A genetically humanized mouse model for hepatitis C virus infection

• Published in: Nature (London) Vol. 474; no. 7350; pp. 208 - 211
• Main Authors: Dorner, Marcus, Horwitz, Joshua A., Robbins, Justin B., Barry, Walter T., Feng, Qian, Mu, Kathy, Jones, Christopher T., Schoggins, John W., Catanese, Maria Teresa, Burton, Dennis R., Law, Mansun, Rice, Charles M., Ploss, Alexander
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.06.2011; Nature Publishing Group
• Subjects: 631/250/248; 631/250/251/1567; 631/326/596/2555; 692/699/1503/234/2513/1551; Adenoviridae - genetics; Adenoviridae - physiology; Animal models; Animals; Antibodies, Blocking - immunology; Antigens, CD - genetics; Antigens, CD - metabolism; Biological and medical sciences; Cells, Cultured; Claudin-1; Disease Models, Animal; Genetics; Genomes; Genotype; Hepacivirus - genetics; Hepacivirus - metabolism; Hepacivirus - physiology; Hepatitis; Hepatitis C - genetics; Hepatitis C - virology; Hepatitis C virus; Hepatocytes - cytology; Hepatocytes - metabolism; Hepatocytes - virology; Human factors; Human viral diseases; Humanities and Social Sciences; Humans; Immunization; Immunization, Passive; Infectious diseases; letter; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; multidisciplinary; Proteins; Receptors, Virus - genetics; Receptors, Virus - metabolism; Rodents; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Science; Science (multidisciplinary); Studies; Tetraspanin 28; Transfection; Vaccinia virus; Viral diseases; Viral hepatitis; Viral Tropism; Animal model; Pathogenesis; Recombinant virus; Hepatic disease; Heterotransplantation; Prevention; Life cycle; Hepatocyte; Antiviral; Vector; Humoral immunity; Viral hepatitis C; Human; Chordopoxvirinae; Orthopoxvirus; Rodentia; Vaccine; Gene expression; Infection; Virus; Vaccinia virus; Immunoprophylaxis; In vivo; Vertebrata; Mammalia; Treatment; Mouse; Poxviridae; Viral disease; Animal; Digestive diseases; Flaviviridae; Hepatitis C virus; Hepacivirus; Passive immunization
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10168

A mouse model for hepatitis C infection The development of therapies for hepatitis C virus (HCV) infection has been hampered by the lack of a small-animal model of the disease. Now Alexander Ploss and colleagues describe the first immunocompetent rodent model for hepatitis C virus infection, using adenoviruses expressing four human factors to enable entry of HCV into mouse cells. These vectors were then used to transduce the livers of mice, which then became susceptible to HCV infection. Although the model does not enable a complete virus replication cycle, it should be useful for the evaluation of HCV vaccines and entry inhibitors. Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro 4 , we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo .