Host proteins in HCV infection
HCV is the leading cause of hepatocellular carcinoma (HCC). Half of the infected patients do not respond to treatment and are at risk of cirrhosis and HCC. Understanding the biology of the virus is therefore of utmost importance for elucidating HCC pathology and designing novel treatments. During budding of the virus outside of the infected cell, it acquires cellular proteins. Mounting evidence indicates that these host proteins get involved in the replication and release steps of the viral cycle. The aim of the EU-funded HCV-BOUND PROTEINS (Hepatitis C virus virion-bound proteins: identification in clinical samples and in vitro dissection of their importance in the viral life cycle) project was to identify these host proteins from clinical samples. Using proteomic analysis, the consortium discovered FIG4 phosphatase as one of the enzymes implicated in HCV infectivity. Interestingly, researchers found that in order to increase its specific infectivity, HCV hijacks Netrin-1, a potent carcinogenic molecule. Expression of Netrin-1 was elevated in infected liver biopsies and exhibited an association with virus replication. Scientists also saw that Netrin-1 promoted viral entry by increasing the activation and the recycling of the epidermal growth factor receptor, which is deregulated in HCC. Considerable effort focussed on the development of an in vitro tool that recapitulates the hepatic microenvironment prior to infection. This should help decipher the early interactions of HCV as well as the infectivity dependence of the virus. Overall, the HCV-BOUND PROTEINS study has provided novel insight into the biology of HCV and the role of host proteins in its infectivity. Importantly, since host proteins are genetically stable, they may serve as robust targets for therapy.
Keywords
Host proteins, hepatitis C virus, hepatocellular carcinoma, budding, Netrin-1
