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Title: Investigation of hepatitis C virus (HCV) interactions with host lipid metabolism : a translational research study
Author: Sheridan, David Anthony
ISNI:       0000 0004 2710 7625
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2010
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Research into chronic hepatitis C virus (HCV) infection (CHC) is needed because only ~50% of patients with CHC are cured with existing treatments. HCV interacts with metabolism of cholesterol and very low density lipoproteins (VLDL) for replication, assembly, secretion and entry. Patients with CHC exhibit a dyslipidemia characterised by low LDL cholesterol (LDL-C) and insulin resistance. This translational study characterised the dyslipidemia apparent in CHC in retrospective and prospective HCV cohorts. Distinct metabolic phenotypes were defined between HCV genotypes 1 and 3. LDL-C was markedly reduced in HCV-G3, which exerted a greater effect than apoE genotype on LDL-C levels. Prospective analysis of non-cholesterol sterol intermediates established that disordered cholesterol synthesis in HCV was mediated predominantly via the lathosterol pathway. In HCV-G3, levels of Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) were low compared to healthy controls, suggesting increased LDL clearance. Low LDL-C and high triglyceride/HDL ratio were found to be predictive of poor response to anti-viral therapy. Collaboration in a genome wide association study revealed that SNPs in IL28B rather than in lipid regulating genes are the major host genetic determinants of treatment response. Analysis of HCV lipoviral particles (LVP) by iodixanol density gradient ultracentrifugation revealed correlations between insulin resistance and triglycerides (TG) with LVP in HCV-G1. Determination of apoB in VLDL1, VLDL2, IDL and LDL fractions confirmed fasting TG are predominately in the VLDL1 fraction, implying that HCV-G1 preferentially associates with the VLDL1 pathway. Interferon γ inducible protein 10 (IP10), a marker of hepatic interferon stimulated gene expression correlated with LDL-C and HCV LVP ratio in HCV-G1, explaining the association between low LDL-C and poor treatment response. A randomised pilot trial in 60 CHC non-responders indicated that 12 weeks of treatment with Fluvastatin can lower total viral load in HCV-G1 & G4 and that low dose n3 PUFAs improved IP10 levels.
Supervisor: Not available Sponsor: LIVEr NORTH
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available