Replication of Subgenomic Hepatitis C Virus Replicons in Mouse Fibroblasts Is Facilitated by Deletion of Interferon Regulatory Factor 3 and Expression of Liver-Specific MicroRNA 122

Lin, Liang-Tzung; Noyce, Ryan S.; Pham, Tram N. Q.; Jw, Wilson; Sisson, Gary; Michalak, T.I.; Mossman, Karen; Richardson, Christopher D.

doi:10.1128/jvi.00559-10

Cited by 61 publications

(68 citation statements)

References 83 publications

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“…HCV RNA replication has also been demonstrated in mouse embryonic fibroblast (MEFs) using JFH1 replicons . This study could be confirmed and extended by Lin and colleagues who showed that expression of the liver-specific miR-122 in MEFs stimulated the synthesis of HCV replicons in the rodent fibroblasts and that the combined effects of miR-122 expres sion and deletion of IRF-3 lead to cooperative stimulation of HCV subgenome replication (Lin, Noyce et al 2010). Therefore, MEFs now provide an important opportunity to utilize the powerful mouse genetic systems and the available mouse strains to unravel host factors that determine or preclude efficient HCV replication in these animals.…”

Section: Permissive Host Cellssupporting

confidence: 68%

Cell Culture Systems for Hepatitis C Virus

Steinmann

Pietschmann

2013

Current Topics in Microbiology and Immunology

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Due to the obligatory intracellular life style of viruses, cell culture systems for efficient viral propagation are crucial to obtain a detailed understanding of the virus host cell interaction. For hepatitis C virus (HCV) the development of permissive and authentic culture models has been and continues to be a challenging task. The first ef forts to culture HCV had limited success and range back to before the virus was molecularly cloned in 1989. Since then several major breakthroughs have gradually overcome limitations in culturing the virus and sequentially permitted analysis of viral RNA replication, cell entry and ultimately the complete replication cycle in cultured cells in 2005. Until today, basic and applied HCV research greatly benefit from these tremendous efforts which spurred multiple com plementary cell based model systems for distinct steps of the HCV replication cycle. When used in combination they now permit deep insights into the fascinating biology of HCV and its interplay with the host cell. In fact drug development has been much facilitated and our understanding of the molecular determinants of HCV replication has grown in parallel to these advances. Building on this ground work and further refining our cellular models to better mimic the ar chitecture, polarization and differentiation of natural hepatocytes should reveal novel unique aspects of HCV replication. Ultimately, models to culture primary HCV isolates across all genotypes may teach us important new lessons about viral functional adaptations that have evolved in exchange with its human host and that may ex plain the variable natural course of hepatitis C.

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Section: Permissive Host Cellssupporting

confidence: 68%

Cell Culture Systems for Hepatitis C Virus

Steinmann

Pietschmann

2013

Current Topics in Microbiology and Immunology

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“…Importantly, this blockade can be overcome by engineering mice to express human occludin and CD81 (5) or by adaptation of HCV to usage of mouse CD81 (6). Second, HCV replication in murine embryonic fibroblasts (7,8), in mouse liver-derived cells (9), and …”

mentioning

confidence: 99%

Control of Hepatitis C Virus Replication in Mouse Liver-Derived Cells by MAVS-Dependent Production of Type I and Type III Interferons

Anggakusuma

Frentzen

Gürlevik

et al. 2015

J Virol

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Hepatitis C virus (HCV) efficiently infects IMPORTANCEIn this study, we found that HCV NS3-4A similarly diminished both human and mouse MAVS-dependent signaling in human and mouse cells. Therefore, it is unlikely that ineffective cleavage of mouse MAVS per se precludes HCV propagation in immunocompetent mouse liver cells. Hence, approaches to reinforce HCV replication in mouse liver cells (e.g., by expression of essential human replication cofactors) should not be thwarted by the poor ability of HCV to counteract MAVS-dependent antiviral signaling. In addition, we show that mouse MAVS induces both type I and type III IFNs, which together control HCV replication. Characterization of type I or type III-dependent interferon-stimulated genes in these cells should help to identify key murine restriction factors that preclude HCV propagation in immunocompetent mouse liver cells. H epatitis C virus (HCV) infection is associated with chronic liver disease, including hepatic steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (1). Recent licensing of directly acting antivirals (DAAs) has considerably improved therapeutic options, and novel drug combinations reach cure rates of more than 90% (2). However, natural or treatment-induced virus elimination does not prevent reinfection by HCV. Moreover, many of ca. 160 million infected individuals are not diagnosed, and the vast majority of HCV patients have not been treated (3). Therefore, development of a prophylactic vaccine that efficiently prevents virus transmission is a major challenge for global control of hepatitis C. However, advances in HCV vaccine research are hampered by a lack HCV-permissive, immunocompetent animal models.HCV, a plus-strand RNA virus and member of the family Flaviviridae, has a narrow species tropism. Besides humans, only chimpanzees are naturally susceptible to chronic HCV infection. However, high costs and ethical concerns severely limit utilization of chimpanzees for research purposes. Thus, understanding of the mechanisms that limit HCV replication in other animals, for instance, mice, is an important step to ultimately develop a robust animal model for HCV. Encouragingly, recent advances have highlighted key prerequisites for HCV infection of murine liver cells. First, occludin and CD81 have been recognized to determine HCV species tropism at the level of viral cell entry (4). Importantly, this blockade can be overcome by engineering mice to express human occludin and CD81 (5) or by adaptation of HCV to usage of mouse CD81 (6). Second, HCV replication in murine embryonic fibroblasts (7,8), in mouse liver-derived cells (9), and

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“…Investigators have shown that miR122 expression increases HCV replication in mouse embryonic fibroblasts and other hepatoma cell lines such as HepG2 cells (17,21,28). Furthermore, HEK-293 cells modified to express miR122 are capable of sustaining selectable HCV subgenomic replicons, although expression of mutated miR122, at sites required for HCV RNA binding, can also sustain these replicons (5).…”

mentioning

confidence: 99%

Reconstitution of the Entire Hepatitis C Virus Life Cycle in Nonhepatic Cells

Costa

Turek

Felmlee

et al. 2012

J Virol

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e Hepatitis C virus (HCV) is a human hepatotropic virus, but the relevant host factors restricting HCV infection to hepatocytes are only partially understood. We demonstrate that exogenous expression of defined host factors reconstituted the entire HCV life cycle in human nonhepatic 293T cells. This study shows robust HCV entry, RNA replication, and production of infectious virus in human nonhepatic cells and highlights key host factors required for liver tropism of HCV.

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Replication of Subgenomic Hepatitis C Virus Replicons in Mouse Fibroblasts Is Facilitated by Deletion of Interferon Regulatory Factor 3 and Expression of Liver-Specific MicroRNA 122

Abstract: Hepatitis C virus (HCV) infection causes

Cited by 61 publications

References 83 publications

Cell Culture Systems for Hepatitis C Virus

Cell Culture Systems for Hepatitis C Virus

Control of Hepatitis C Virus Replication in Mouse Liver-Derived Cells by MAVS-Dependent Production of Type I and Type III Interferons

Reconstitution of the Entire Hepatitis C Virus Life Cycle in Nonhepatic Cells

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