A small-animal model for hepatitis C virus (HCV) infection was developed using severe combined immunodeficiency (SCID) mice encoding homozygous urokinase-type plasminogen activator (uPA) transplanted with human hepatocytes. Currently, limited information is available concerning the HCV clearance rate in the SCID mouse model and the virion production rate in engrafted hepatocytes. In this study, several cohorts of uPA/SCID mice with nearly half of their livers repopulated by human hepatocytes were infected with HCV genotype 1b and used to evaluate HCV dynamics by pharmacokinetic and pharmacodynamic analyses of a specific NS3-4A protease inhibitor (telaprevir). A dose-dependent reduction in serum HCV RNA was observed. At telaprevir exposure equivalent to that in clinical studies, rapid turnover of serum HCV was also observed in this mouse model and the estimated slopes of virus decline were 0.11–0.17 log h. During the initial phase of treatment, the log reduction level of HCV RNA was dependent on the drug concentration, which was about fourfold higher in the liver than in plasma. HCV RNA levels in the liver relative to human endogenous gene expression were correlated with serum HCV RNA levels at the end of treatment for up to 10 days. A mathematical model analysis of viral kinetics suggested that 1 g of the chimeric human liver could produce at least 10 virions per day, and this may be comparable to HCV production in the human liver.


Article metrics loading...

Loading full text...

Full text loading...



  1. Boonstra, A., van der Laan, L. J. W., Vanwolleghem, T., Harry, L. A. & Janssen, H. L. A.(2009). Experimental models for hepatitis C viral infection. Hepatology 50, 1646–1655.[CrossRef] [Google Scholar]
  2. Chang, M., Williams, O., Mittler, J., Quintanilla, A., Carithers, R. L., Jr, Perkins, J., Corey, L. & Gretch, D. R.(2003). Dynamics of hepatitis C virus replication in human liver. Am J Pathol 163, 433–444.[CrossRef] [Google Scholar]
  3. Dahari, H., Feliu, A., Garcia-Retortillo, M., Forns, X. & Neumann, A. U.(2005). Second hepatitis C replication compartment indicated by viral dynamics during liver transplantation. J Hepatol 42, 491–498.[CrossRef] [Google Scholar]
  4. Forestier, N., Reesink, H. W., Weegink, C. J., McNair, L., Kieffer, T. L., Chu, H.-M., Purdy, S., Jansen, P. L. M. & Zeuzem, S.(2007). Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology 46, 640–648.[CrossRef] [Google Scholar]
  5. Fried, M. W., Shiffman, M., Reddy, K. R., Smith, C., Marinos, G., Gonçales, F. L., Jr, Häussinger, D., Diago, M., Carosi, G. & other authors(2002). Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347, 975–982.[CrossRef] [Google Scholar]
  6. Herrmann, E., Lee, J.-H., Marinos, G., Modi, M. & Zeuzem, S.(2003). Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology 37, 1351–1358.[CrossRef] [Google Scholar]
  7. Hézode, C., Forestier, N., Dusheiko, G., Ferenci, P., Pol, S., Goeser, T., Bronowicki, M.,, Bourlière, J.-P., Gharakhanian, S. & other authors(2009). Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 360, 1839–1850.[CrossRef] [Google Scholar]
  8. Hiraga, N., Imamura, M., Tsuge, M., Noguchi, C., Takahashi, S., Iwao, E., Fujimoto, Y., Abe, H., Maekawa, T. & other authors(2007). Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis C virus and its susceptibility to interferon. FEBS Lett 581, 1983–1987.[CrossRef] [Google Scholar]
  9. Katoh, M., Sawada, T., Soeno, Y., Nakajima, M., Tateno, C., Yoshizato, K. & Yokoi, T.(2007).In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver. J Pharm Sci 96, 428–437.[CrossRef] [Google Scholar]
  10. Katoh, M., Tateno, C., Yoshizato, K. & Yokoi, T.(2008). Chimeric mice with humanized liver. Toxicology 246, 9–17.[CrossRef] [Google Scholar]
  11. Kimura, T., Imamura, M., Hiraga, N., Hatakeyama, T., Miki, D., Noguchi, C., Mori, N., Tsuge, M., Takahashi, S. & other authors(2008). Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice. J Gen Virol 89, 2108–2113.[CrossRef] [Google Scholar]
  12. Kneteman, N. M., Weiner, A. J., O’Connell, J., Collett, M., Gao, T., Aukerman, L., Kovelsky, R., Ni, Z.-J., Hashash, A. & other authors(2006). Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application. Hepatology 43, 1346–1353.[CrossRef] [Google Scholar]
  13. Kneteman, N. M., Howe, A. Y. M., Gao, T., Lewis, J., Pevear, D., Lund, G., Douglas, D., Mercer, D. F., Tyrrell, D. L. J. & other authors(2009). HCV796: a selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus. Hepatology 49, 745–752.[CrossRef] [Google Scholar]
  14. Lauer, G. M. & Walker, B. D.(2001). Hepatitis C virus infection. N Engl J Med 345, 41–52.[CrossRef] [Google Scholar]
  15. Liang, T. J., Rehermann, B., Seeff, L. B. & Hoofnagle, J. H.(2000). Pathogenesis, natural history, treatment and prevention of hepatitis C. Ann Intern Med 132, 296–305.[CrossRef] [Google Scholar]
  16. Lindenbach, B. D., Meuleman, P., Ploss, A., Vanwolleghem, T., Syder, A. J., McKeating, J. A., Lanford, R. E., Feinstone, S. M., Major, M. E. & other authors(2006). Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci U S A 103, 3805–3809.[CrossRef] [Google Scholar]
  17. Lohmann, V., Körner, F., Koch, J., Herian, U., Theilmann, L. & Bartenschlager, R.(1999). Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285, 110–113.[CrossRef] [Google Scholar]
  18. Manns, M. P., McHutchison, J. G., Gordon, S. C., Rustgi, V. K., Shiffman, M., Reindollar, R., Goodman, Z. D., Koury, K., Ling, M.-H. & other authors(2001). Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958–965.[CrossRef] [Google Scholar]
  19. Manns, M. P., Foster, G. R., Rockstroh, J. K., Zeuzem, S., Zoulim, F. & Houghton, M.(2007). The way forward in HCV treatment – finding the right path. Nat Rev Drug Discov 6, 991–1000.[CrossRef] [Google Scholar]
  20. McHutchison, J. G., Everson, G. T., Gordon, S. C., Jacobson, I. M., Sulkowski, M., Kauffman, R., McNair, L., Alam, J., Muir, A. J. & other authors(2009). Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 360, 1827–1838.[CrossRef] [Google Scholar]
  21. Mercer, D. F., Schiller, D. E., Elliott, J. F., Douglas, D. N., Hao, C., Rinfret, A., Addison, W. R., Fischer, K. P., Churchill, T. A. & other authors(2001). Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7, 927–933.[CrossRef] [Google Scholar]
  22. Neumann, A. U., Lam, N. P., Dahari, H., Gretch, D. R., Wiley, T. E., Layden, T. J. & Perelson, A. S.(1998). Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 282, 103–107.[CrossRef] [Google Scholar]
  23. Pawlotsky, J.-M., Dahari, H., Neumann, A. U., Hezode, C., Germanidis, G., Lonjon, I., Castera, L. & Dhumeaux, D.(2004). Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology 126, 703–714.[CrossRef] [Google Scholar]
  24. Pereira, A. A. & Jacobson, I. M.(2009). New and experimental therapies for HCV. Nat Rev Gastroenterol Hepatol 6, 403–411.[CrossRef] [Google Scholar]
  25. Perelson, A. S. & Ribeiro, R. M.(2008). Estimating drug efficacy and viral dynamic parameters: HIV and HCV. Stat Med 27, 4647–4657.[CrossRef] [Google Scholar]
  26. Perni, R. B., Almquist, S. J., Byrn, R. A., Chandorkar, G., Chaturvedi, P. R., Courtney, L. F., Decker, C. J., Dinehart, K., Gates, C. A. & other authors(2006). Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother 50, 899–909.[CrossRef] [Google Scholar]
  27. Powers, K. A., Ribeiro, R. M., Patel, K., Pianko, S., Nyberg, L., Pockros, P., Conrad, A. J., McHutchison, J. & Perelson, A. S.(2006). Kinetics of hepatitis C virus reinfection after liver transplantation. Liver Transpl 12, 207–216.[CrossRef] [Google Scholar]
  28. Poynard, T., Yuen, M.-F., Ratziu, V. & Lai, C. L.(2003). Viral hepatitis C. Lancet 362, 2095–2100.[CrossRef] [Google Scholar]
  29. Quinkert, D., Bartenschlager, R. & Lohmann, V.(2005). Quantitative analysis of the hepatitis C virus replication complex. J Virol 79, 13594–13605.[CrossRef] [Google Scholar]
  30. Ramratnam, B., Bonhoeffer, S., Binley, J., Hurley, A., Zhang, L., Mittler, J. E., Minarkowitz, M., Moore, J. P., Perelson, A. S. & Ho, D. D.(1999). Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet 354, 1782–1785.[CrossRef] [Google Scholar]
  31. Reesink, H. W., Zeuzem, S., Weegink, C. J., Forestier, N., Vliet, A., van de Wetering de Rooij,, J., McNair, L, Purdy, S., Kauffman, R. & other authors(2006). Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 131, 997–1002.[CrossRef] [Google Scholar]
  32. Sarrazin, C., Kieffer, T. L., Bartels, D., Hanzelka, B., Möh, U., Welker, M., Wincheringer, D., Zhou, Y., Chu, H.-M. & other authors(2007). Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132, 1767–1777.[CrossRef] [Google Scholar]
  33. Schiano, T. D., Gutierrez, J. A., Walewski, J. L., Fiel, M. I., Cheng, B., Bodenheimer, H., Jr, Thung, S. N., Chung, R. T., Schwartz, M. E. & other authors(2005). Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors. Hepatology 42, 1420–1428.[CrossRef] [Google Scholar]
  34. Sherman, K. E., Fleischer, R., Laessig, K., Murray, J., Tauber, W. & Birnkrant, D.(2007). Development of novel agents for the treatment of chronic hepatitis C infection: summary of the FDA antiviral products advisory committee recommendations. Hepatology 46, 2014–2020.[CrossRef] [Google Scholar]
  35. Talal, A. H., Ribeiro, R. M., Powers, K. A., Grace, M., Cullen, C., Hussain, M., Markatou, M. & Perelson, A. S.(2006). Pharmacodynamics of PEG-IFN α differentiate HIV/HCV coinfected sustained virological responders from nonresponders. Hepatology 43, 943–953.[CrossRef] [Google Scholar]
  36. Tateno, C., Yoshizane, Y., Saito, N., Kataoka, M., Utoh, R., Yamasaki, C., Tachibana, A., Soeno, Y., Asahina, K. & other authors(2004). Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol 165, 901–912.[CrossRef] [Google Scholar]
  37. Tsuge, M., Hiraga, N., Takaishi, H., Noguchi, C., Oga, H., Imamura, M., Takahashi, S., Iwao, E., Fujimoto, Y. & other authors(2005). Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis B virus. Hepatology 42, 1046–1054.[CrossRef] [Google Scholar]
  38. Vanwolleghem, T., Meuleman, P., Libbrecht, L., Roskams, T., De Vos, R. & Leroux–Roels, G.(2007). Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse. Gastroenterology 133, 1144–1155.[CrossRef] [Google Scholar]
  39. Vona, G., Tuveri, R., Delpuech, O., Vallet, A., Canioni, D., Ballardini, G., Trabut, J. B., Le Bail, B., Nalpas, B. & other authors(2004). Intrahepatic hepatitis C virus RNA quantification in microdissected hepatocytes. J Hepatol 40, 682–688.[CrossRef] [Google Scholar]
  40. Wasley, A. & Alter, M. J.(2000). Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis 20, 1–16.[CrossRef] [Google Scholar]

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error