Arrest all accessories--inhibition of hepatitis C virus by compounds that target host factors

Most novel drugs directed against the hepatitis C virus (HCV) including the recently approved NS3/4A protease inhibitors boceprevir and telaprevir are inhibitors of viral enzymes. Since HCV is an RNA virus with a short and highly variable genome, these direct-acting antivirals (DAAs) are prone to rapidly inducing the emergence of resistant HCV variants. This problem could be mitigated by the development of drugs that target host factors that the virus depends on during the various stages of its replication cycle. An increasing understanding of the molecular interactions between the virus and its host cell has allowed the identification of promising host targets for anti-HCV therapy and several host-targeting agents (HTAs) are currently under development. The most advanced compounds as yet may be inhibitors of cyclophilin A, a host factor known to be critical for viral RNA replication and possible virion assembly or release. One such compound, alisporivir, has demonstrated in vivo efficacy and is now in a phase 3 trial. Several other HTAs with very different host targets are further upstream in the development pipeline. This paper reviews promising host targets, their role in the viral replication cycle, and the HTAs that target them.