Abstract
Due to the obligatory intracellular lifestyle 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 continues to be a challenging task. The first efforts 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 complementary 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 groundwork and further refining our cellular models to better mimic the architecture, 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 explain the variable natural course of hepatitis C.
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Abbreviations
- BMEC:
-
Brain microvascular endothelial cells
- CNS:
-
Central nervous system
- Con1:
-
Consensus genome 1
- DAA:
-
Direct acting antiviral
- DC-SIGN:
-
Dendritic cell-specific intracellular adhesion molecule-3-grabbing non-integrin
- EGFR:
-
Epidermal growth factor receptor
- EMCV:
-
Encephalomyocarditis virus
- EphA2:
-
Ephrin receptor A2
- GFP:
-
Green fluorescent protein
- HCV:
-
Hepatitis C virus
- HCVTCP:
-
Hepatitis C virus trans-complemented particles
- HBV:
-
Hepatitis B virus
- HIV:
-
Human immunodeficiency virus
- iPSC:
-
Induced pluripotent stem cells
- IRES:
-
Internal ribosomal entry site
- JFH1:
-
Japanese fulminant hepatitis
- LDL-R:
-
Low-density lipoprotein receptor
- MEF:
-
Mouse embryonic fibroblasts
- MPCC:
-
Micropattern co-cultures
- mL:
-
Milliliter
- MLV:
-
Murine leukemia virus
- NPC1L1:
-
Niemann-Pick C1-like cholesterol adsorption receptor
- PBMC:
-
Peripheral blood mononuclear cells
- PHH:
-
Primary human hepatocytes
- REM:
-
Replication enhancing mutations
- RIG-I:
-
Retinoic acid-inducible gene I
- SEAP:
-
Secreted embryonic alkaline phosphatase
- siRNA:
-
small interfering RNAs
- TCID50:
-
Tissue culture infectious dose 50
- VSV:
-
Vesicular stomatitis virus
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Acknowledgments
The authors thank Gisa Gerold for critical reading of the manuscript and Dorothea Bankwitz for helping with the preparation of the figures. Work in the authors’ laboratory is supported by grants from the European Research Council (VIRAFRONT), the Deutsche Forschungsgemeinschaft (DFG) (SFB 900, Teilprojekt A6; PI 734/1-1 and PI734/2-1), and by grants from the Initiative and Networking Fund of the Helmholtz Association SO-024 and HA-202 to T.P. E.S. is supported by DFG (STE 1954/1-1).
Financial and competing interest disclosure The authors declare no conflict of interest. T.P. has received consulting fees from Biotest AG and from Janssen Global Services, LLC.
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Steinmann, E., Pietschmann, T. (2013). Cell Culture Systems for Hepatitis C Virus. In: Bartenschlager, R. (eds) Hepatitis C Virus: From Molecular Virology to Antiviral Therapy. Current Topics in Microbiology and Immunology, vol 369. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27340-7_2
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