Host cell kinases and the hepatitis C virus life cycle

• Cellular kinases play key roles in the HCV life cycle.
• EGFR, EphA1 and PKA regulate localization of cellular HCV entry factors.
• Interactions between PI4KIIIα and HCV NS5A regulate formation of the membranous webs, the site of viral replication.
• The phosphorylation status of NS5A, regulated by cellular kinases, drives HCV assembly.
• Cellular kinases represent targets for adjunctive host-targeted antiviral therapies.

Hepatitis C virus (HCV) infection relies on virus–host interactions with human hepatocytes, a context in which host cell kinases play critical roles in every step of the HCV life cycle. During viral entry, cellular kinases, including EGFR, EphA2 and PKA, regulate the localization of host HCV entry factors and induce receptor complex assembly. Following virion internalization, viral genomes replicate on endoplasmic reticulum-derived membranous webs. The formation of membranous webs depends on interactions between the HCV NS5a protein and PI4KIIIα. The phosphorylation status of NS5a, regulated by PI4KIIIα, CKI and other kinases, also acts as a molecular switch to virion assembly, which takes place on lipid droplets. The formation of lipid droplets is enhanced by HCV activation of IKKα. In view of the multiple crucial steps in the viral life cycle that are mediated by host cell kinases, these enzymes also represent complementary targets for antiviral therapy.This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.