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In Vivo Study of HCV in Mice with Chimeric Human Livers

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Hepatitis C

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 510))

Abstract

Estimates of hepatitis C virus infection include 170 million people worldwide, who face increased risk of development of cirrhosis, liver failure, and hepatocellular carcinoma. Standard of care therapy with pegylated interferon and ribavirin is effective in just half of patients, is challenged by substantial treatment-related morbidity, and is prohibitively expensive in most parts of the world. New therapeutics for treatment and prevention are clearly needed. Development of effective therapies has been significantly hampered by difficulties in establishing in vitro and in vivo models of viral replication. This chapter reviews development, validation, and early application of a mouse model with a chimeric human liver.

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References

  1. World Health Organization (1999) Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J. Viral Hepat. 6, 35–47.

    Article  Google Scholar 

  2. Alter, M. J., Kruszon-Moran, D., Nainan,O. V., McQuillan, G. M., Gao, F., Moyer,L. A., et al. (1999) The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N. Engl. J. Med. 341, 556–562.

    Article  CAS  PubMed  Google Scholar 

  3. Alter, M. J., Margolis, H. S., Krawczynski, K., Judson, F. N., Mares, A., Alexander, W. J.,et al. (1992) The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N. Engl. J. Med. 327, 1899–1905.

    Article  CAS  PubMed  Google Scholar 

  4. McHutchison, J. G., Gordon, S. C., Schiff,E. R., Shiffman, M. L., Lee, W. M., Rustgi,V. K., et al. (1998) Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N. Engl. J. Med. 339, 1485–1492.

    Article  CAS  PubMed  Google Scholar 

  5. Moreno-Otero, R. (2005) Therapeutic modalities in hepatitis C: challenges and development. J. Viral Hepat. 12,10–19.

    Article  CAS  PubMed  Google Scholar 

  6. Heckel, J. L., Sandgren, E. P., Degen, J. L., Palmiter, R. D., and Brinster, R. L. (1990) Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Cell 62, 447–456.

    Article  CAS  PubMed  Google Scholar 

  7. Sandgren, E. P., Palmiter, R. D., Heckel, J. L., Daugherty, C. C., Brinster, R. L., and Degen, J. L. (1991) Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell 66, 245–256.

    Article  CAS  PubMed  Google Scholar 

  8. Rhim, J. A., Sandgren, E. P., Degen, J. L., Palmiter, R. D., and Brinster, R. L. (1994) Replacement of diseased mouse liver by hepatic cell transplantation. Science 263, 1149–1152.

    Article  CAS  PubMed  Google Scholar 

  9. Rhim, J. A., Sandgren, E. P., Palmiter, R. D., and Brinster, R. L. (1995) Complete reconstitution of mouse liver with xenogeneic hepatocytes. Proc. Natl. Acad. Sci. USA 92, 4942–4946.

    Article  CAS  PubMed  Google Scholar 

  10. Dandri, M., Burda, M. R., Torok, E., Pollok, J. M., Iwanska, A., Sommer, G., et al. (2001) Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus. Hepatology 33, 981–988.

    Article  CAS  PubMed  Google Scholar 

  11. Kneteman, N. M. and Mercer, D. F. (2005) Mice with chimeric human livers: who says supermodels have to be tall? Hepatology 41, 703–706.

    Article  CAS  PubMed  Google Scholar 

  12. Mercer, D. F., Schiller, D. E., Elliott, J. F., Douglas, D. N., Hao, C., Rinfret, A., et al. (2001) Hepatitis C virus replication in mice with chimeric human livers. Nat. Med. 7, 927–933.

    Article  CAS  PubMed  Google Scholar 

  13. Meuleman, P., Vanlandschoot, P., and Leroux-Roels, G. (2003) A simple and rapid method to determine the zygosity of uPA-transgenic SCID mice. Biochem. Biophys. Res. Commun. 308, 375–378.

    Article  CAS  PubMed  Google Scholar 

  14. Meuleman, P., Libbrecht, L., De Vos, R., de Hemptinne, B., Gevaert, K., Vandekerckhove, J., et al. (2005) Morphological and biochemical characterization of a human liver in auPA-SCID mouse chimera. Hepatology 41, 847–856.

    Article  CAS  PubMed  Google Scholar 

  15. Katoh, M., Sawada, T., Soeno, Y., Nakajima, M., Tateno, C., Yoshizato, K., et al. (2007) In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver. J. Pharm. Sci. 96, 428–437.

    Article  CAS  PubMed  Google Scholar 

  16. Kakinuma, S., Asahina, K., Okamura, K.,Teramoto, K., Tateno, C., Yoshizato, K., et al. (2007) Human cord blood cells transplanted into chronically damaged liver exhibit similar characteristics to functional hepatocytes. Transplant. Proc. 39, 240–243.

    Article  CAS  PubMed  Google Scholar 

  17. Okumura, H., Katoh, M., Sawada, T.,Nakajima, M., Soeno, Y., Yabuuchi, H., et al. (2007) Humanization of excretory pathway in chimeric mice with humanized liver. Toxicol. Sci. 97, 533–538.

    Article  CAS  PubMed  Google Scholar 

  18. Yoshitsugu, H., Nishimura, M., Tateno, C., Kataoka, M., Takahashi, E., Soeno, Y., et al. (2006) Evaluation of human CYP1A2 and CYP3A4 mRNA expression in hepatocytes from chimeric mice with humanized liver. Drug Metab. Pharmacokinet. 21, 465–474.

    Article  CAS  PubMed  Google Scholar 

  19. Tateno, C., Yoshizane, Y., Saito, N., Kataoka, M., Utoh, R., Yamasaki, C., et al. (2004) Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am. J. Pathol. 165, 901–912.

    Article  CAS  PubMed  Google Scholar 

  20. Morosan, S., Hez-Deroubaix, S., Lunel, F., Renia, L., Giannini, C., Van Rooijen, N.,et al. (2006) Liver-stage development of Plasmodium falciparum, in a humanized mouse model. J. Infect. Dis. 193, 996–1004.

    Article  CAS  PubMed  Google Scholar 

  21. Lindenbach, B. D., Evans, M. J., Syder,A. J., Wolk, B., Tellinghuisen, T. L., Liu, C. C., et al. (2005) Complete replication of hepatitis C virus in cell culture. Science 309, 623–626.

    Article  CAS  PubMed  Google Scholar 

  22. Hiraga, N., Imamura, M., Tsuge, M., Noguchi, C., Takahashi, S., Iwao, E.,et al. (2007) Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis C virus and its susceptibility to interferon. FEBS Lett. 581, 1983–1987.

    Article  CAS  PubMed  Google Scholar 

  23. Hao, C., Song, J. H., Hsi, B., Lewis, J., Song, D. K., Petruk, K. C., et al. (2004) TRAIL inhibits tumor growth but is nontoxic to human hepatocytes in chimeric mice. Cancer Res. 64, 8502–8506.

    Article  CAS  PubMed  Google Scholar 

  24. Prince, A. M. and Brotman, B. (1998) Biological and immunological aspects of hepatitis C virus infection in chimpanzees, in Hepatitis C Virus (Reesink, H. W., ed.), Current Studies in Hematology and Blood Transfusion 62, Karger, Basel, New York, pp. 250–265.

    Google Scholar 

  25. Xie, Z. C., Riezu-Boj, J. I., Lasarte, J. J., Guillen, J., Su, J. H., Civeira, M. P., et al. (1998) Transmission of hepatitis C virus infection to tree shrews. Virology 244, 513–520.

    Article  CAS  PubMed  Google Scholar 

  26. Beames, B., Chavez, D., Guerra, B., Notvall, L., Brasky, K. M., and Lanford, R. E. (2000) Development of a primary tamarin hepatocyte culture system for GB virus-B: a surrogate model for hepatitis C virus. J. Virol. 74, 11764–11772.

    Article  CAS  PubMed  Google Scholar 

  27. Brass, V., Blum, H. E. and Moradpour, D. (2002) Of mice and men: a small animal model of hepatitis C virus replication. Hepatology 35, 722–724.

    Article  PubMed  Google Scholar 

  28. Cagnon, L., Wagaman, P., Bartenschlager, R., Pietschmann, T., Gao, T., Kneteman, N. M., et al. (2004) Application of the trak-C HCV core assay for monitoring antiviral activity in HCV replication systems. J. Virol. Methods 118, 23–31.

    Article  CAS  PubMed  Google Scholar 

  29. Kneteman, N. M., Weiner, A. J., O’Connell, J., Collett, M., Gao, T., Aukerman, L., et al. (2006) Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application. Hepatology 43, 1346–1353.

    Article  CAS  PubMed  Google Scholar 

  30. Lamarre, D., Anderson, P. C., Bailey, M., Beaulieu, P., Bolger, G., Bonneau, P., et al. (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426, 186–189.

    Article  CAS  PubMed  Google Scholar 

  31. Lin, C., Lin, K., Luong, Y. P., Rao, B. G., Wei, Y. Y., Brennan, D. L., et al. (2004) In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J. Biol. Chem. 279, 17508–17514.

    Article  CAS  PubMed  Google Scholar 

  32. Lin, C., Gates, C. A., Rao, B. G., Brennan,D. L., Fulghum, J. R., Luong, Y. P.,et al. (2005) In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J. Biol. Chem. 280, 36784–36791.

    Article  CAS  PubMed  Google Scholar 

  33. Reiser, M., Hinrichsen, H., Benhamou, Y., Reesink, H. W., Wedemeyer, H., Avendano, C., et al. (2005) Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology 41, 832–835.

    Article  CAS  PubMed  Google Scholar 

  34. Thibeault, D., Bousquet, C., Gingras, R., Lagace, L., Maurice, R., White, P. W.,et al. (2004) Sensitivity of NS3 serine proteases from hepatitis C virus genotypes 2 and 3 to the inhibitor BILN 2061. J. Virol. 78, 7352–7359.

    Article  CAS  PubMed  Google Scholar 

  35. Vanwolleghem, T., Meuleman, P., Libbrecht, L., Roskams T., De Vos R., and Leroux-Roels, G. (2006) The human liver uPA-SCID mouse model allows for the rapid detection of antiviral and cardiotoxic effects of BILN2061. 13th International meeting on Hepatitis C Virus and Related Viruses, Cairns, Australia. Abstract 520.

    Google Scholar 

  36. Kneteman, N., Howe, A., Gao, T., Lewis, J., Collett, M., Pevear, D., et al. (2007) An NS5B polymerase inhibitor with potent anti-HCV impact in vitro, in mice with chimeric human livers in humans infected with the hepatitis C virus (HCV). Hepatology,submitted.

    Google Scholar 

  37. Viropharma Press Release (2006) HCV 796 Viropharma announces presentation of HCV 796 Phase Ib data at Digestive Disease Week. 21 May 2006. http://www.viropharma.com.

  38. Gopalsamy, A., Aplasca, A., Ciszewski, G., Park, K., Ellingboe, J. W., Orlowski, M., et al. (2006) Design and synthesis of 3,4-dihydro-1H-[1]-benzothieno[2,3-c]pyran and 3,4-dihydro-1H-pyrano[3,4-b]benzofuran derivatives as non-nucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase. Bioorg. Med. Chem. Lett. 16, 457–460.

    Article  CAS  PubMed  Google Scholar 

  39. Viropharma Press Release (2003) HCV 371 Viropharma announces results of hepatitis C phase 1b Study. 15 July 2003. http://www.viropharma.com.

  40. Hsu, E. C., Hsi, B., Hirota-Tsuchihara, M., Ruland, J., Iorio, C., Sarangi, F., et al. (2003) Modified apoptotic molecule (BID) reduces hepatitis C virus infection in mice with chimeric human livers. Nat. Biotechnol. 21, 519–525.

    Article  CAS  PubMed  Google Scholar 

  41. Sacci, J. B., Jr., Alam, U., Douglas, D., Lewis, J., Tyrrell, D. L., Azad, A. F., et al. (2006) Plasmodium falciparum infection and exoerythrocytic development in mice with chimeric human livers. Int. J. Parasitol. 36, 353–360.

    Article  CAS  PubMed  Google Scholar 

  42. Walters, K. A., Joyce, M. A., Thompson,J. C., Smith, M. W., Yeh, M. M., Proll, S., et al. (2006) Host-specific response to HCV infection in the chimeric SCID-beige/Alb-uPA mouse model: role of the innate antiviral immune response. PLoS Pathog. 2, e59.

    Article  PubMed  Google Scholar 

  43. Jo, M., Kim, T. H., Seol, D. W., Esplen, J. E., Dorko, K., Billiar, T. R., et al. (2000) Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat. Med. 6, 564–567.

    Article  CAS  PubMed  Google Scholar 

  44. Mahieu-Caputo, D., Allain, J. E., Branger, J., Coulomb, A., Delgado, J. P., Andreoletti, M., et al. (2004) Repopulation of athymic mouse liver by cryopreserved early human fetal hepatoblasts. Hum. Gene Ther. 15, 1219–1228.

    Article  CAS  PubMed  Google Scholar 

  45. Nguyen, T. H., Mai, G., Villiger, P., Oberholzer, J., Salmon, P., Morel, P., et al. (2005) Treatment of acetaminophen-induced acute liver failure in the mouse with conditionally immortalized human hepatocytes. J. Hepatol. 43, 1031–1037.

    Article  CAS  PubMed  Google Scholar 

  46. Ruhnke, M., Ungefroren, H., Nussler, A., Martin, F., Brulport, M., Schormann, W., et al. (2005) Differentiation of in vitro-modified human peripheral blood monocytes into hepatocyte-like and pancreatic islet-like cells. Gastroenterology 128, 1774–1786.

    Article  CAS  PubMed  Google Scholar 

  47. Fu, T., Blei, A. T., Takamura, N., Lin, T., Guo, D., Li, H., et al. (2004) Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. Cell Transplant 13, 667–676.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery Faculty of Medicine and Oral Health Sciences, University of Alberta, Edmonton, Canada

    Norman M. Kneteman & Christian Toso

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  1. Norman M. Kneteman
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  2. Christian Toso
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Editors and Affiliations

  1. Florida State University, Tallahassee, FL, USA

    Hengli Tang

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© 2009 Humana Press, a part of Springer Science+Business Media, LLC

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Kneteman, N.M., Toso, C. (2009). In Vivo Study of HCV in Mice with Chimeric Human Livers. In: Tang, H. (eds) Hepatitis C. Methods in Molecular Biology™, vol 510. Humana Press. https://doi.org/10.1007/978-1-59745-394-3_29

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  • DOI: https://doi.org/10.1007/978-1-59745-394-3_29

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-970-3

  • Online ISBN: 978-1-59745-394-3

  • eBook Packages: Springer Protocols

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