Potential roles for cellular cofactors in hepatitis C virus replication complex formation.

Over 130 million people worldwide are chronically infected with hepatitis C virus (HCV). New antiviral treatment strategies are needed due to limitations with current therapy. The identification of cellular cofactors of infection has the potential to broadly expand our therapeutic targets. We recently reported an RNA interference screen of host membrane trafficking genes in HCV infection and replication and identified several cellular co-factors for viral replication. Phosphatidylinositol 4-kinase III alpha (PI4K-IIIalpha) was found to be essential for HCV replication. PI4K-IIIalpha co-localized with viral replication markers. Silencing of PI4K-IIIalpha by siRNAs prior to HCV infection prevented rearrangement of intracellular membranes associated with viral replication complexes, termed the membranous web. Our data suggest that PI4K-IIIalpha is involved in establishing HCV replication complexes, however the mechanism is unknown. From our analysis, along with several other studies that have identified cellular cofactors for HCV replication, we propose that PI4K-IIIalpha may nucleate replication complex formation by facilitating the interaction of viral and/or cellular proteins with cellular membrane-associated phospholipids.