Journal
JOURNAL OF HEPATOLOGY
Volume 64, Issue 3, Pages 556-564Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2015.10.030
Keywords
Hepatitis B virus; Hepatitis D virus; HBV; HDV; NTCP; Cell fusion; Mouse model
Categories
Funding
- German Centre for Infectious Research (DZIF), TTU Hepatitis [5.807, 5.704]
- Heidelberg Cell Network initiative of Excellence
- Deutsche Forschungsgemeinschaft (DFG) [FOR1202]
- Deutsche Forschungsgemeinschaft (DFG), Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy)
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Background & Aims: Hepatitis B virus (HBV) is a major human pathogen restricted to hepatocytes. Expression of the specific receptor human sodium taurocholate cotransporting polypeptide (hNTCP) in mouse hepatocytes renders them susceptible to hepatitis delta virus (HDV), a satellite of HBV; however, HBV remains restricted at an early stage of replication. This study aims at clarifying whether this restriction is caused by the lack of a dependency factor or the activity of a restriction factor. Methods: Six hNTCP-expressing mouse and human cell lines were generated and functionally characterized. By fusion with replication-supporting but non-infectable HepG2 cells, we analysed the ability of these heterokaryonic cells to fully support HBV replication by HBcAg expression and HBsAg/HBeAg secretion. Results: While hNTCP expression in three mouse cell lines and the non-hepatic human HeLa cells conferred susceptibility to HDV, HBV replication was still restricted. Upon fusion of refractive cells to HepG2 cells, all heterokaryonic cells supported receptor-mediated infection with HBV. hNTCP was provided by the mouse cells and replication competence came from the HepG2 cell line. Transfection of a covalently closed circular DNA (cccDNA)-like molecule into non-susceptible cells promoted gene expression, indicating that the limiting step is upstream of cccDNA formation. Conclusions: In addition to the expression of hNTCP, establishment of HBV infection in mouse and non-hepatocytic human cell lines requires supplementation with a dependency factor and is not limited by a restriction factor. This result opens new avenues for the development of a fully permissive immunocompetent HBV mouse model. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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