Hepatitis C virus/ host lipid metabolism interaction: a novel application for lipid-modulating agents?

Hepatitis C virus is responsible for persistent infection in up to 500,000 people in the UK and 170 people million worldwide and is associated with both cirrhosis and liver cancer. Current treatment regimes are effective in only 50% of patients overall. Chronic HCV infection results in, often severe, disruption of the liver?s ability to regulate the secretion and storage of fats and in insensitivity to insulin which may, in some cases, result in diabetes. Fats traffic round the body in lipoprotein coated particles which are secreted from liver cells and taken up either by other liver cells or cells in other parts of the body. Accumulating evidence suggests that HCV highjacks the production of host lipoprotein particles in infected cells to produce hybrid particles which contain both virus and host lipoproteins and can gain entry to fresh cells by the normal lipoprotein pathways. This may give some protection against host antibody responses and facilitate persistence of the virus. We suggest that the disruption of host fat metabolism is a side effect of this process. If so, we should be able to demonstrate that the degree of disturbance of host metabolism is correlated to the level of secretion of hybrid virus/lipoprotein particles and is reversed on clearance of the virus by conventional antiviral therapy. Experiments are planned which will test this correlation. The hypothesis also predicts that the treatment of HCV infected patients with lipid lowering agents should reduce both virus secretion and disturbances of fat metabolism. Here we propose to test the efficacy of two such agents, polyunsaturated fatty acids and statins. Both of these agents have been shown to inhibit the replication of the virus in cell culture systems. They are relatively inexpensive and safe and are both existing therapies used extensively in the prevention heart disease. If efficacious, their application to HCV infections would have a major impact upon chronic liver disease in the short to medium term.

Hepatitis C virus is responsible for persistent infection in up to 500,000 people in the UK and 170 million worldwide and is associated with both cirrhosis and liver cancer. Current treatment regimes are effective in only 50% of patients overall. There is accumulating evidence supporting a profound effect of HCV replication on lipid metabolism and insulin resistance. Data indicates that, in vivo, infectivity is largely associated with virus/host lipoprotein complexes, termed lipo-viro-particles (LVP). These resemble host VLDL and are intimately associated with apoB and apoE. Entry into hepatocytes can be mediated by interaction of the host lipoproteins with cell surface receptors (LDLr and SR-B1) and patients with the apoE isoform (E2) which binds poorly to LDLr are more likely to clear infection. Our hypothesis is that HCV hijacks the VLDL pathway, to produce LVP and that the more HCV-LVP that are produced, the greater the disturbance in host lipids (decrease in serum cholesterol, triglycerides, apoB and increase in hepatic lipid) and insulin resistance. Thus disturbance in metabolic parameters would be expected to be greater in those with higher LVP load. Conversely pharmacological intervention to decrease the hepatic secretion of VLDL would be expected to decrease LVP load.

This has clearly raised the question whether lipid lowering agents, such as Omega-3 PUFAs and/or statins, which have been shown in vitro to inhibit HCV RNA replication, may be beneficial in vivo. Fish oils are safe, well tolerated and have long been known to reduce VLDL concentrations and heart disease risk. They are therefore an attractive candidate to evaluate in chronic hepatitis C infection and could potentially be used alone to slow progression of fibrotic liver disease or in combination with statins.

Here, we propose a two part study in part A of which, we propose experiments to evaluate whether PUFAs and/or statins show a trend towards efficacy in patients with chronic HCV. In part B, we will collect information that can be used to support or refute the underlying hypothesis that HCV replication within the liver cell commandeers the hepatic VLDL production pathway. We will characterize LVP by size, density, host lipoprotein and viral protein content in order to establish their precise relationship to the host lipoprotein cascade. We will also evaluate the effects of HCV infection upon the kinetics of VLDL metabolism, using a stable label technique, studying patients both before and after clearance of virus infection by interferon/ribavirin treatment.