Journal ArticleDOI
HCV genotype 1b chimeric replicon with NS5B of JFH-1 exhibited resistance to cyclosporine A.
TLDR
It is demonstrated that NS5 B of JFH-1 contributed to this strain’s CsA-resistant phenotype and NS5B and CyPA are significant for determining HCV‘s sensitivity toCsA.Abstract:
Cyclosporine A (CsA) is a well-characterized anti-HCV reagent. Recently it was reported that the genotype 2a JFH-1 strain was more resistant than genotype 1 HCV strains to CsA in a cell culture system. However, the JFH-1 responsible region for the resistance to CsA remains unclear. It was also demonstrated that in genotype 1b HCVs, NS5B interacts with cyclophilin (CyP). To clarify whether or not NS5B of JFH-1 is significant for CsA resistance, we developed a chimeric replicon with NS5B of JFH-1 in the genotype 1b backbone. The chimeric replicon was more resistant to CsA than the parental genotype 1b replicon. Furthermore, reduction of CyPA had a greater effect on HCV RNA replication and sensitivity to CsA than reduction of CyPB. Here, we demonstrated that NS5B of JFH-1 contributed to this strain’s CsA-resistant phenotype. NS5B and CyPA are significant for determining HCV’s sensitivity to CsA.read more
Citations
More filters
Journal ArticleDOI
Hcv resistance to cyclosporin a does not correlate with a resistance of the ns5a-cyclophilin a interaction to cyclophilin inhibitors
Udayan Chatterji,Precious J. Lim,Michael Bobardt,Stefan Wieland,Daniel G. Cordek,Grégoire Vuagniaux,Francis V. Chisari,Craig E. Cameron,Paul Targett-Adams,Tanya Parkinson,Philippe Gallay +10 more
TL;DR: It is shown that CypA, via its isomerase pocket, binds directly to NS5A, and most importantly, that disrupting this interaction stops HCV replication.
Journal ArticleDOI
A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach
Feng Yang,Jason M. Robotham,Henry Grise,Stephen D. Frausto,Vanesa Madan,Margarita Zayas,Ralf Bartenschlager,Margaret Robinson,Andrew E. Greenstein,Anita Nag,Timothy M. Logan,Ewa A. Bienkiewicz,Hengli Tang +12 more
TL;DR: A new genetic selection scheme was reported that identified a major viral determinant of HCV's dependence on CyPA and susceptibility to cyclosporine A and the importance of this major CsA-sensitivity determinant was confirmed in additional genotypes (GT) other than GT 2a.
Journal ArticleDOI
The ESCRT System Is Required for Hepatitis C Virus Production
Yasuo Ariumi,Misao Kuroki,Masatoshi Maki,Masanori Ikeda,Hiromichi Dansako,Takaji Wakita,Nobuyuki Kato +6 more
TL;DR: It is suggested that the ESCRT system is required for infectious HCV production, and the infectivity of HCV in the supernatants was significantly suppressed in these knockdown cells.
Journal ArticleDOI
Cyclophilin inhibitors as antiviral agents.
TL;DR: Synthetic modifications of the CsA scaffold allows for selective binding to CypA and CN separately, thus providing access to novel, non-immunosuppressive antiviral agents.
Journal ArticleDOI
Cyclophilin Inhibitors as a Novel HCV Therapy
TL;DR: Given the high genetic barrier to development of resistance and the distinctness of their mechanism from that of either the current standard of care or any specifically targeted antiviral therapy for HCV (STAT-C), CyP inhibitors hold promise as a novel class of anti-HCV therapy.
References
More filters
Journal ArticleDOI
Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
Michael W. Fried,Mitchell L. Shiffman,K. Rajender Reddy,C. Smith,George Marinos,Fernando L. Gonçales,Dieter Häussinger,Moisés Diago,Giampiero Carosi,Daniel Dhumeaux,Antonio Craxì,A. Lin,Joseph Hoffman,Jian Yu +13 more
TL;DR: In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferonAlfa- 2b plus Ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interfer on alfa -2b plus ribvirin or pegin terferonalfa-3a alone.
Journal ArticleDOI
Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes.
TL;DR: The immunosuppressant cyclosporin A (CsA) was found to have a suppressive effect on the HCV replicon RNA level and HCV protein expression in these cells.
Journal ArticleDOI
Cyclophilin B Is a Functional Regulator of Hepatitis C Virus RNA Polymerase
Koichi Watashi,Naoto Ishii,Makoto Hijikata,Daisuke Inoue,Takayuki Murata,Yusuke Miyanari,Kunitada Shimotohno +6 more
TL;DR: It is demonstrated that a cellular peptidyl-prolyl cis-trans isomerase, cyclophilin B (CyPB), is critical for the efficient replication of the hepatitis C virus (HCV) genome.
Journal ArticleDOI
Different anti-HCV profiles of statins and their potential for combination therapy with interferon.
TL;DR: Assessment of the anti‐HCV activity of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors and their effects in combination with IFN‐α found statins, especially fluvastatin, could be potentially useful as new anti-HCV reagents in combinationWith IFN.
Journal ArticleDOI
The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro†
Jan Paeshuyse,Artur Kaul,Erik De Clercq,Brigitte Rosenwirth,Jean-Maurice Dumont,Pietro Scalfaro,Ralf Bartenschlager,Johan Neyts +7 more
TL;DR: DBIO‐025, a compound that is also endowed with potent anti‐HIV activity and is well tolerated in animals and humans, may form an attractive new option for the therapy of HCV infections, particularly in HCV/HIV co‐infected patients.