inhibits the interaction between HCV and SR-BI in a noncompetitive manner. We tested whether serum oxLDL levels correlate with sustained virologic response (SVR) rates after interferon-based treatment of chronic hepatitis C.
  
  
  METHODS
  Baseline oxLDL was determined in 379 participants with chronic HCV genotype 1 infection from the INDIV-2 study using a commercial enzyme-linked immunosorbent assay. The mechanistic in vitro studies used full-length and subgenomic HCV genomes replicating in hepatoma cells.
  
  
  RESULTS
  In the multivariate analysis, oxLDL was found to be an independent predictor of SVR. Oxidized LDL did not correlate with markers of inflammation (alanine transaminase, ferritin), nor was serum oxLDL affected by exogenous interferon administration. Also, oxLDL did not alter the sensitivity of HCV replication to interferon. However, oxLDL was found to be a potent inhibitor of cell-to-cell spread of HCV between adjacent cells in vitro. It could thus reduce the rate at which new cells are infected by HCV through either the cell-free or cell-to-cell route. Finally, serum oxLDL was significantly associated with the estimated infected cell loss rate under treatment.
  
  
  CONCLUSIONS
  Oxidized LDL is a novel predictor of SVR after interferon-based therapy and may explain the previously observed association of LDL with SVR. Rather than being a marker of activated antiviral defenses it may improve chances of SVR by limiting spread of infection to naive cells through the cell-to-cell route.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Hannover, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Solbach
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Hannover, Germany; Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Westhaus
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Hannover, Germany; Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Deest
authors.affiliation: Institute of Biostatistics and Mathematical Modeling, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Hepatology Section, Department of Gastroenterology and Rheumatology, Universitätsklinikum Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Hannover, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Hannover, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ciesek
authors.affiliation: German Center for Infection Research (DZIF), Hannover, Germany; Medical Clinic I, Zentrum der Inneren Medizin, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Hannover, Germany; Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
keywords: Cell-to-Cell Spread; DAA, direct-acting antiviral drug; DMEM, Dulbecco’s modified Eagle medium; DTT, dithiothreitol; HCV, hepatitis C virus; HCVcc, cell culture–grown hepatitis C virus; IPS1, interferon promoter stimulator-1; ITX-5061, N-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-2-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]-2-oxoacetamide;hydrochloride; LDL, low-density lipoprotein; NLS, nuclear localization signal; PBS, phosphate-buffered saline; RBV, ribavirin; RFP, red fluorescent protein; ROC, receiver operating characteristic; SR-BI; SR-BI, scavenger receptor class B member I; SVR; SVR, sustained virologic response; oxLDL; oxLDL, oxidized low-density lipoprotein; peg-IFN, pegylated interferon α