Replication of Hepatitis C Virus (HCV) RNA in Mouse Embryonic Fibroblasts: Protein Kinase R (PKR)-Dependent and PKR-Independent Mechanisms for Controlling HCV RNA Replication and Mediating Interferon Activities

Chang, Kyung-Soo; Cai, Zhaohui; Zhang, Chen; Sen, Ganes C.; Williams, Bryan R.G.; Luo, Guangxiang

doi:10.1128/jvi.00586-06

Cited by 88 publications

(69 citation statements)

References 76 publications

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“…Hepatitis C virus (HCV) subgenomic replicons have been shown to replicate more efficiently in PKR null MEF cell lines, suggesting that PKR is involved in the control of HCV replication (6). Other studies have shown that HCV can block the host cell's response to IFN by inhibiting PKR activity (22).…”

Section: Discussionmentioning

confidence: 99%

West Nile Virus-Induced Interferon Production Is Mediated by the Double-Stranded RNA-Dependent Protein Kinase PKR

Gilfoy¹,

Mason

2007

J Virol

102

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Section: Discussionmentioning

confidence: 99%

West Nile Virus-Induced Interferon Production Is Mediated by the Double-Stranded RNA-Dependent Protein Kinase PKR

Gilfoy¹,

Mason

2007

J Virol

102

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“…Moreover, several human cells of non-liver origin are well established . Finally, a spectrum of non-human cells have been reported that sustain HCV replication (Zhu, Guo et al 2003;Chang, Cai et al 2006;Uprichard, Chung et al 2006;Long, Hiet et al 2011) (Figure 2). However, it is important to note that RNA-replication is in general lower in these cells, particularly in transient replication assays, com pared to Huh7-derived cell clones.…”

Section: Permissive Host Cellsmentioning

confidence: 99%

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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“…A number of independent groups, including us, have previously shown that the genotype 2a HCV (JFH1) was able to efficiently replicate in various human and murine hepatic and extrahepatic cell types in vitro (31)(32)(33), suggesting that HCV RNA replication was not strictly restricted to human hepatocytes. The cell tropism of HCV infection and replication in human hepatocytes was probably determined by expression of a subset of key receptors and coreceptors on the surface of human hepatocytes, including CD81, claudin, occludin, and SR-BI (34).…”

Section: Discussionmentioning

confidence: 99%

The Serum Very-Low-Density Lipoprotein Serves as a Restriction Factor against Hepatitis C Virus Infection

Jiang

Kang

Hall

et al. 2015

J Virol

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Recent studies demonstrated that transgenic mice expressing key human hepatitis C virus (HCV) receptors are susceptible to HCV infection, albeit at very low efficiency. Robust mouse models of HCV infection and replication are needed to determine the importance of host factors in HCV replication, pathogenesis, and carcinogenesis as well as to facilitate the development of antiviral agents and vaccines. The low efficiency of HCV replication in the humanized mouse models is likely due to either the lack of essential host factors or the presence of restriction factors for HCV infection and/or replication in mouse hepatocytes. To determine whether HCV infection is affected by restriction factors present in serum, we examined the effects of mouse and human sera on HCV infectivity. Strikingly, we found that mouse and human sera potently inhibited HCV infection. Mechanistic studies demonstrated that mouse serum blocked HCV cell attachment without significant effect on HCV replication. Fractionation analysis of mouse serum in conjunction with targeted mass spectrometric analysis suggested that serum very-low-density lipoprotein (VLDL) was responsible for the blockade of HCV cell attachment, as VLDL-depleted mouse serum lost HCV-inhibitory activity. Both purified mouse and human VLDL could efficiently inhibit HCV infection. Collectively, these findings suggest that serum VLDL serves as a major restriction factor of HCV infection in vivo. The results also imply that reduction or elimination of VLDL production will likely enhance HCV infection in the humanized mouse model of HCV infection and replication. IMPORTANCEHCV is a major cause of liver diseases, such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Recently, several studies suggested that humanized mouse or transgenic mouse expressing key HCV human receptors became susceptible to HCV infection. However, HCV infection and replication in the humanized animals were very inefficient, suggesting either the lack of cellular genes important for HCV replication or the presence of restriction factors inhibiting HCV infection and replication in the mouse. In this study, we found that both mouse and human sera effectively inhibited HCV infection. Mechanistic studies demonstrated that VLDL is the major restriction factor that blocks HCV infection. These findings suggest that VLDL is beneficial to patients by restricting HCV infection. More importantly, our findings suggest that elimination of VLDL will lead to the development of more robust mouse models for the study of HCV pathogenesis, host response to HCV infection, and evaluation of HCV vaccines. H epatitis C virus (HCV) is an enveloped RNA virus containing a single-stranded and positive-sense RNA genome of 9.6 kb in length. It is the prototype of the Hepacivirus genus in the Flaviviridae family. The virion RNA (vRNA) genome encodes a large polyprotein precursor that is proteolytically cleaved by cellular and viral proteases into structural (core, E1, E2, and p7) and nonstructural (NS) proteins (NS2, ...

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Replication of Hepatitis C Virus (HCV) RNA in Mouse Embryonic Fibroblasts: Protein Kinase R (PKR)-Dependent and PKR-Independent Mechanisms for Controlling HCV RNA Replication and Mediating Interferon Activities

Cited by 88 publications

References 76 publications

West Nile Virus-Induced Interferon Production Is Mediated by the Double-Stranded RNA-Dependent Protein Kinase PKR

West Nile Virus-Induced Interferon Production Is Mediated by the Double-Stranded RNA-Dependent Protein Kinase PKR

Cell Culture Systems for Hepatitis C Virus

The Serum Very-Low-Density Lipoprotein Serves as a Restriction Factor against Hepatitis C Virus Infection

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