12:00 AM
Jun 16, 2011
 |  BC Innovations  |  Cover Story

HCV's mighty mouse

The most widely used animal model of HCV infection requires transplanting human hepatocytes into immunodeficient mice. These mice are useful for testing antivirals, but the absence of an immune system makes the animals unsuitable for studying other classes of HCV products such as vaccines and immunotherapeutics. Now, researchers from The Rockefeller University have developed an immunocompetent, genetically humanized mouse that allows limited HCV infection, albeit not replication.1

The researchers are in discussions with an undisclosed company interested in exclusivelylicensing the technology to evaluate HCV entry inhibitors and vaccines.

The Rockefeller group used a two-pronged approach to develop the model: genetically humanizing the mice with human HCV entry factors and infecting the animals with a sensitive HCV luciferase reporter system.

First, the researchers intravenously delivered adenovirus vectors encoding human host entry factors CD81, scavenger receptor class B member 1 (SCARB1), claudin 1 (CLDN1) and/or occludin (OCLN) to mice. About 18%-25% of murine hepatocytes had strong expression of human CD81 and OCLN, and all 4 proteins showed up in about 5% of murine hepatocytes.

To detect HCV infection in the liver, mice were engineered to express the luciferase gene following inoculation with HCV.

The signal peaked at 72 hours postinfection and subsequently decreased, suggesting a single cycle of HCV infection occurred without additional viral replication. This limits the system's use to screening inhibitors of HCV entry but not inhibitors of other aspects of the HCV life cycle (see Box 1, "A vaccine is not just a vaccine").

The researchers suspect the short viral life span is due to both the host immune response induced by the adenovirus vectors used to express the human host entry factors and the lack of human-specific host factors needed to foster assembly and release of infectious virus particles.

HCV infection took place in about 5% of murine hepatocytes expressing human CD81 and OCLN and in up to 20% of murine hepatocytes expressing all 4 factors, indicating that expression of CD81 and OCLN is sufficient for HCV infectivity.

The researchers said the range of infection frequencies resembles that seen in HCV-positive patient tissues. Indeed, the mouse model mimics the hepatocyte context of a chronically infected patient and would provide a reasonable entry inhibitor assessment model, said Geneviève Inchauspé, department head of infectious diseases at Transgene S.A.


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