A genetically humanized mouse model for hepatitis C virus infection

Marcus Dorner, Joshua A. Horwitz, Justin B. Robbins, Walter T. Barry, Qian Feng, Kathy Mu, Christopher T. Jones, John W. Schoggins, Maria Teresa Catanese, Dennis R. Burton, Mansun Law, Charles M. Rice, Alexander Ploss

Research output: Contribution to journalArticle

274 Citations (Scopus)

Abstract

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, 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.

Original languageEnglish (US)
Pages (from-to)208-212
Number of pages5
JournalNature
Volume474
Issue number7350
DOIs
StatePublished - Jun 8 2011

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Virus Diseases
Hepacivirus
Virus Internalization
CD36 Antigens
Occludin
Heterologous Transplantation
Passive Immunization
Vaccinia virus
Humoral Immunity
Life Cycle Stages
Antiviral Agents
Hepatocytes
Immunity
Rodentia
Vaccines
Animal Models
Therapeutics
Genes

ASJC Scopus subject areas

  • General

Cite this

Dorner, M., Horwitz, J. A., Robbins, J. B., Barry, W. T., Feng, Q., Mu, K., ... Ploss, A. (2011). A genetically humanized mouse model for hepatitis C virus infection. Nature, 474(7350), 208-212. https://doi.org/10.1038/nature10168

A genetically humanized mouse model for hepatitis C virus infection. / 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.

In: Nature, Vol. 474, No. 7350, 08.06.2011, p. 208-212.

Research output: Contribution to journalArticle

Dorner, M, Horwitz, JA, Robbins, JB, Barry, WT, Feng, Q, Mu, K, Jones, CT, Schoggins, JW, Catanese, MT, Burton, DR, Law, M, Rice, CM & Ploss, A 2011, 'A genetically humanized mouse model for hepatitis C virus infection', Nature, vol. 474, no. 7350, pp. 208-212. https://doi.org/10.1038/nature10168
Dorner M, Horwitz JA, Robbins JB, Barry WT, Feng Q, Mu K et al. A genetically humanized mouse model for hepatitis C virus infection. Nature. 2011 Jun 8;474(7350):208-212. https://doi.org/10.1038/nature10168
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. / A genetically humanized mouse model for hepatitis C virus infection. In: Nature. 2011 ; Vol. 474, No. 7350. pp. 208-212.
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