Every year nearly 200 million people are infected with Hepatitis C virus (HCV), an event which often leads to liver disease. New, targeted therapies are urgently needed as current therapies are only effective in 50% of HCV infections. The process by which HCV infects liver cells is poorly understood; however, previous work has indicated that the low density lipoprotein receptor (LDL-R) protein on the surface of cells may facilitate the ability of HCV to enter the cells during infection. To determine if LDL-R is involved in HCV entry into cells, David Owen and VIDI affiliate investigator, Dr. Michael Gale Jr. examined the interaction between HCV and lipoproteins in a tissue culture system using HCV JFH1 genotype 2a, a particular type of HCV strain that has the ability to replicate in tissue culture.
Their work with this tissue culture system indicated that Apolipoprotien E (ApoE), a protein connected to a fat which helps control the amount of cholesterol in the blood, facilitates HCV infection through a physical interaction with LDL-R, which is known to bind to ApoE. Using binding competition assays, treatment of cells with b-VLDL (a mixture of ApoE and other proteins that are connected with fat) or with anti-ApoE antibody (an immune protein which specifically binds to ApoE) was able to block the ability of HCV to infect the cells, indicating that ApoE facilitates the ability of HCV to infect cells.
Furthermore, the researchers found that HCV infectious particles could be isolated from tissue cultures using anti-ApoE antibodies, thus indicating that HCV particles that infect cells contain ApoE. In addition, they found that LDL-R indeed facilitates HCV entry into cells, as cells that had reduced amounts of LDL-R were less likely to be infected by HCV. Finally, the group used density gradients (assays that measure density by varying the density over a known area) to show that the Apoliprotein-interacting HCV particles are dependent upon LDL-R for their ability to infect cells.
By uncovering a new route for HCV entry into cells during infection, Owen and his colleagues have discovered a potential new target for HCV therapies. Future work will be needed to determine if LDL-R-based therapies can control HCV infection.
Apolipoprotein E on hepatitis C virion facilitates infection through interaction with low-density lipoprotein receptor. Owen DM, Huang H, Ye J, Gale M Jr. Virology. 2009 Nov 10;394(1):99-108.