Thursday, May 3, 2012

A connection between hepatitis C virus (HCV) replication and sterol metabolism: A new antiviral target for HCV?

It is well known that viruses utilize host-derived lipids in order to replicate. However, the functional importance of specific lipids to the viral replication process has not been well-characterized until very recently, when a group from Harvard Medical School uncovered a connection between hepatitis C virus (HCV) replication and cellular levels of a specific biogenic precursor to cholesterol called desmosterol. Desmosterol, shown above (middle structure), is simply D24-dehydrocholesterol, the immediate precursor to cholesterol (rightmost structure) in the Bloch branch of the cholesterol biosynthetic pathway. The Harvard group noted that HCV infection is associated with hypolipidemia that is reversible upon treatment. This provided a clue that HCV is able to manipulate host lipid metabolism to promote its replication, and thus, pharmacological inhibition of this process might represent an antiviral therapeutic strategy. LC/MS analysis of steady-state lipid abundance in an HCV cell culture model identified a lipid metabolite (later identified as desmosterol) with a 13-fold increase in abundance in infected cells relative to uninfected controls.
As depicted in the scheme above, desmosterol is produced by reduction of 7-dehydrodesmosterol, a biosynthetic transformation catalyzed by an enzyme called DHCR7. Treatment of cells with a known small molecule inhibitor of DHCR7 (AY9944) resulted in reduction of cellular desmosterol to undetectable levels. Importantly, pharmacological inhibition of DHCR7 was also associated with a dose-dependent decrease in steady-state expression of the HCV core, NS5A and NS5B proteins. This seems to indicate that DHCR7 activity is important for viral replication in the case of HCV. The therapeutic potential of targeting desmosterol metabolism as an antiviral strategy is not currently known. AY9944, like many other drugs that inhibit enzymes involved in cholesterol biosynthesis, is plagued by side effects (e.g. impairment of brain development) that prevent its clinical use. Nonetheless, the Harvard study is a unique application of lipid metabolite profiling that has clearly identified a specific sterol molecule that is required for HCV replication. Additional work in this area is warranted to elucidate the specific function (mechanism) of desmosterol and DHCR7 during HCV infection.

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