There is presently no effective therapy for the most severe form of hepatitis, which is caused by hepatitis delta virus (HDV). The failure of classical antivirals in halting HDV replication might be due to its unique features, as revealed by recent studies. Jeffrey Glenn and colleagues have capitalized on these fresh insights and developed a new method of preventing HDV replication. In The Journal of Clinical Investigation, the team presents the first evidence of the in vivo efficacy of their strategy.

HDV requires hepatitis B virus (HBV) surface antigens to enter and exit host cells. Derived from co-infecting HBV, these antigens are incorporated into the HDV envelope through interactions with large delta antigen, a product of the HDV genome. Large delta antigen contains a unique amino-acid motif — the 'CXXX box' — which is the substrate for prenyltransferases. Members of this family of host-derived enzymes — the farnesyltransferases — catalyse the covalent addition of the prenyl lipid farnesyl to the cysteine of the CXXX box, a modification that is essential to the assembly of HDV virions. Glenn's group speculated that disrupting this reaction with farnesyltransferase inhibitors (FTIs) might abrogate the HDV life cycle at the crucial stage of viral assembly.

Investigation of this hypothesis was hampered by the lack of a practical animal model of HDV viraemia. So, the authors created their own, by transfecting HBV-transgenic mice with an HDV-encoding plasmid. The proportion of infected hepatocytes in these mice was equivalent to that in HDV-infected humans, and HDV replication within these cells produced mature virions that were released into serum. But would this viraemia succumb to treatment with FTIs?

Transfected mice were injected with one of two FTIs at 50 mg per kg per d for seven days. Both FTI-277 and FTI-2153 — peptidomimetics of the CXXX box of Ras signal transduction GTPases — suppressed HDV viraemia to undetectable levels. As the levels of intrahepatic HDV RNA were similar in treated and control cohorts, the authors concluded that the prenylation-dependent step of virion assembly had been successfully targeted. FTIs that target Ras have been well tolerated in Phase I/II oncological trials, so the potential for their application to medically important viruses, including HDV, is good — Glenn's group is keen to spearhead such efforts with appropriate partners.