title: Apolipoprotein-E and hepatitis C lipoviral particles in genotype 1 infection: evidence for an association with interferon sensitivity.
abstract: OBJECTIVE
  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) and 'non-LVP' (d >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.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. david.sheridan@ncl.ac.uk
authors.forename: David A
authors.initials: DA
authors.lastname: Sheridan
authors.forename: Simon H
authors.initials: SH
authors.lastname: Bridge
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Felmlee
authors.forename: Mary M E
authors.initials: MM
authors.lastname: Crossey
authors.forename: Howard C
authors.initials: HC
authors.lastname: Thomas
authors.forename: Simon D
authors.initials: SD
authors.lastname: Taylor-Robinson
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Toms
authors.forename: R Dermot G
authors.initials: RD
authors.lastname: Neely
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Bassendine
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000097:blood; D001057:Apolipoproteins E / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D024882:Drug Resistance, Viral / Q000502:physiology; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D019562:Viral Load / Q000502:physiology; D014771:Virion / Q000235:genetics / Q000378:metabolism*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D015415:Biomarkers; D054357:Chemokine CXCL10; D016898:Interferon-alpha; D007371:Interferon-gamma; D007372:Interferons; D007378:Interleukins; D008055:Lipids; C000624353:interferon-lambda, human; D000095022:Interferon Lambda