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

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

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.

Technical Summary

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.

Publications

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Bassendine MF (2011) HCV and the hepatic lipid pathway as a potential treatment target. in Journal of hepatology

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Bassendine MF (2013) Lipids and HCV. in Seminars in immunopathology

 
Description Genetic variants in IL28B and hepatitis C treatment outcome
Geographic Reach National 
Policy Influence Type Citation in clinical reviews
Impact Editorial in Nature Genetics outlining the importance of genetic variants in IL28B in individualizing treatment decisions. "Predictive models for HCV treatment response hold the potential to inform treatment decisions for millions of patients who are infected with HCV" [Nature Genetics, 41;1048-50].
 
Description HCV Research UK Resource Consortium project
Amount £1,924,918 (GBP)
Funding ID C0365 
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2015
 
Description Project grant
Amount £50,212 (GBP)
Funding ID JAG/ML/0712 
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust 
Department Newcastle Healthcare Charity
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 12/2013
 
Title Assay for hepatitis C virus lipo-viral particles 
Description Laboratory method fractionating HCV by density and assaying HCV RNA associated with apolipoprotein B, a pututative measure of more infectious HCV. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This assay is an end-point in our pilot study investigating lipid modulating agents in the treatment of HCV and has potential utility in other trials. 
 
Title Database of HCV host lipid study in Symphony, a web-based electronic data capture system 
Description Clinical, biochemical and virological data on all patients with chronic hepatitis C recruited into research studies funded by this grant. 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact This allows coordinated and standised data collection between multiple sites. Currently 2 centres are entering data but it can be expanded in future, e.g. for a multi-centre clinical trial. 
 
Title The use of lipid emulsions for binding hepatitis C virus 
Description We have made the novel observation that HCV can transfer onto triglyceride rich lipoproteins and lipid emulsions in vivo and in vitro. This may be used in the development of novel therapy and/or in the development of an assay to measure this previously unrecognised phase of the HCV life-cycle. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact UK patent application number GB0915957.5 
 
Description Assessment of hepatitis C virus associated with apolipoprotein B48 
Organisation University of Ottawa
Country Canada 
Sector Academic/University 
PI Contribution It is widely accepted that infectious HCV associates with apolipoprotein (apo) B100 but controversial whether it associates with apoB48. We established this collaboration in order to access reagents that are able to distinquish between apoB100 and apoB48.
Collaborator Contribution Access to reagents and expertise in the biochemistry of apolipoprotein B100 and B48, which are the structural proteins of VLDL and chylomicrons.
Impact Publication in Gastroenteroloogy
Start Year 2008
 
Description Diagnostic test to measure hepatitis C lipo-viral particles 
Organisation HB Innovations Ltd, Newcastle upon Tyne
Country United Kingdom 
Sector Private 
PI Contribution We have developed an assay for hepatitis C lipo-viral particles which could be more clinically useful that HCV total viral load. We have entered into this colloboration to simplify and commercialise the assay.
Impact Still in development.
Start Year 2010
 
Description Iodixanol density gradient analysis of HCVcc 
Organisation University of Birmingham
Department College of Medical and Dental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Iodixanol gradient analysis of HCV RNA derived from HCVcc.
Collaborator Contribution This collaboration was to analyse HCVcc in iodixanol density gradients before and after "neutralisation" with pooled chronic hepatitis C patient IgG. Professor Mckeating aproached us in view of our expertise in this methodology.
Impact Our data showed for the first time that low density HCV is less susceptible to neutralisation by patient antibodies. Co-authorship of publication [PMID 18829747].
Start Year 2007
 
Description Multi-centre genome-wide association study of response to treatment in chronic hepatitis C 
Organisation University of Sydney
Country Australia 
Sector Academic/University 
PI Contribution One of the centres that contributed DNA and phenotying of chronic hepatitis C (CHC) patients to this study. We have contributed material from both CHC genotype 1 and CHC genotype 3.
Collaborator Contribution Professor J George approached us to participate in this genome-wide association study of treatment response in chronic hepatitis C; he was aware of our MRC experimental medicine grant and hence knew we had a large well characterised cohort of patients for inclusion in the multi-centre study.
Impact This has so far resulted in a Nature Genetics publication from the CHC genotype 1 group ( PMID 19749756) and 2 further 2011 publications. It is anticipated that further publication(s) will follow from this collaboration
Start Year 2008
 
Description Proprotein Convertase Subtilisin Kexin type 9 (PCSK9): a key molecule in the regulation of LDL receptor (LDLr) 
Organisation University of Montreal
Country Canada 
Sector Academic/University 
PI Contribution The LDL receptor (LDLr) is a candidate receptor for hepatitis C virus. PCSK9 has recently been identified as a key molecule in the regulation of cell surface expression of LDLr. Prof J Davignon have developed an ELISA assay for measurement of serum PCSK9 so we established a collaboration in order to measure this key enzyme in our cohort of well characterised patients with chronic hepatitis C infection. This assay is informative for LDL turnover which we are investigating in the apolipoprotein B kinetics component of this grant
Collaborator Contribution Access to an assay for PCSK9 which was not commercially available and to data on PCSK9 in healthy volunteers.
Impact Initial results have been presented at the 16th International Symposium on Hepatitis C Virus and Related Viruses, held in Nice (October 2009). The manuscript is in preparation.
Start Year 2008
 
Title The use of lipid emulsions for binding hepatitis C virus 
Description HCV particles in serum transfer onto triglyceride rich lipoproteins including lipid emulsion(s). This is the first demonstration of an intravascular phase of the HCV life-cycle. This may be exploited therapeutically. 
IP Reference GB0915957.5 
Protection Patent application published
Year Protection Granted 2009
Licensed No
Impact UK patent [GB0915957.5] was filed recently and developmental work is in progress.
 
Title Assay for Hepatitis C lipoviroparticles 
Description We have developed an assay for Hepatitis C lipo-viral particles and demonstrated a significant correlation with insulin resistance in patients with chronic hepatitis C genotype 1 infection. Insulin resistance is an important predictor of fibrosis progression and non-respose to anti-viral treatment. This assay has demonstrated a direct link between infectious virus and host factors. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2009
Development Status Under active development/distribution
Impact The assay is being used in our pilot intervention trial with lipid modulating therapy and has potential utility in future trials. 
 
Title Omacor and/or Fluvastatin 
Description 'A randomised, controlled, factorial pilot study investigating Omacor and/or Fluvastatin in patients with chronic hepatitis C who have not responded to standard combination anti-viral therapy' 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Recruitment is now closed, the data is being analysed and a publication is pending. 
 
Description Hepatitis Nurse specialists regional forum 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Presentation about options for anti-viral treatment non-responders, including our pilot study.

Increased awareness.
Year(s) Of Engagement Activity 2009
 
Description LIVErNORTH - Newcastle patient support group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Presentation of future treatment options in hepatitis C and of our research using lipid modulating agents

Increased awareness and participation in studies
Year(s) Of Engagement Activity 2008
 
Description The clinical trial featured in the Hepatitis C Trust website (http://www.hepctrust.org.uk/news/2009/March/Hepatitis+C+patients+who+have+failed+treatment+needed+for+UK+trial+using+fish+oils+and+statins.htm) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Dissemination of details of the trial to the major UK patient group

Improved recruitment to the trial.
Year(s) Of Engagement Activity 2009
URL http://www.hepctrust.org.uk/news/2009/March/Hepatitis+C+patients+who+have+failed+treatment+needed+fo...