Project 171106

This project will focus on studying distinct aspects of the biochemistry, physiology, genetics and clinical applications of two members of a family of human proteases known as PCSK9 and SKI-1 and their relationship to hepatitis C virus (HCV) infection. Both enzymes are known to regulate the levels of circulating low density lipoprotein (LDL)-cholesterol and fatty acids. We recently genetically linked the liver protein PCSK9 to the development of cardiovascular diseases in humans. We also showed that PCSK9 degrades the major HCV receptors, namely the LDL-cholesterol receptor (LDLR) and CD81. We demonstrated that this effect of PCSK9 results in a drastic reduction of HCV infectivity. The objectives of this proposal center on the characterization of the structural elements in CD81 that recognize PCSK9, and whether these are linked to those recognizing the LDLR. The identification of the CD81 motif implicated in this recognition would allow us to design molecular mimics that could be used to block viral infectivity. We will also develop novel therapeutic approaches aimed to silence SKI-1 and/or increase the expression of PCSK9 and test their efficacy on HCV infection. Finally, the availability of an assay to measure circulating PCSK9 in blood, will allow us to develop diagnostic tools correlating the level of PCSK9 to that of HCV titers in human patients infected by HCV and to test the effects of presently prescribed HCV antivirals on PCSK9 levels.

investigating the role of PCSK9 and SKI-1 in hepatitis C virus infection and developing novel therapeutic and diagnostic tools