The mechanisms by which cyclophilin A (CypA) governs (HCV) replication remain unknown. Since CypA binds two essential components of the HCV replication complex (RC) – the polymerase NS5B and the phosphoprotein NS5A – we asked in this study whether CypA regulates their RC association. We found that CypA, via its isomerase pocket, locates in a protease-resistant compartment similar to that where HCV replicates. CypA association with this compartment is not mediated by HCV. Moreover, CypA depletion of RC does not influence NS5A and NS5B RC association, arguing against a model where CypA governs HCV replication by recruiting NS5A or NS5B into RC.


Article metrics loading...

Loading full text...

Full text loading...



  1. Appel, N., Schaller, T., Penin, F. & Bartenschlager, R.(2006). From structure to function: new insights into hepatitis C virus RNA replication. J Biol Chem 281, 9833–9836.[CrossRef] [Google Scholar]
  2. Azouzi, S., El Kirat, K. & Morandat, S.(2010). The potent antimalarial drug cyclosporin A preferentially destabilizes sphingomyelin-rich membranes. Langmuir 26, 1960–1965.[CrossRef] [Google Scholar]
  3. Chatterji, U., Bobardt, M., Selvarajah, S., Yang, F., Tang, H., Sakamoto, N., Vuagniaux, G., Parkinson, T. & Gallay, P.(2009). The isomerase active site of cyclophilin A is critical for hepatitis C virus replication. J Biol Chem 284, 16998–17005.[CrossRef] [Google Scholar]
  4. Chatterji, U., Lim, P., Bobardt, M., Wieland, S., Cordek, D. G., Vuagniaux, G., Chisari, F., Cameron, C. E., Targett-Adams, P. & Parkinson, T.(2010). HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A-cyclophilin A interaction to cyclophilin inhibitors. J Hepatol in press [Google Scholar]
  5. Coelmont, L., Kaptein, S., Paeshuyse, J., Vliegen, I., Dumont, J.-M., Vuagniaux, G. & Neyts, J.(2009). Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (STAT-C) inhibitors. Antimicrob Agents Chemother 53, 967–976.[CrossRef] [Google Scholar]
  6. Epand, R. M., Epand, R. F. & McKenzie, R. C.(1987). Effects of viral chemotherapeutic agents on membrane properties. Studies of cyclosporin A, benzyloxycarbonyl-d-Phe-l-Phe-Gly and amantadine. J Biol Chem 262, 1526–1529. [Google Scholar]
  7. Fernandes, F., Poole, D. S., Hoover, S., Middleton, R., Andrei, A. C., Gerstner, J. & Striker, R.(2007). Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B. Hepatology 46, 1026–1033. [Google Scholar]
  8. Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. & Schmid, F. X.(1989). Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337, 476–478.[CrossRef] [Google Scholar]
  9. Flisiak, R., Horban, A., Gallay, P., Bobardt, M., Selvarajah, S., Wiercinska-Drapal, A., Siwak, E., Cielniak, I., Higersberger, J. & other authors(2008). The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 47, 817–826.[CrossRef] [Google Scholar]
  10. Flisiak, R., Feinman, S. V., Jablkowski, M., Horban, A., Kryczka, W., Pawlowska, M., Heathcote, J. E., Mazzella, G., Vandelli, C. & other authors(2009). The cyclophilin inhibitor Debio 025 combined with PEG IFNα2a significantly reduces viral load in treatment-naïve hepatitis C patients. Hepatology 49, 1460–1468.[CrossRef] [Google Scholar]
  11. Gallay, P. A.(2009). Cyclophilin inhibitors. Clin Liver Dis 13, 403–417.[CrossRef] [Google Scholar]
  12. Goto, K., Watashi, K., Murata, T., Hishiki, T., Hijikata, M. & Shimotohno, K.(2006). Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Biochem Biophys Res Commun 343, 879–884.[CrossRef] [Google Scholar]
  13. Goto, K., Watashi, K., Inoue, D., Hijikata, M. & Shimotohno, K.(2009). Identification of cellular and viral factors related to anti-hepatitis C virus activity of cyclophilin inhibitor. Cancer Sci 100, 1943–1950.[CrossRef] [Google Scholar]
  14. Hanoulle, X., Badillo, A., Wieruszeski, J. M., Verdegem, D., Landrieu, I., Bartenschlager, R., Penin, F. & Lippens, G.(2009). Hepatitis C virus NS5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B. J Biol Chem 284, 13589–13601.[CrossRef] [Google Scholar]
  15. Hopkins, S., Heuman, D., Gavis, E., Lalezari, J., Glutzer, E., DiMasso, B., Rusnak, P., Wring, S., Smitley, S. & Ribeill, Y.(2009). SCY-635 Demonstrates Clinically Relevant Single-agent Results in a Phase 1b Study in Adults with HCV. 44th Annual Meeting of the European Association for the Study of the Liver; Copenhagen, Denmark; Abstr. 89.
  16. Ishii, N., Watashi, K., Hishiki, T., Goto, K., Inoue, D., Hijikata, M., Wakita, T., Kato, N. & Shimotohno, K.(2006). Diverse effects of cyclosporine on hepatitis C virus strain replication. J Virol 80, 4510–4520.[CrossRef] [Google Scholar]
  17. Kaul, A., Stauffer, S., Berger, C., Pertel, T., Schmitt, J., Kallis, S., Lopez, M. Z., Lohmann, V., Luban, J. & Bartenschlager, R.(2009). Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics. PLoS Pathog 5, e1000546[CrossRef] [Google Scholar]
  18. Liu, Z., Yang, F., Robotham, J.-M. & Tang, H.(2009). Critical role of cyclophilin A and its prolyl-peptidyl isomerase activity in the structure and function of the hepatitis C virus replication complex. J Virol 83, 6554–6565.[CrossRef] [Google Scholar]
  19. Ma, S., Boerner, J. E., TiongYip, C., Weidmann, B., Ryder, N. S., Cooreman, M. P. & Lin, K.(2006). NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother 50, 2976–2982.[CrossRef] [Google Scholar]
  20. Mathy, J. E., Ma, S., Compton, T. & Lin, K.(2008). Combinations of cyclophilin inhibitor NIM811 with hepatitis C virus NS3–4A protease or NS5B polymerase inhibitors enhance antiviral activity and suppress the emergence of resistance. Antimicrob Agents Chemother 52, 3267–3275.[CrossRef] [Google Scholar]
  21. Nakagawa, M., Sakamoto, N., Enomoto, N., Tanabe, Y., Kanazawa, T., Koyama, N., Kurosaki, M., Maekawa, S., Yamashiro, T. & other authors(2004). Specific inhibition of hepatitis C virus replication by cyclosporin A. Biochem Biophys Res Commun 313, 42–47.[CrossRef] [Google Scholar]
  22. Paeshuyse, J., Kaul, A., De Clercq, E., Rosenwirth, B., Dumont, J.-M., Scalfaro, P., Bartenschlager, R. & Neyts, J.(2006). The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 43, 761–770.[CrossRef] [Google Scholar]
  23. Penin, F., Dubuisson, J., Rey, F. A., Moradpour, D. & Pawlotsky, J.-M.(2004). Structural biology of hepatitis C virus. Hepatology 39, 5–19.[CrossRef] [Google Scholar]
  24. Quinkert, D., Bartenschlager, R. & Lohmann, V.(2005). Quantitative analysis of the hepatitis C virus replication complex. J Virol 79, 13594–13605.[CrossRef] [Google Scholar]
  25. Robida, J. M., Nelson, H. B., Liu, Z. & Tang, H.(2007). Characterization of hepatitis C virus subgenomic replicon resistance to cyclosporine in vitro. J Virol 81, 5829–5840.[CrossRef] [Google Scholar]
  26. Watashi, K., Hijikata, M., Hosaka, M., Yamaji, M. & Shimotohno, K.(2003). Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 38, 1282–1288.[CrossRef] [Google Scholar]
  27. Watashi, K., Ishii, N., Hijikata, M., Inoue, D., Murata, T., Miyanari, Y. & Shimotohno, K.(2005). Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 19, 111–122.[CrossRef] [Google Scholar]
  28. Yang, F., Robotham, J. M., Nelson, H. B., Irsigler, A., Kenworthy, R. & Tang, H.(2008). Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J Virol 82, 5269–5278.[CrossRef] [Google Scholar]
  29. Zydowsky, L. D., Etzkorn, F. A., Chang, H. Y., Ferguson, S. B., Stolz, L. A., Ho, S. I. & Walsh, C. T.(1992). Active site mutants of human cyclophilin A separate peptidyl-prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition. Protein Sci 1, 1092–1099.[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