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A genetically humanized mouse model for hepatitis C virus infection


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.


  1. 1

    Pileri, P. et al. Binding of hepatitis C virus to CD81. Science 282, 938–941 (1998)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Scarselli, E. et al. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J. 21, 5017–5025 (2002)

    CAS  Article  Google Scholar 

  3. 3

    Evans, M. J. et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446, 801–805 (2007)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Ploss, A. et al. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457, 882–886 (2009)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Zhu, Q., Guo, J. T. & Seeger, C. Replication of hepatitis C virus subgenomes in nonhepatic epithelial and mouse hepatoma cells. J. Virol. 77, 9204–9210 (2003)

    CAS  Article  Google Scholar 

  6. 6

    Uprichard, S. L., Chung, J., Chisari, F. V. & Wakita, T. Replication of a hepatitis C virus replicon clone in mouse cells. Virol. J. 3, 89 (2006)

    Article  Google Scholar 

  7. 7

    Chang, K. S. et al. Replication of hepatitis C virus (HCV) RNA in mouse embryonic fibroblasts: protein kinase R (PKR)-dependent and PKR-independent mechanisms for controlling HCV RNA replication and mediating interferon activities. J. Virol. 80, 7364–7374 (2006)

    CAS  Article  Google Scholar 

  8. 8

    Lin, L. T. et al. Replication of subgenomic hepatitis C virus replicons in mouse fibroblasts is facilitated by deletion of interferon regulatory factor 3 and expression of liver-specific microRNA 122. J. Virol. 84, 9170–9180 (2010)

    CAS  Article  Google Scholar 

  9. 9

    McCaffrey, A. P. et al. Determinants of hepatitis C translational initiation in vitro, in cultured cells and mice. Mol. Ther. 5, 676–684 (2002)

    CAS  Article  Google Scholar 

  10. 10

    Schoggins, J. W. et al. A diverse array of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Safran, M. et al. Mouse reporter strain for noninvasive bioluminescent imaging of cells that have undergone Cre-mediated recombination. Mol. Imaging 2, 297–302 (2003)

    CAS  Article  Google Scholar 

  12. 12

    Awatramani, R., Soriano, P., Mai, J. J. & Dymecki, S. An Flp indicator mouse expressing alkaline phosphatase from the ROSA26 locus. Nature Genet. 29, 257–259 (2001)

    CAS  Article  Google Scholar 

  13. 13

    Ploss, A. et al. Persistent hepatitis C virus infection in microscale primary human hepatocyte cultures. Proc. Natl Acad. Sci. USA 107, 3141–3145 (2010)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Jones, C. T. et al. Real-time imaging of hepatitis C virus infection using a fluorescent cell-based reporter system. Nature Biotechnol. 28, 167–171 (2010)

    CAS  Article  Google Scholar 

  15. 15

    Liang, Y. et al. Visualizing hepatitis C virus infections in human liver by two-photon microscopy. Gastroenterology 137, 1448–1458 (2009)

    CAS  Article  Google Scholar 

  16. 16

    Higginbottom, A. et al. Identification of amino acid residues in CD81 critical for interaction with hepatitis C virus envelope glycoprotein E2. J. Virol. 74, 3642–3649 (2000)

    CAS  Article  Google Scholar 

  17. 17

    Rigotti, A. et al. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc. Natl Acad. Sci. USA 94, 12610–12615 (1997)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Catanese, M. T. et al. High-avidity monoclonal antibodies against the human scavenger class B type I receptor efficiently block hepatitis C virus infection in the presence of high-density lipoprotein. J. Virol. 81, 8063–8071 (2007)

    CAS  Article  Google Scholar 

  19. 19

    Meuleman, P. et al. Anti-CD81 antibodies can prevent a hepatitis C virus infection in vivo . Hepatology 48, 1761–1768 (2008)

    CAS  Article  Google Scholar 

  20. 20

    Law, M. et al. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nature Med. 14, 25–27 (2008)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Youn, J. W. et al. Evidence for protection against chronic hepatitis C virus infection in chimpanzees by immunization with replicating recombinant vaccinia virus. J. Virol. 82, 10896–10905 (2008)

    CAS  Article  Google Scholar 

  22. 22

    Ralston, R. et al. Characterization of hepatitis C virus envelope glycoprotein complexes expressed by recombinant vaccinia viruses. J. Virol. 67, 6753–6761 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Bissig, K. D. et al. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J. Clin. Invest. 120, 924–930 (2010)

    CAS  Article  Google Scholar 

  24. 24

    Mercer, D. F. et al. Hepatitis C virus replication in mice with chimeric human livers. Nature Med. 7, 927–933 (2001)

    CAS  Article  Google Scholar 

  25. 25

    Meuleman, P. et al. Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera. Hepatology 41, 847–856 (2005)

    CAS  Article  Google Scholar 

  26. 26

    de Jong, Y. P., Rice, C. M. & Ploss, A. New horizons for studying human hepatotropic infections. J. Clin. Invest. 120, 650–653 (2010)

    CAS  Article  Google Scholar 

  27. 27

    Stoller, J. Z. et al. Cre reporter mouse expressing a nuclear localized fusion of GFP and β-galactosidase reveals new derivatives of Pax3-expressing precursors. Genesis 46, 200–204 (2008)

    CAS  Article  Google Scholar 

  28. 28

    Lindenbach, B. D. et al. Complete replication of hepatitis C virus in cell culture. Science 309, 623–626 (2005)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Flint, M. et al. Characterization of hepatitis C virus E2 glycoprotein interaction with a putative cellular receptor, CD81. J. Virol. 73, 6235–6244 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Schoggins, J. W., Gall, J. G. & Falck-Pedersen, E. Subgroup B and F fiber chimeras eliminate normal adenovirus type 5 vector transduction in vitro and in vivo . J. Virol. 77, 1039–1048 (2003)

    CAS  Article  Google Scholar 

  31. 31

    Selby, M. et al. Hepatitis C virus envelope glycoprotein E1 originates in the endoplasmic reticulum and requires cytoplasmic processing for presentation by class I MHC molecules. J. Immunol. 162, 669–676 (1999)

    CAS  PubMed  Google Scholar 

  32. 32

    Cooper, S. et al. Analysis of a successful immune response against hepatitis C virus. Immunity 10, 439–449 (1999)

    CAS  Article  Google Scholar 

  33. 33

    Law, M. & Smith, G. L. in Vaccinia Virus and Poxvirology Methods and Protocols Methods in Molecular Biology Series (ed. Isaacs, S. N.) 187–204 (Humana, 2004)

    Book  Google Scholar 

  34. 34

    Marukian, S. et al. Cell culture-produced hepatitis C virus does not infect peripheral blood mononuclear cells. Hepatology 48, 1843–1850 (2008)

    Article  Google Scholar 

  35. 35

    Gottwein, J. M. et al. Development and characterization of hepatitis C virus genotype 1–7 cell culture systems: role of CD81 and scavenger receptor class B type I and effect of antiviral drugs. Hepatology 49, 364–377 (2009)

    CAS  Article  Google Scholar 

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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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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).

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