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Completion of the entire hepatitis C virus life cycle in genetically humanized mice
The entire hepatitis C virus life cycle can be recapitulated in an inbred mouse model, allowing preclinical assessment of antiviral therapeutics and vaccines. Humanized mouse model for hepatitis C infection In a 2009 Nature paper, Alexander Ploss and colleagues showed that transient expression of th...
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Published in: | Nature (London) 2013-09, Vol.501 (7466), p.237-241 |
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Main Authors: | , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | The entire hepatitis C virus life cycle can be recapitulated in an inbred mouse model, allowing preclinical assessment of antiviral therapeutics and vaccines.
Humanized mouse model for hepatitis C infection
In a 2009
Nature
paper, Alexander Ploss and colleagues showed that transient expression of the human genes
CD81
and occludin (
OCLN
) constituted a minimal set of cellular factors required for uptake of hepatitis C virus (HCV) into immune-competent mouse cells. Now they report that transgenic immune-deficient mice stably expressing CD81 and OCLN can sustain the complete HCV replication cycle with measurable viraemia. The availability of this genetically humanized mouse model opens the way to closer study of HCV infection
in vivo
and should provide a valuable platform for testing potential therapeutics.
More than 130 million people worldwide chronically infected with hepatitis C virus (HCV) are at risk of developing severe liver disease. Antiviral treatments are only partially effective against HCV infection, and a vaccine is not available. Development of more efficient therapies has been hampered by the lack of a small animal model. Building on the observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive to HCV entry
1
, we previously showed that transient expression of these two human genes is sufficient to allow viral uptake into fully immunocompetent inbred mice
2
. Here we demonstrate that transgenic mice stably expressing human CD81 and OCLN also support HCV entry, but innate and adaptive immune responses restrict HCV infection
in vivo
. Blunting antiviral immunity in genetically humanized mice infected with HCV results in measurable viraemia over several weeks. In mice lacking the essential cellular co-factor cyclophilin A (CypA), HCV RNA replication is markedly diminished, providing genetic evidence that this process is faithfully recapitulated. Using a cell-based fluorescent reporter activated by the NS3-4A protease we visualize HCV infection in single hepatocytes
in vivo
. Persistently infected mice produce
de novo
infectious particles, which can be inhibited with directly acting antiviral drug treatment, thereby providing evidence for the completion of the entire HCV life cycle in inbred mice. This genetically humanized mouse model opens new opportunities to dissect genetically HCV infection
in vivo
and provides an important preclinical platform for testing and prioritizing d |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature12427 |