Cyclophilin A Is the Key to Hepatitis C Virus Replication

Cyclophilins catalyze the proper folding of proteins and the formation of large protein assemblies.

Health care officials estimate that more than 200 million people around the world are infected with hepatitis C - an overall incidence of around 3.3% of the world's population. Approximately 80% of HCV patients are chronically infected and have a high risk of developing serious liver inflammation, liver cirrhosis, or liver cancer.

Previous studies had shown that cyclosporin, known to sequester cyclophilins by direct binding, profoundly blocked HCV replication in cultured human hepatoma cells. However, conflicting results were obtained as to the particular cyclophilin (Cyp) required for viral RNA replication and the underlying possible mode of action.

In the current study, investigators at the University of Heidelberg (Germany) worked with a set of cell lines with stable knockdown of CypA or CypB. They reported in the August 14, 2009, online edition of the journal PLoS Pathogens that replication of HCV replicons of different genotypes was reduced by CypA depletion up to 1,000-fold whereas knockdown of CypB had no effect. Normal replication was restored by over-expression of wild type CypA, but not by a mutant lacking isomerase activity.

The cyclosporin analogue used in these experiments was DEBIO-25, which inhibits CypA but does not generally suppress the immune system. "The therapeutic potential of inhibiting cellular factors essential for virus replication has thus far hardly been tapped," said senior author Dr. Ralf Bartenschlager, professor of molecular virology at the University of Heidelberg. "But this approach has the major advantage that resistance arises less frequently and to a lesser extent in comparison to therapies directly targeting viral factors."

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