Editors' Choicehepatitis C

A Hepatitis C Mouse Model That Isn’t Chopped Liver

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Science Translational Medicine  22 Jun 2011:
Vol. 3, Issue 88, pp. 88ec94
DOI: 10.1126/scitranslmed.3002782

Hepatitis C virus (HCV), which affects between 2 and 4 million individuals in the United States and over 120 million worldwide, is a leading cause of cirrhosis and hepatocellular carcinoma and claims the lives of over 350,000 people each year. At present, no vaccine exists for HCV, and antiviral therapies are only effective in a fraction of cases. Hepatitis C infection occurs exclusively in humans and chimpanzees; rodent cells are completely protected against infection. This lack of a small-animal model that faithfully recapitulates the life cycle of hepatitis C is a major barrier to the development of improved treatments or even a vaccine to HCV. Now, Dorner et al. have identified a cocktail of four critical human molecules needed to establish HCV infection in the liver of mice. In a recent Nature article, they use recombinant adenoviral technology to deliver these four factors—CD81, occludin (OCLN), scavenger receptor type B Class I (SCARB1), and claudin (CLDN1)—to establish a humanized mouse model for hepatitis C viral infection.

Infecting mice with HCV is hard and tedious work, and requires some clever tools to monitor infection. To this end, Dorner et al. first created a bicistronic HCV genome that expressed the genetic material of hepatitis C as well as CRE recombinase. Genetically altered but immunocompetent mice that synthesize nuclear green fluorescent protein in the presence of CRE recombinase could thus be used to monitor infection. After systemic administration of adenoviral vectors encoding the four human proteins described above, HCV-infected cells would fluoresce green. Using this approach, one in five mouse hepatocytes expressing CD81, OCLN, SCARB1, and CLDN1 were successfully infected with HCV.

The beauty of this system lies in its potential ability to inform scientists about the biology of hepatitis C. More importantly, this small-animal model provides a platform to test vaccination and treatment strategies. As proof of principle, the group showed that passive immunization with antibodies to CD81 was able to decrease infection by 70%, whereas active immunization with recombinant vaccinia virus protected 20% of HCV-challenged animals. Hepatitis C has been described as both a silent and smoldering public health epidemic. It is silent no longer; Dorner and colleagues are using the first humanized mouse model of HCV infection to shine (fluorescent green) light on this important problem.

M. Dorner et al., A genetically humanized mouse model for hepatitis C virus infection. Nature 474, 208–211 (2011). [Abstract]

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