Combined interferon α2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial

Inoue, Kazuaki; Sekiyama, Kazuhiko; Yamada, Masaya; Watanabe, Tsunamasa; Yasuda, Hiroshi; Yoshiba, Makoto

doi:10.1007/s00535-002-1104-5

Cited by 163 publications

(107 citation statements)

References 20 publications

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“…The NS5B serine/glycine polymorphism at position 556 or NS5A polymorphisms that distinguish genotype 2/3 from genotype 1 could potentially be responsible for the differences in CsA susceptibility. 27,28 Nevertheless, the data presented here points to a polymorphic region of NS5A as having the largest effect on CsA susceptibility.…”

Section: Discussionmentioning

confidence: 63%

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Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

et al. 2007

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HCV reoccurs after liver transplantation and increases mortality. Cyclosporine, but not tacrolimus, has potent antiviral effects against HCV replication in cell culture. To determine the conditions, if any, under which HCV is susceptible to cyclosporine in vivo, we selected for cyclosporine-resistant mutant HCV in vitro. The resulting mutations were mapped to x-ray crystallographic structures and sequence databases. Mutations selected by cyclosporine were clustered in the nonstructural (NS) proteins NS5A and NS5B. Different sets of mutations in NS5A, paired with the same 2 NS5B mutations, conferred different levels of cyclosporine resistance when engineered back into the HCV replicon. Mutations in NS5B are structurally consistent with a proposed model of regulation of RNA binding by cyclophilin B (CyPB). These mutations also highlight a natural polymorphism between different HCV genotypes that correlates with the variation in response to cyclosporine A (CsA) noted in some clinical trials. Replicons engineered to have mutations in only NS5A (P < 0.0001) or only NS5B (P ‫؍‬ 0.002) suggest that while both NS5A or NS5B variants alter cyclosporine susceptibility, NS5A has the largest effect. Conclusion: Preexisting sequence variation could alter the effect of cyclosporine on HCV in vivo. (HEPATOLOGY

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Section: Discussionmentioning

confidence: 63%

“…25 Studies that have demonstrated a beneficial effect of CsA on HCV have only been able to do so in genotype 1, generally in conjunction with interferon. [26][27][28][29][30] We used a forward genetics approach to investigate the mechanism of CsA inhibition of the HCV replicon. CsA selected for mutations in NS5A and NS5B.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

et al. 2007

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“…There are reports on anti-HCV effects of immunosuppressive agents such as cyclosporine. 16,17 In addition, antiretroviral therapy used for HIV suppression may confer additional suppression of HCV, ultimately enabling HCV clearance. 18 The mechanism for spontaneous clearance of chronic HCV infection observed in our coinfected patients post-OLT, however, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous clearance of hepatitis C virus after liver transplantation in two patients coinfected with hepatitis C virus and human immunodeficiency virus

Bhagat¹,

Foont²,

Schiff³

et al. 2007

Liver Transpl

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Spontaneous resolution of chronic hepatitis C virus (HCV) infection is exceedingly rare and poorly understood. As HCV and human immunodeficiency virus (HIV) have shared routes of transmission, HCV coinfection is estimated to affect 15%-30% of the HIV-positive population. We report 2 patients with HCV-HIV coinfection who underwent orthotopic liver transplantation at our center and had spontaneous clearance of their chronic HCV infection after transplantation without any anti-HCV treatment. Both patients showed no evidence of HCV recurrence for more than 3 years despite long-term immunosuppressant therapy. Spontaneous clearance of chronic HCV infection can occur in HIV-HCV-coinfected patients after liver transplantation. The mechanism of this phenomenon remains unclear. Liver Transpl 14:92-95, 2008.

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“…Controlled trials showed that a combination of CsA with IFN␣ is more effective than IFN␣ alone, especially in patients with a high viral load (4,5). Moreover, recent in vitro studies provided evidence that CsA prevents both HCV RNA replication and HCV protein production in an IFN␣-independent manner (6 -10).…”

mentioning

confidence: 99%

The Isomerase Active Site of Cyclophilin A Is Critical for Hepatitis C Virus Replication

Chatterji

Bobardt

Selvarajah

et al. 2009

Journal of Biological Chemistry

176

220

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Cyclosporine A and nonimmunosuppressive cyclophilin (Cyp) inhibitors such as Debio 025, NIM811, and SCY-635 block hepatitis C virus (HCV) replication in vitro. This effect was recently confirmed in HCV-infected patients where Debio 025 treatment dramatically decreased HCV viral load, suggesting that Cyps inhibitors represent a novel class of anti-HCV agents. However, it remains unclear how these compounds control HCV replication. Recent studies suggest that Cyps are important for HCV replication. However, a profound disagreement currently exists as to the respective roles of Cyp members in HCV replication. In this study, we analyzed the respective contribution of Cyp members to HCV replication by specifically knocking down their expression by both transient and stable small RNA interference. Only the CypA knockdown drastically decreased HCV replication. The re-expression of an exogenous CypA escape protein, which contains escape mutations at the small RNA interference recognition site, restored HCV replication, demonstrating the specificity for the CypA requirement. We then mutated residues that reside in the hydrophobic pocket of CypA where proline-containing peptide substrates and cyclosporine A bind and that are vital for the enzymatic or the hydrophobic pocket binding activity of CypA. Remarkably, these CypA mutants fail to restore HCV replication, suggesting for the first time that HCV exploits either the isomerase or the chaperone activity of CypA to replicate in hepatocytes and that CypA is the principal mediator of the Cyp inhibitor anti-HCV activity. Moreover, we demonstrated that the HCV NS5B polymerase associates with CypA via its enzymatic pocket. The study of the roles of Cyps in HCV replication should lead to the identification of new targets for the development of alternate anti-HCV therapies. Hepatitis C virus (HCV)2 is the main contributing agent of acute and chronic liver diseases worldwide (1). Primary infection is often asymptomatic or associated with mild symptoms. However, persistently infected individuals develop high risks for chronic liver diseases such as hepatocellular carcinoma and liver cirrhosis (1). The combination of IFN␣ and ribavirin that serves as current therapy for chronically HCV-infected patients not only has a low success rate (about 50%) (2) but is often associated with serious side effects (2). There is thus an urgent need for the development of novel anti-HCV treatments (2).The immunosuppressive drug cyclosporine A (CsA) was reported to be clinically effective against HCV (3). Controlled trials showed that a combination of CsA with IFN␣ is more effective than IFN␣ alone, especially in patients with a high viral load (4, 5). Moreover, recent in vitro studies provided evidence that CsA prevents both HCV RNA replication and HCV protein production in an IFN␣-independent manner (6 -10). CsA exerts this anti-HCV activity independently of its immunosuppressive activity because the nonimmunosuppressive Cyp inhibitors such as Debio 025, NIM811, and SCY-635 also block HCV RNA and...

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Combined interferon α2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial

Abstract: In patients with chronic hepatitis C; combined interferon and cyclosporin A treatment was more effective than interferon monotherapy. The benefit was mostly achieved in patients with a high viral load and HCV genotype 1.

Cited by 163 publications

References 20 publications

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

Spontaneous clearance of hepatitis C virus after liver transplantation in two patients coinfected with hepatitis C virus and human immunodeficiency virus

The Isomerase Active Site of Cyclophilin A Is Critical for Hepatitis C Virus Replication

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