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The cyclophilin inhibitor alisporivir prevents hepatitis C virus–mediated mitochondrial dysfunction
Author(s) -
Quarato Giovanni,
D'Aprile Annamaria,
Gavillet Bruno,
Vuagniaux Grégoire,
Moradpour Darius,
Capitanio Nazzareno,
Piccoli Claudia
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25514
Subject(s) - cyclophilin , hepatitis c virus , peptidylprolyl isomerase , mitochondrion , biology , viral replication , cyclophilin a , mitochondrial permeability transition pore , virology , immunology , virus , microbiology and biotechnology , programmed cell death , biochemistry , apoptosis , enzyme , isomerase , gene
Abstract Alisporivir (Debio‐025) is an analogue of cyclosporine A and represents the prototype of a new class of non‐immunosuppressive cyclophilin inhibitors. In vitro and in vivo studies have shown that alisporivir inhibits hepatitis C virus (HCV) replication, and ongoing clinical trials are exploring its therapeutic potential in patients with chronic hepatitis C. Recent data suggest that the antiviral effect is mediated by inhibition of cyclophilin A, which is an essential host factor in the HCV life cycle. However, alisporivir also inhibits mitochondrial permeability transition by binding to cyclophilin D. Because HCV is known to affect mitochondrial function, we explored the effect of alisporivir on HCV protein‐mediated mitochondrial dysfunction. Through the use of inducible cell lines, which allow to investigate the effects of HCV polyprotein expression independent from viral RNA replication and which recapitulate the major alterations of mitochondrial bioenergetics observed in infectious cell systems, we show that alisporivir prevents HCV protein‐mediated decrease of cell respiration, collapse of mitochondrial membrane potential, overproduction of reactive oxygen species and mitochondrial calcium overload. Strikingly, some of the HCV‐mediated mitochondrial dysfunctions could even be rescued by alisporivir. Conclusion: These observations provide new insights into the pathogenesis of HCV‐related liver disease and reveal an additional mechanism of action of alisporivir that is likely beneficial in the treatment of chronic hepatitis C. (H EPATOLOGY 2012)