Resistance to Cyclophilin Inhibitors

  • Philippe GallayEmail author
Reference work entry


The best approach to avoid hepatitis C virus (HCV) resistance to a specific therapy is rapid and massive suppression of viral replication. This is best accomplished by combining several drugs with potent antiviral activity across multiple genotypes, with each possessing a high barrier to resistance, different mechanisms of action, and no cross-resistance. A novel class of anti-HCV agents that have shown great promise in HCV patients – the cyclophilin inhibitors (CypI) – possess such properties. CypI are host-targeting antivirals (HTAs) with a mechanism of action that differs from those of all existing direct-acting antivirals (DAAs). CypI are pan-genotypic due to their distinct mechanism of action that targets the host protein cyclophilin A (CypA), which is required for HCV replication. HCV has to develop a lengthy mutational strategy to efficiently replicate in vitro independently of the host factor CypA leading to a high genetic barrier that the virus has to cross to develop resistance to CypI. CypI mediate rapid and profound viral load suppression in patients. Very low viral breakthrough rates are associated with the CypI treatment, which result mostly from suboptimal drug exposure rather than viral resistance. The high genetic barrier and the lack of cross-resistance to DAAs make CypI attractive drug candidates to be part of a regimen with one or two DAAs that may constitute the backbone of a new, safe, and effective IFN-free therapy. The characteristic resistance profile of CypI offers an exceptional opportunity to cure HCV.


Hepatitic cyclophilin cyclophilia inhibitas NSSA resistance 



Taken twice a day


Complete early virological response = no virus detected after 12 weeks


Extended rapid virological response = no virus detected at week 4 and week 12


Early virological response = 2 log drop of HCV RNA after 12 weeks


Taken once a day


Rapid virological response = no virus detected at week 4


Sustained virological response = no virus detected at 12 weeks after completion of treatment


No virus detected at 24 weeks after completion of treatment



We thank Drs Baugh, Chatterji, Garcia-Rivera, Lin, Hopkins, and Borroto-Esoda for the careful reading of the manuscript. We also thank J. Kuhns for the administrative assistance. We acknowledge financial support from the US Public Health Service grant no. AI087746 (P.A.G.). This is publication no. 23007 from the Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.


  1. Alberti M, Chuang WL, Flisiak R et al (2012) Alisporivir (ALV) plus peg-interferon/ribavirin (PR) in HCV G1 treatment-experienced patients achieves primary endpoint with superior efficacy at treatment week 12 compared to retreatment with PR. J Hepatol 56:S553–S554. Abstract 1406CrossRefGoogle Scholar
  2. Alter MJ (2007) Epidemiology of hepatitis C virus infection. World J Gastroenterol 13:2436–2441PubMedPubMedCentralCrossRefGoogle Scholar
  3. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ (2006) The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 144:705–714PubMedCrossRefGoogle Scholar
  4. Balagopal A, Thomas DL, Thio CL (2010) IL28B and the control of hepatitis C virus infection. Gastroenterology 139(6):1865–1876. doi:10.1053/j.gastro.2010.10.004. Epub 2010 Oct 13. ReviewPubMedPubMedCentralCrossRefGoogle Scholar
  5. Bartels DJ, Zhou Y, Zhang EZ, Marcial M, Byrn RA, Pfeiffer T et al (2008) Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3/4A protease inhibitors in treatment-naive subjects. J Infect Dis 198(6):800–807PubMedCrossRefGoogle Scholar
  6. Borel JF (2002) History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 114(12):433–437PubMedGoogle Scholar
  7. Braaten D, Luban J (2001) Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells. EMBO J 20:1300–1309PubMedPubMedCentralCrossRefGoogle Scholar
  8. 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 284:16998–17005PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chatterji U, Lim P, Bobardt MD, Wieland S, Cordek DG, Vuagniaux G, Chisari F, Cameron CE, Targett-Adams P, Parkinson T, Gallay PA (2010) HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A-cyclophilin A interaction to cyclophilin inhibitors. J Hepatol 53:50–56PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chevaliez S, Rodriguez C, Soulier A, Ahmed-Belkacem A, Hezode C, Pawlotsky JM (2011) Molecular characterization of HCV resistance to telaprevir by means of ultra-deep pyrosequencing: preexisting resistant variants and dynamics of resistant populations. J Hepatol 54:S30CrossRefGoogle Scholar
  11. Coelmont L, Kaptein S, Paeshuyse J et al (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(3):967–976. doi:10.1128/AAC.00939-08PubMedCrossRefGoogle Scholar
  12. Coelmont L, Hanoulle X, Chatterji U, Berger C, Snoeck J, Bobardt M, Lim P, Vliegen I, Paeshuyse J, Vuagniaux G, Vandamme AM, Bartenschlager R, Gallay P, Lippens G (2010) Neyts. DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A. J PLoS One 5:e13687CrossRefGoogle Scholar
  13. Colgan J, Asmal M, Yu B, Luban J (2005) Cyclophilin A-deficient mice are resistant to immunosuppression by cyclosporine. J Immunol 174:6030–6038PubMedCrossRefGoogle Scholar
  14. Cross TJ, Antoniades CG, Harrison PM (2008) Current and future management of chronic hepatitis C infection. Postgrad Med J 84:172–176PubMedCrossRefGoogle Scholar
  15. Davis G, Kao J, Alberti A et al (2012) Alisporivir (ALV) plus Peg-interferon/Ribavirin (P/R) achieves high on-treatment undetectable HCV RNA levels among the most difficult to treat HCV G1 patients. Results of a planned treatment week 24 interim analysis of a randomized, double blind, placebo controlled trial (FUNDAMENTAL study). In: 63rd annual meeting of the American Association for the Study of Liver Diseases, Boston, 9–12 Nov 2012Google Scholar
  16. Dienstag JL, McHutchison JG (2006) American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 130:231–264PubMedCrossRefGoogle Scholar
  17. Everson GT, Sims KD, Rodriguez-Torres M et al (2012) An interferon-free, ribavirin-free 12-week regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94 % in treatment-naive patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection. In: 63rd annual meeting of the American Association for the Study of Liver Diseases (AASLD 2012), Boston, 9–13 Nov 2012. Abstract LB-3Google Scholar
  18. Fernandes F, Poole DS, Hoover S, Middleton R, Andrei AC, Gerstner J, Striker R (2007) Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B. Hepatology 46(4):1026–33PubMedCrossRefGoogle Scholar
  19. Fernandes F, Ansari IU, Striker R (2010) Cyclosporine inhibits a direct interaction between cyclophilins and hepatitis C NS5A. PLoS One 5:e9815PubMedPubMedCentralCrossRefGoogle Scholar
  20. Fischer G, Bang H, Berger E, Schellenberger A (1984) Conformational specificity of chymotrypsin toward proline-containing substrates. Biochim Biophys Acta 791(1):87–97PubMedCrossRefGoogle Scholar
  21. Fischer G, Wittmann-Liebold B, Lang K et al (1989) Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337(6206):476–478PubMedCrossRefGoogle Scholar
  22. Fischer G, Gallay P, Hopkins S (2010) Cyclophilin inhibitors for the treatment of HCV infection. Curr Opin Investig Drugs 11(8):911–918PubMedGoogle Scholar
  23. Flechner SM (1983) Cyclosporine: a new and promising immunosuppressive agent. Urol Clin N Am 10(2):263–275Google Scholar
  24. Flisiak R, Dumont JM, Crabbé R (2007) Cyclophilin inhibitors in hepatitis C viral infection. Expert Opin Investig Drugs 16:1345–1354PubMedCrossRefGoogle Scholar
  25. Flisiak R, Horban A, Gallay P, Bobardt M, Selvarajah S, Wiercinska-Drapalo A, Siwak E, Cielniak I, Higersberger J, Kierkus J, Aeschlimann C, Grosgurin P, Nicolas-M’etral V, Dumont JM, Porchet H, Crabb’e R, Scalfaro P (2008) The cyclophilin inhibitor Debio-025 shows potent anti–hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 47:817–826PubMedCrossRefGoogle Scholar
  26. Flisiak R, Feinman SV, Jablkowski M, Horban A, Kryczka W, Pawlowska M, Heathcote JE, Mazella G, Vandelli C, Nicolas-M’etral V, Grosgurin P (2009) The cyclophilin inhibitor Debio 025 combined with Peg-Ifna2a significantly reduces viral load in treatment naïve hepatitis C patients. Hepatology 49:1460–1468PubMedCrossRefGoogle Scholar
  27. Flisiak R, Pawlotsky JM, Crabbe R, Calistru P, Kryczka W, Haussinger D, Mazella G, Romero M, Purcea D, Vuagniaux G, Bao W, Avila C, Zeuzem S (2011) Once daily alisporivir (DEB025) plus Peg-IFN-alfa-2A/ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment-naïve patients – the ESSENTIAL study. J Hepatol 55(Suppl 1): S2. Abstract 190Google Scholar
  28. Foster TL, Gallay P, Stonehouse NJ, Harris M (2011) Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. J Virol. 85(14):7460–4. doi: 10.1128/JVI. 00393-11PubMedPubMedCentralCrossRefGoogle Scholar
  29. Fridell RA, Qiu DK, Wang CF, Valera L, Gao M (2010) Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother 54(9):3641–3650PubMedPubMedCentralCrossRefGoogle Scholar
  30. Fridell RA, Wang CF, Sun JH, O’Boyle DR, Nower P, Valera L et al (2011) Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations. Hepatology 54(6):1924–1935PubMedCrossRefGoogle Scholar
  31. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr et al (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347(13):975–982PubMedCrossRefGoogle Scholar
  32. Gallay PA (2009) Cyclophilin inhibitors. Clin Liver Dis 13:403–417PubMedCrossRefGoogle Scholar
  33. Gallay PA (2012) Cyclophilin inhibitors: a novel class of promising host-targeting anti-HCV agents. Immunol Res. 52(3):200–10. doi:10.1007/s12026-011-8263-5PubMedCrossRefGoogle Scholar
  34. Gane EJ, Stedman CA, Hyland RH et al (2012) Once daily sofosbuvir (GS-7977) plus ribavirin in patients with HCV genotypes 1, 2, and 3: the ELECTRON trial. In: 63rd annual meeting of the American Association for the Study of Liver Diseases (AASLD 2012), Boston, 9–13 Nov 2012. Abstract 229Google Scholar
  35. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA et al (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465(7294):96–100. doi:10.1038/nature08960PubMedCrossRefGoogle Scholar
  36. Garcia-Rivera JA, Bobardt MD, Chatterji U, Hopkins S, Gregory MA, Wilkinson B, Lin K, Gallay PA (2012a) Multiple mutations in HCV NS5A domain II are required to confer a significant level of resistance to alisporivir. Antimicrob Agents Chemother 56:5113–5121. doi:10.1128/AAC.00919-12. Epub 2012 Jul 16. PMCID: PMC3457393 (Available on 2013/4/1)PubMedPubMedCentralCrossRefGoogle Scholar
  37. Garcia-Rivera JA, Lin K, Hopkins S, Gregory MA, Wilkinson B, Gallay PA (2012b) Development of a flow cytometry live cell assay for the screening of inhibitors of hepatitis C virus (HCV) replication. Open Virol J 6:97–102. doi:10.2174/1874357901206010097. Epub 2012 Nov 26. Pub Med Central PMCID: PMC3514710PubMedPubMedCentralCrossRefGoogle Scholar
  38. Gaudieri S, Rauch A, Pfafferott K, Barnes E, Cheng W, McCaughan G et al (2009) Hepatitis C virus drug resistance and immune driven adaptations: relevance to new antiviral therapy. Hepatology 49(4):1069–1082PubMedCrossRefGoogle Scholar
  39. Global Surveillance and Control of Hepatitis C (1999) Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 6:35–47CrossRefGoogle Scholar
  40. Goto K, Watashi K, Murata T et al (2006) Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Biochem Biophys Res Commun 343:879–884PubMedCrossRefGoogle Scholar
  41. 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(10):1943–1950. doi:10.1111/j.1349-7006.2009.01263.x. Epub 2009 Jun 26PubMedCrossRefGoogle Scholar
  42. Gottwein JM, Scheel TKH, Jensen TB, Ghanem L, Bukh J (2011) Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses. Gastroenterology 141(3):1067–1079PubMedCrossRefGoogle Scholar
  43. Gregory MA, Moss SJ, Coates N, Foster T, Bobardt M, Chatterji U, Gallay PA, Leyssen P, Neyts J, Nur-E-Alam M, Piraee M, Suthar D, Warneck T, Zhang M-Q, Wilkinson B (2011) Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family. Antimicrob Agents Chemother 55:1975–1981PubMedPubMedCentralCrossRefGoogle Scholar
  44. Handschumacher RE, Harding MW, Rice J et al (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226(4674):544–547PubMedCrossRefGoogle Scholar
  45. He Y, Staschke KA, Tan SL (2006) HCV NS5A: a multifunctional regulator of cellular pathways and virus replication, Chapter 9. In: Tan SL (ed) Hepatitis C viruses: genomes and molecular biology. Horizon Bioscience, NorfolkGoogle Scholar
  46. Hopkins S, Scorneaux B, Huang Z, Murray MG, Wring S, Smitley C, Harris R, Erdmann F, Fischer G, Ribeill Y (2010) SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro. Antimicrob Agents Chemother. 54(2):660–72. doi:10.1128/AAC. 00660-09PubMedCrossRefGoogle Scholar
  47. Hopkins S, Gallay P (2012) Cyclophilin inhibitors: an emerging class of therapeutics for the treatment of chronic hepatitis C infection. Viruses 4(11):2558–2577. doi:10.3390/v4112558PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hopkins S, Bobardt M, Chatterji U, Garcia-Rivera JA, Lim P, Gallay PA (2012a) The cyclophilin inhibitor SCY-635 disrupts hepatitis C virus NS5A-cyclophilin A complexes. Antimicrob Agents Chemother 56:3888–3897. doi:10.1128/AAC.00693-12. Epub 2012 May 14. PMCID: PMC3393457PubMedPubMedCentralCrossRefGoogle Scholar
  49. Hopkins S, DiMassimo B, Rusnak P, Heuman D, Lalezari J, Sluder A, Scorneaux B, Mosier S, Kowalczyk P, Ribeill Y, Baugh J, Gallay PA (2012b) The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection. J Hepatol 57:47–54. doi:10.1016/j.jhep.2012.02.024. Epub 2012 Mar 13PubMedCrossRefGoogle Scholar
  50. Houck DR, Hopkins S (2006) Preclinical evaluation of SCY-635, a cyclophilin inhibitor with potent anti-HCV activity. Hepatology 44(Suppl 1):S534–S535. Abstract 934Google Scholar
  51. Huang L, Hwang J, Sharma SD, Hargittai MR, Chen Y, Arnold JJ, Raney KD, Cameron CE (2005) Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding protein. J Biol Chem 280(43):36417–36428. Epub 2005 Aug 25PubMedCrossRefGoogle Scholar
  52. Hwang J, Huang L, Cordek DG, Vaughan R, Reynolds SL, Kihara G, Raney KD, Kao CC, Cameron CE (2010) Hepatitis C virus nonstructural protein 5A: biochemical characterization of a novel structural class of RNA-binding proteins. J Virol 84(24):12480–12491. doi:10.1128/JVI.01319-10. Epub 2010 Oct 6PubMedPubMedCentralCrossRefGoogle Scholar
  53. Ishii N, Watashi K, Hishiki T et al (2006) Diverse effects of cyclosporine on hepatitis C virus strain replication. J Virol 80:4510–4520PubMedPubMedCentralCrossRefGoogle Scholar
  54. Jacobson IM, Catlett I, Marcellin P, Bzowej NH, Muir AJ, Adda N et al (2011a) Telaprevir substantially improved SVR rates across all IL28B genotypes in the advance trial. J Hepatol 54:S542–S543CrossRefGoogle Scholar
  55. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH et al (2011b) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364(25):2405–2416PubMedCrossRefGoogle Scholar
  56. Kaul A, Stauffer S, Berger C, Pertel T, Schmitt J, Kallis S, Zayas M, 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:e1000546PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kitahata MM, Koepsell TD, Deyo RA et al (1996) Physicians’ experience with the acquired immunodeficiency syndrome as a factor in patients’ survival. N Engl J Med 334(11):701–706PubMedCrossRefGoogle Scholar
  58. Kitahata MM, Van Rompaey SE, Shields AW (2000) Physician experience in the care of HIV-infected persons is associated with earlier adoption of new antiretroviral therapy. J Acquir Immune Defic Syndr 24(2):106–114PubMedCrossRefGoogle Scholar
  59. Kofron JL, KuzmiE P, Kishore V, Colon-Bonilla E, Rich DH (1991) Determination of kinetic constants for peptidyl-prolyl cis-trans isomerases by an improved spectrophotometric assay. Biochemistry 30:6127–6134PubMedCrossRefGoogle Scholar
  60. Kowdley KV, Lawitz E, Poordad F et al (2012) A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR rates (observed data) of 99 % in treatment-naive patients and 93 % in prior null responders with HCV genotype 1 infection. In: 63rd annual meeting of the American Association for the Study of Liver Diseases (AASLD 2012), Boston, 9–13 Nov 2012. Abstract LB-1Google Scholar
  61. Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK et al (2008) Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology 48(6):1769–1778PubMedPubMedCentralCrossRefGoogle Scholar
  62. Lang K, Schmid FX, Fischer G (1987) Catalysis of protein folding by prolyl isomerase. Nature 329(6136):268–270PubMedCrossRefGoogle Scholar
  63. Lawitz E, Godofsky E, Rouzier R, Marbury T, Nguyen T, Ke J, Huang M, Praestgaard J, Serra D, Evans TG (2011) Safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor NIM811 alone or in combination with pegylated interferon in HCV-infected patients receiving 14 days of therapy. Antivir Res 89:238–245PubMedCrossRefGoogle Scholar
  64. Lemm JA, O’Boyle D 2nd, Liu M et al (2010) J Virol 84(1):482–491. doi:10.1128/JVI.01360-09PubMedCrossRefGoogle Scholar
  65. Lenz O, Fevery B, Vijgen L, Verbeeck J, Peeters M, Beumont M et al (2011) TMC435 in combination with peginterferon alpha-2a/ribavirin in treatment-naive patients infected with HCV genotype 1: virology analysis of the pillar study. Hepatology 54:985AGoogle Scholar
  66. Li B, Snoeck J, Tang Y, Jones CT, Tiongyip C, Bao W, Yu J, Vandamme A, Vuagniaux G, Crabbe R, Avila C, Naoumov NV, Lin K (2011) Alisporivir – a host-targeting antiviral, provides low viral breakthrough rate and high barrier to resistance in HCV genotype 1 treatment-naïve patients in the phase IIb ESSENTIAL study. American Association for Study of the Liver Congress, San FranciscoGoogle Scholar
  67. Lin K (2010) Development of novel antiviral therapies for hepatitis C virus. Virol Sin 25:246–266PubMedCrossRefGoogle Scholar
  68. Liu Z, Yang F, Robotham JM, 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 83:6554–6565PubMedPubMedCentralCrossRefGoogle Scholar
  69. Ma S, Boerner JE, TiongYip C et al (2006) NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother 50:2976–2982PubMedPubMedCentralCrossRefGoogle Scholar
  70. Manns MP, Wedemeyer H, Cornberg M (2006) Treating viral hepatitis C: efficacy, side effects, and complications. Gut 55:1350–1359PubMedPubMedCentralCrossRefGoogle Scholar
  71. Margeridon S, Le Pogam S, Liu TF, Hanczaruk B, Simen BB, Shulman N et al (2011) No detection of variants bearing NS5B S282T mericitabine (MCB) resistance mutation in DAA treatment-naive HCV genotype 1 (G1)-infected patients using ultra-deep pyrosequencing (UDPS). Hepatology 54:532AGoogle Scholar
  72. Martell M, Esteban JI, Quer J, Genesca J, Weiner A, Esteban R et al (1992) Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J Virol 66(5):3225–3229PubMedPubMedCentralGoogle Scholar
  73. Nakagawa M, Sakamoto N, Enomoto N et al (2004) Specific inhibition of hepatitis C virus replication by cyclosporin A. Biochem Biophys Res Commun 313:42–47PubMedCrossRefGoogle Scholar
  74. Nelson DR, Ghalib RH, Sulkowski M, Schiff E, Rustgi V, Pockros PJ, Wang C, Kerhuel GD, Grosgurin P, Porchet H, Crabb’e R (2009) Efficacy and safety of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon alpha-2A and ribavirin in previously null responder genotype 1 HCV patients. J Hepatol 50:S1. Abstract 95Google Scholar
  75. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ et al (1998) Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282(5386):103–107PubMedCrossRefGoogle Scholar
  76. Paeshuyse J, Kaul A, De Clercq E et al (2006) The non-immunosuppressive cyclosporin DEBIO 025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 43:761–770PubMedCrossRefGoogle Scholar
  77. Pawlotsky JM (2012) The science of direct-acting antiviral and host-targeted agent therapy. Antivir Ther 17(6 Pt B):1109–1117. doi:10.3851/IMP2423. Epub 2012 Oct 5PubMedCrossRefGoogle Scholar
  78. Pawlotsky JM, Sarin SK, Foster GR, Peng CY, Rasenack J, Flisiak R, Piratvisuth T, Wedemeyer H, Chuang WL, Zhang WM, Naoumov NV (2012a) Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-G2 or G3 patients: SVR12 results from VITAL-1 phase 2b study. J Hepatol 56(Suppl 2):S553. Abstract 1405CrossRefGoogle Scholar
  79. Pawlotsky JM, Sarin SK, Foster GR et al (2012b) Alisporivir plus Ribavirin achieves high rates of sustained HCV clearance (SVR24) as interferon (IFN)-free or IFN-add-on regimen in treatment-naive patients with HCV GT2 or GT3: final results from VITAL-1 study. In: 63rd annual meeting of the American Association for the Study of Liver Diseases, Boston, 9–12 Nov 2012. Abstract 233Google Scholar
  80. Pockros PJ (2010) New direct-acting antivirals in the development for hepatitis C virus infection. Therap Adv Gastroenterol 3:191–202PubMedPubMedCentralCrossRefGoogle Scholar
  81. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS et al (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364(13):1195–1206PubMedPubMedCentralCrossRefGoogle Scholar
  82. Poordad F, Bronowicki JP, Gordon SC, Zeuzem S, Jacobson IM, Sulkowski MS et al (2012) Factors that predict response of patients with HCV infection to boceprevir. Gastroenterology. Epub ahead of printGoogle Scholar
  83. Powdrill MH, Tchesnokov EP, Kozak RA, Russell RS, Martin R, Svarovskaia ES et al (2011) Contribution of a mutational bias in hepatitis C virus replication to the genetic barrier in the development of drug resistance. Proc Natl Acad Sci U S A 108(51):20509–20513PubMedPubMedCentralCrossRefGoogle Scholar
  84. Puyang X, Poulin DL, Mathy JE, Anderson LJ, Ma S, Fang Z, Zhu S, Lin K, Fujimoto R, Compton T, Wiedmann B (2010) Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors. Antimicrob Agents Chemother 54(5):1981–1987. doi:10.1128/AAC.01236-09. Epub 2010 Feb 22PubMedPubMedCentralCrossRefGoogle Scholar
  85. Robida JM, Nelson HB, Liu Z, Tang H (2007) Characterization of hepatitis C virus subgenomic replicon resistance to cyclosporine in vitro. J Virol 81(11):5829–40PubMedPubMedCentralCrossRefGoogle Scholar
  86. Rong L, Dahari H, Ribeiro RM, Perelson AS (2010) Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2(30):30ra2CrossRefGoogle Scholar
  87. Rosnoblet C, Fritzinger B, Legrand D, Launay H, Wieruszeski JM, Lippens G, Hanoulle X (2012) Hepatitis C virus NS5B and host cyclophilin A share a common binding site on NS5A. J Biol Chem 287(53):44249–44260. doi:10.1074/jbc.M112.392209. Epub 2012 Nov 14PubMedPubMedCentralCrossRefGoogle Scholar
  88. Sarrazin C, Zeuzem S (2010) Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138(2):447–462PubMedCrossRefGoogle Scholar
  89. Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, Welker M et al (2007a) Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132(5):1767–1777PubMedCrossRefGoogle Scholar
  90. Sarrazin C, Rouzier R, Wagner F, Forestier N, Larrey D, Gupta SK et al (2007b) SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology 132:1270–1278PubMedCrossRefGoogle Scholar
  91. Shepard CW, Finelli L, Alter MJ (2005) Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5:558–567PubMedCrossRefGoogle Scholar
  92. Shirota Y, Luo H, Qin W, Kaneko S, Yamashita T, Kobayashi K, Murakami S (2002) Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RdRP) NS5B and modulates RNA-dependent RNA polymerase activity. J Biol Chem 277:11149–11155PubMedCrossRefGoogle Scholar
  93. Simmonds P, Bukh J, Combet C et al (2005) Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 42:962–973PubMedCrossRefGoogle Scholar
  94. Soriano V, Madejon A, Vispo E et al (2008a) Emerging drugs for hepatitis C. Expert Opin Emerg Drugs 13:1–19PubMedCrossRefGoogle Scholar
  95. Soriano V, Perelson AS, Zoulim F (2008b) Why are there different dynamics in the selection of drug resistance in HIV and hepatitis B and C viruses? J Antimicrob Chemother 62(1):1–4PubMedPubMedCentralCrossRefGoogle Scholar
  96. Sulkowski MS, Gardiner DF, Rodriguez-Torres M et al (2012) High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV genotype 1, 2, or 3. In: 63rd annual meeting of the American Association for the Study of Liver Diseases (AASLD 2012), Boston, 9–13 Nov 2012. Abstract LB-2Google Scholar
  97. Sullivan JC, De Meyer S, Bartels DJ, Dierynck I, Zhang E, Spanks J et al (2011) Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials. J Hepatol 54:S4CrossRefGoogle Scholar
  98. Sun SCC, Bae A, Qi X, Harris J, Wong KA, Miller MD et al (2011) Natural variation in drug susceptibility to HCV polymerase inhibitors in treatment-naive HCV patient isolates. J Viral Hepat 18(12):861–870PubMedCrossRefGoogle Scholar
  99. Sy T, Jamal MM (2006) Epidemiology of hepatitis C virus (HCV) infection. Int J Med Sci 3:41–46PubMedPubMedCentralCrossRefGoogle Scholar
  100. Tiongyip X, Badillo A, Wieruszeski JM, 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 284:13589–13601CrossRefGoogle Scholar
  101. Tiongyip C, Jones CT, Tang Y et al (2011) Host targeting cyclophilin inhibitor alisporivir presents a high barrier to resistance with no cross-resistance to direct acting antivirals. In: 6th international workshop on hepatitis C, resistance and new compounds, Cambridge, MA, 24 June 2011Google Scholar
  102. Tong MJ, Reddy KR, Lee WM et al (1997) Treatment of chronic hepatitis C with consensus interferon: a multicenter, randomized, controlled trial. Consens Interferon Study Group Hepatol 26:747–754Google Scholar
  103. Verdegem D, Badillo A, Wieruszeski JM, Landrieu I, Leroy A, Bartenschlager R, Penin F, Lippens G, Hanoulle X (2011) Domain 3 of NS5A protein from the hepatitis C virus has intrinsic alpha-helical propensity and is a substrate of cyclophilin A. J Biol Chem 286:20441–20454PubMedPubMedCentralCrossRefGoogle Scholar
  104. Vermehren J, Sarrazin C (2011) New hepatitis C therapies in clinical development. Eur J Med Res 16:303–314PubMedPubMedCentralCrossRefGoogle Scholar
  105. Vicenti I, Rosi A, Saladini F, Meini G, Pippi F, Rossetti B et al (2012) Naturally occurring hepatitis C virus (HCV) NS3/4A protease inhibitor resistance-related mutations in HCV genotype 1-infected subjects in Italy. J Antimicrob Chemother 67(4):984–987PubMedCrossRefGoogle Scholar
  106. von Hahn T, Ciesek S, Manns MP (2011) Arrest all accessories – inhibition of hepatitis C virus by compounds that target host factors. Discov Med 12:237–244Google Scholar
  107. von Hahn T, Schiene-Fischer C, Van ND, Pfaender S, Karavul B, Steinmann E, Potthoff A, Strassburg C, Hamdi N, Abdelaziz AI, Sarrazin C, Müller T, Berg T, Trépo E, Wedemeyer H, Manns MP, Pietschmann T, Ciesek S (2012) Hepatocytes that express variants of cyclophilin A are resistant to HCV infection and replication. Gastroenterology 143(2):439.e1–447.e1. doi:10.1053/j.gastro.2012.04.053. Epub 2012 May 8Google Scholar
  108. Waller H, Chatterji U, Gallay P, Parkinson T, Targett-Adams P (2010) The use of AlphaLISA technology to detect interaction between hepatitis C virus-encoded NS5A and cyclophilin A. J Virol Methods 165:202–210PubMedCrossRefGoogle Scholar
  109. Watashi K, Hijikata M, Hosaka M et al (2003) Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 38:1282–1288PubMedCrossRefGoogle Scholar
  110. World Health Organization (2012) Hepatitis C factsheet no. 164. http://www.whoint/mediacentre/factsheets/fs164/en/index. Accessed online on 28 June 2012
  111. Wyles DL (2013) Antiviral resistance and the future landscape of hepatitis C virus infection therapy. J Infect Dis 207(Suppl 1):S33–S39. doi:10.1093/infdis/jis761PubMedCrossRefGoogle Scholar
  112. Yang F, Robotham JM, Nelson HB, 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 82:5269–5278PubMedPubMedCentralCrossRefGoogle Scholar
  113. Yang F, Robotham JM, Grise H, Frausto S, Madan V, Zayas M, Bartenschlager R, Robinson M, Greenstein AE, Nag A, Logan TM, Bienkiewicz E, Tang H (2010) A major determinant of cyclophilin dependence and cyclosporine susceptibility of hepatitis C virus identified by a genetic approach. PLoS Pathog 6:e1001118PubMedPubMedCentralCrossRefGoogle Scholar
  114. Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse A, Mullhaupt B et al (2012) SVR4 and SVR12 with an interferon-free regimen of BI 201335 and BI 207127, +/− ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: interim results of sound-C2. J Hepatol 56:S45CrossRefGoogle Scholar

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Immunology and Microbial Science, IMM-9The Scripps Research InstituteLa JollaUSA

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