Liver transplantation (LT) of hepatitis C virus (HCV)-infected grafts into HCV-infected recipients leads to superinfection with two different virus strains. To characterize the virological outcomes of HCV superinfection immediately after LT, we performed phylogenetic analysis of a fragment of the NS5B gene in donor and recipient serum samples prospectively collected before and after LT, starting on day 1. In four of six cases, the donor strain finally prevailed, while in the remaining two cases, the native recipient strain overtook the donor quasispecies. Clonal sequence analysis showed that, in three cases, the expelled strain was undetectable 1 day after LT. Our study shows that superinfection with a different HCV strain can lead to the exclusion of one strain by the other as soon as the first day after LT. This would suggest that competition might not be limited to the replication level, but could also take place during virus entry.


Article metrics loading...

Loading full text...

Full text loading...



  1. Blasco, A., Forns, X., Carrion, J. A., Garcia-Pagan, J. C., Gilabert, R., Rimola, A., Miquel, R., Bruguera, M., Garcia-Valdecasas, J. C. & other authors(2006). Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation. Hepatology 43, 492–499.[CrossRef] [Google Scholar]
  2. Clarke, D. K., Duarte, E. A., Elena, S. F., Moya, A., Domingo, E. & Holland, J.(1994). The red queen reigns in the kingdom of RNA viruses. Proc Natl Acad Sci U S A 91, 4821–4824.[CrossRef] [Google Scholar]
  3. Eyster, M. E., Sherman, K. E., Goedert, J. J., Katsoulidou, A. & Hatzakis, A.(1999). Prevalence and changes in hepatitis C virus genotypes among multitransfused persons with hemophilia. The Multicenter Hemophilia Cohort Study. J Infect Dis 179, 1062–1069.[CrossRef] [Google Scholar]
  4. Fan, X., Lang, D. M., Xu, Y., Lyra, A. C., Yusim, K., Everhart, J. E., Korber, B. T., Perelson, A. S. & Di Bisceglie, A. M.(2003). Liver transplantation with hepatitis C virus-infected graft: interaction between donor and recipient viral strains. Hepatology 38, 25–33. [Google Scholar]
  5. Farci, P., Alter, H. J., Govindarajan, S., Wong, D. C., Engle, R., Lesniewski, R. R., Mushahwar, I. K., Desai, S. M., Miller, R. H. & Ogata, N.(1992). Lack of protective immunity against reinfection with hepatitis C virus. Science 258, 135–140.[CrossRef] [Google Scholar]
  6. Feliu, A., Gay, E., Garcia-Retortillo, M., Saiz, J. C. & Forns, X.(2004). Evolution of hepatitis C virus quasispecies immediately following liver transplantation. Liver Transpl 10, 1131–1139.[CrossRef] [Google Scholar]
  7. Forns, X., Purcell, R. H. & Bukh, J.(1999). Quasispecies in viral persistence and pathogenesis of hepatitis C virus. Trends Microbiol 7, 402–410.[CrossRef] [Google Scholar]
  8. Fukumoto, T., Berg, T., Ku, Y., Bechstein, W. O., Knoop, M., Lemmens, H. P., Lobeck, H., Hopf, U. & Neuhaus, P.(1996). Viral dynamics of hepatitis C early after orthotopic liver transplantation: evidence for rapid turnover of serum virions. Hepatology 24, 1351–1354.[CrossRef] [Google Scholar]
  9. Garcia-Retortillo, M., Forns, X., Feliu, A., Moitinho, E., Costa, J., Navasa, M., Rimola, A. & Rodes, J.(2002). Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology 35, 680–687.[CrossRef] [Google Scholar]
  10. Gause, G. F.(1971).Struggle for Existence. New York: Dover Publications.
  11. Gretch, D. R., Polyak, S. J., Wilson, J. J., Carithers, R. L., Jr, Perkins, J. D. & Corey, L.(1996). Tracking hepatitis C virus quasispecies major and minor variants in symptomatic and asymptomatic liver transplant recipients. J Virol 70, 7622–7631. [Google Scholar]
  12. Herring, B. L., Page-Shafer, K., Tobler, L. H. & Delwart, E. L.(2004). Frequent hepatitis C virus superinfection in injection drug users. J Infect Dis 190, 1396–1403.[CrossRef] [Google Scholar]
  13. Hughes, M. G., Jr, Rudy, C. K., Chong, T. W., Smith, R. L., Evans, H. L., Iezzoni, J. C., Sawyer, R. G. & Pruett, T. L.(2004). E2 quasispecies specificity of hepatitis C virus association with allografts immediately after liver transplantation. Liver Transpl 10, 208–216.[CrossRef] [Google Scholar]
  14. Kao, J. H., Chen, P. J., Lai, M. Y. & Chen, D. S.(1993). Superinfection of heterologous hepatitis C virus in a patient with chronic type C hepatitis. Gastroenterology 105, 583–587. [Google Scholar]
  15. Khapra, A. P., Agarwal, K., Fiel, M. I., Kontorinis, N., Hossain, S., Emre, S. & Schiano, T. D.(2006). Impact of donor age on survival and fibrosis progression in patients with hepatitis C undergoing liver transplantation using HCV+ allografts. Liver Transpl 12, 1496–1503.[CrossRef] [Google Scholar]
  16. Kuiken, C. & Simmonds, P.(2009). Nomenclature and numbering of the hepatitis C virus. Methods Mol Biol 510, 33–53. [Google Scholar]
  17. Laskus, T., Wang, L. F., Rakela, J., Vargas, H., Pinna, A. D., Tsamandas, A. C., Demetris, A. J. & Fung, J.(1996). Dynamic behavior of hepatitis C virus in chronically infected patients receiving liver graft from infected donors. Virology 220, 171–176.[CrossRef] [Google Scholar]
  18. Laskus, T., Wang, L. F., Radkowski, M., Vargas, H., Nowicki, M., Wilkinson, J. & Rakela, J.(2001). Exposure of hepatitis C virus (HCV) RNA-positive recipients to HCV RNA-positive blood donors results in rapid predominance of a single donor strain and exclusion and/or suppression of the recipient strain. J Virol 75, 2059–2066.[CrossRef] [Google Scholar]
  19. Lavanchy, D.(2009). The global burden of hepatitis C. Liver Int 29 (Suppl. 1), 74–81. [Google Scholar]
  20. Lerat, H., Rumin, S., Habersetzer, F., Berby, F., Trabaud, M. A., Trepo, C. & Inchauspe, G.(1998).In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype. Blood 91, 3841–3849. [Google Scholar]
  21. Marroquin, C. E., Marino, G., Kuo, P. C., Plotkin, J. S., Rustgi, V. K., Lu, A. D., Edwards, E., Taranto, S. & Johnson, L. B.(2001). Transplantation of hepatitis C-positive livers in hepatitis C-positive patients is equivalent to transplanting hepatitis C-negative livers. Liver Transpl 7, 762–768.[CrossRef] [Google Scholar]
  22. Martell, M., Esteban, J. I., Quer, J., Genesca, J., Weiner, A., Esteban, R., Guardia, J. & Gomez, J.(1992). Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J Virol 66, 3225–3229. [Google Scholar]
  23. 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-alpha therapy. Science 282, 103–107.[CrossRef] [Google Scholar]
  24. Neumann, U. P., Berg, T., Bahra, M., Seehofer, D., Langrehr, J. M., Neuhaus, R., Radke, C. & Neuhaus, P.(2004). Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J Hepatol 41, 830–836.[CrossRef] [Google Scholar]
  25. Okamoto, H., Mishiro, S., Tokita, H., Tsuda, F., Miyakawa, Y. & Mayumi, M.(1994). Superinfection of chimpanzees carrying hepatitis C virus of genotype II/1b with that of genotype III/2a or I/1a. Hepatology 20, 1131–1136.[CrossRef] [Google Scholar]
  26. Pal, S., Sullivan, D. G., Kim, S., Lai, K. K., Kae, J., Cotler, S. J., Carithers, R. L., Jr, Wood, B. L., Perkins, J. D. & Gretch, D. R.(2006). Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: implications of HCV lymphotropism. Gastroenterology 130, 1107–1116.[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. Prince, A. M., Brotman, B., Huima, T., Pascual, D., Jaffery, M. & Inchauspe, G.(1992). Immunity in hepatitis C infection. J Infect Dis 165, 438–443.[CrossRef] [Google Scholar]
  29. Radkowski, M., Wang, L. F., Vargas, H., Wilkinson, J., Rakela, J. & Laskus, T.(2001). Changes in hepatitis C virus population in serum and peripheral blood mononuclear cells in chronically infected patients receiving liver graft from infected donors. Transplantation 72, 833–838.[CrossRef] [Google Scholar]
  30. Ramirez, S., Perez-Del-Pulgar, S., Carrion, J. A., Costa, J., Gonzalez, P., Massaguer, A., Fondevila, C., Garcia-Valdecasas, J. C., Navasa, M. & Forns, X.(2009). Hepatitis C virus compartmentalization and infection recurrence after liver transplantation. Am J Transplant 9, 1591–1601.[CrossRef] [Google Scholar]
  31. Ramratnam, B., Bonhoeffer, S., Binley, J., Hurley, A., Zhang, L., Mittler, J. E., Markowitz, 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]
  32. Ray, S. C., Wang, Y. M., Laeyendecker, O., Ticehurst, J. R., Villano, S. A. & Thomas, D. L.(1999). Acute hepatitis C virus structural gene sequences as predictors of persistent viremia: hypervariable region 1 as a decoy. J Virol 73, 2938–2946. [Google Scholar]
  33. Scheuer, P. J.(1995). The nomenclature of chronic hepatitis: time for a change. J Hepatol 22, 112–114. [Google Scholar]
  34. Vargas, H. E., Laskus, T., Wang, L. F., Lee, R., Radkowski, M., Dodson, F., Fung, J. J. & Rakela, J.(1999). Outcome of liver transplantation in hepatitis C virus-infected patients who received hepatitis C virus-infected grafts. Gastroenterology 117, 149–153.[CrossRef] [Google Scholar]
  35. Velidedeoglu, E., Mange, K. C., Frank, A., Abt, P., Desai, N. M., Markmann, J. W., Reddy, R. & Markmann, J. F.(2004). Factors differentially correlated with the outcome of liver transplantation in HCV+ and HCV− recipients. Transplantation 77, 1834–1842.[CrossRef] [Google Scholar]

Data & Media loading...


[ Single PDF file] (58 KB)


[ Single PDF file] (396 KB)


Most cited this month Most Cited RSS feed

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