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A genetically humanized mouse model for hepatitis C virus infection

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 vitro4, 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.

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Figure 1: Genetic requirements for HCV entry in vivo.
Figure 2: HCV entry into murine hepatocytes in vivo can be blocked by antibodies or passive transfer of vaccine-induced antiserum.
Figure 3: Use of genetically humanized mouse model to evaluate vaccines against multiple HCV genotypes.

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Acknowledgements

We thank J. Sable, E. Castillo, A. Forrest, M. Panis, S. Pouzol, S. Shirley, A. Webson and E. Giang for laboratory support, L. Chiriboga and H. Yee for technical assistance, J. Bukh and Apath, LLC for providing the prototype intergenotypic HCV chimaeras and C. Murray for editing the manuscript. This study was supported in part by award number RC1DK087193 (to C.M.R. and A.P.) from the National Institute of Diabetes and Digestive and Kidney Diseases, R01AI072613 (to C.M.R.), R01AI079031 (to M.L.) and R01AI071084 (to D.R.B.) from the National Institute for Allergy and Infectious Disease, The Starr Foundation and the Greenberg Medical Institute. M.D. was supported by a postdoctoral fellowship from the German Research Foundation (Deutsche Forschungsgesellschaft) and M.T.C. by funds from The Rockefeller University’s Women & Science Fellowship Program. J.W.S. and C.T.J are recipients of Ruth L. Kirschstein National Research Service Awards from the National Institute of Health (F32DK082155 to J.W.S., F32DK081193 to C.T.J.).

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Authors

Contributions

M.D., C.M.R. and A.P. designed the project, analysed results and wrote the manuscript. M.D., J.A.H., J.B.R., W.T.B., Q.F., K.M., M.T.C. and M.L. performed the experimental work, J.W.S., C.T.J. and D.R.B. provided reagents.

Corresponding author

Correspondence to Alexander Ploss.

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Competing interests

The authors declare the following conflicts of interest, which are managed under University policy: C.M.R. has equity in Apath, LLC, which holds commercial licenses for the Huh-7.5 cell line and the HCV cell culture system.

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Dorner, M., Horwitz, J., Robbins, J. et al. A genetically humanized mouse model for hepatitis C virus infection. Nature 474, 208–211 (2011). https://doi.org/10.1038/nature10168

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