Apolipoprotein-E and hepatitis C lipoviral particles in genotype 1 infection: Evidence for an association with interferon sensitivity

Background & Aims: Hepatitis C virus (HCV) interacts with apolipoproteins B (apoB) and E (apoE) to form infectious lipoviral particles (LVP). Response to peginterferon is influenced by interferon-stimulated genes (ISGs) and IL28B genotype. LDL cholesterol (LDL-C) also predicts interferon response, therefore we hypothesised that LVP may also be associated with interferon sensitivity. Methods: LVP (HCV RNA density 1.07 g/ml) were measured in 72 fasted HCV-G1 patients by iodixanol density gradient ultracentrifugation and the LVP ratio (LVP/LVP + non-LVP) was calculated. Fasting lipid profiles and apolipoproteins B and E were measured. Interferon-gamma-inducible protein 10 kDa (IP10), a marker of ISGs, was measured by ELISA. Results: Complete early virological response (EVR) was associated with lower apoE (23.9 +/- 7.7 vs. 36.1 +/- 15.3 mg/L, p = 0.013), higher LDL-C (p = 0.039) and lower LVP ratios (p = 0.022) compared to null responders. In multivariate linear regression analysis, apoE was independently associated with LVP (R-2 19.5%, p = 0.003) and LVP ratio (p = 0.042), and negatively with LDL-C (p <0.001). IP10 was significantly associated with ApoB (p = 0.001) and liver stiffness (p = 0.032). IL28B rs12979860 CC was associated with complete EVR (p = 0.044), low apoE (CC 28 +/- 11 vs. CT/TT 35 +/- 13 mg/L, p = 0.048) and higher non-LVP (p = 0.008). Logistic regression analysis indicated that patients with high LVP ratios were less likely to have EVR (odds ratio 0.01, p = 0.018). Conclusions: In HCV-G1, interferon sensitivity is characterised by low LVP ratios and low apoE levels in addition to higher LDL-C and IL28B rs12979860 CC. Null-response is associated with increased LVP ratio. The association of apoE and LVP with peginterferon treatment response suggests that lipid modulation is a potential target to modify interferon sensitivity