Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation

被引:74
|
作者
Anggakusuma [1 ]
Romero-Brey, Ines [2 ]
Berger, Carola [2 ]
Colpitts, Che C. [3 ,4 ,5 ]
Boldanova, Tujana [6 ,7 ]
Engelmann, Michael [1 ]
Todt, Daniel [1 ]
Perin, Paula Monteiro [1 ]
Behrendt, Patrick [1 ,8 ]
Vondran, Florian W. R. [9 ,10 ]
Xu, Shuting [1 ]
Goffinet, Christine [1 ]
Schang, Luis M. [3 ,4 ,5 ]
Heim, Markus H. [6 ,7 ]
Bartenschlager, Ralf [2 ,11 ]
Pietschmann, Thomas [1 ]
Steinmann, Eike [1 ]
机构
[1] Twincore Ctr Expt & Clin Infect Res, Inst Expt Virol, D-30625 Hannover, Germany
[2] Heidelberg Univ, Dept Infect Dis, Mol Virol, Heidelberg, Germany
[3] Univ Alberta, Dept Biochem, Edmonton, AB, Canada
[4] Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB, Canada
[5] Univ Alberta, Li Ka Shing Inst Virol, Edmonton, AB, Canada
[6] Univ Basel, Dept Biomed, Basel, Switzerland
[7] Univ Basel Hosp, Div Gastroenterol & Hepatol, CH-4031 Basel, Switzerland
[8] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany
[9] Hannover Med Sch, Dept Gen Visceral & Transplantat Surg, ReMediES, Hannover, Germany
[10] German Ctr Infect Res, Hannover, Germany
[11] Heidelberg Univ, German Ctr Infect Res, Heidelberg, Germany
关键词
OXYSTEROL-BINDING-PROTEIN; CHOLESTEROL; 25-HYDROXYLASE; RNA REPLICATION; ANTIVIRAL RESPONSE; IMMUNE-RESPONSES; INNATE IMMUNITY; MX PROTEINS; 25-HYDROXYCHOLESTEROL; ACTIVATION; INFECTION;
D O I
10.1002/hep.27913
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Hepatitis C virus (HCV) is a positive-strand RNA virus that primarily infects human hepatocytes. Infections with HCV constitute a global health problem, with 180 million people currently chronically infected. Recent studies have reported that cholesterol 25-hydroxylase (CH25H) is expressed as an interferon-stimulated gene and mediates antiviral activities against different enveloped viruses through the production of 25-hydroxycholesterol (25HC). However, the intrinsic regulation of human CH25H (hCH25H) expression within the liver as well as its mechanistic effects on HCV infectivity remain elusive. In this study, we characterized the expression of hCH25H using liver biopsies and primary human hepatocytes. In addition, the antiviral properties of this protein and its enzymatic product, 25HC, were further characterized against HCV in tissue culture. Levels of hCH25H messenger RNA were significantly up-regulated both in HCV-positive liver biopsies and in HCV-infected primary human hepatocytes. The expression of hCH25H in primary human hepatocytes was primarily and transiently induced by type I interferon. Transient expression of hCH25H in human hepatoma cells restricted HCV infection in a genotype-independent manner. This inhibition required the enzymatic activity of CH25H. We observed an inhibition of viral membrane fusion during the entry process by 25HC, which was not due to a virucidal effect. Yet the primary effect by 25HC on HCV was at the level of RNA replication, which was observed using subgenomic replicons of two different genotypes. Further analysis using electron microscopy revealed that 25HC inhibited formation of the membranous web, the HCV replication factory, independent of RNA replication. Conclusion: Infection with HCV causes up-regulation of interferon-inducible CH25H in vivo, and its product, 25HC, restricts HCV primarily at the level of RNA replication by preventing formation of the viral replication factory. (Hepatology 2015;62:702-714)
引用
收藏
页码:702 / 714
页数:13
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