Phosphorylation of hepatitis C virus NS5A nonstructural protein: a new paradigm for phosphorylation-dependent viral RNA replication?

The hepatitis C virus (HCV) nonstructural 5A (NS5A) phosphoprotein has been intensely studied due to its ability to subvert the host interferon-induced antiviral response. However, more recent studies suggest that it may also play an important regulatory role in HCV RNA replication as well as modulate host intracellular signaling pathways. Phosphorylation of NS5A appears to be a highly regulated process and several cellular protein kinases responsible for NS5A phosphorylation have been identified in vitro. Studies utilizing the HCV replicon cell culture system have suggested a provocative role for the differential phosphorylation of NS5A in the regulation of viral RNA replication through its association with the viral replication complex, including several host cell factors. Importantly, recent in vivo data linking loss of NS5A hyperphosphorylation to non-productive HCV replication in the chimpanzee model have provided high validation for targeting the cellular kinases involved, particularly the kinases responsible for NS5A phosphorylation, for antiviral therapeutic intervention. Understanding the process of NS5A phosphorylation and the definite identification of the culprit cellular protein kinase(s) will shed light on the mechanisms of HCV RNA replication and/or pathogenesis.