title: The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways.
abstract: Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)-λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ(2) test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA-C1C1 (P = 0.027), IFN-λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA-B (TapG:HLA-B(114D) ) (P = 0.007) and HLA-DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ(2) test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN-λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA-C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non-interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Hydes
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: B
authors.initials: B
authors.lastname: Moesker
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Traherne
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Alexander
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.|Academic Unit of Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: B D
authors.initials: BD
authors.lastname: Dimitrov
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Woelk
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Trowsdale
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: S I
authors.initials: SI
authors.lastname: Khakoo
mesh_terms: D018450:Disease Progression; D004843:Epistasis, Genetic / Q000276:immunology*; D015870:Gene Expression; D018740:Genetic Heterogeneity; D005838:Genotype; D016174:Hepacivirus / Q000276:immunology* / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000821:virology; D016015:Logistic Models; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology; D015999:Multivariate Analysis; D011379:Prognosis; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology; D012075:Remission, Spontaneous; D012189:Retrospective Studies; D000095022:Interferon Lambda
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007372:Interferons; D007378:Interleukins; D026901:Membrane Transport Proteins; D054340:Receptors, KIR; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human; C107762:tapasin
keywords: IFN-λ3/4; hepatitis C; immunogenetics; interferon; killer cell immunoglobulin receptors; tapasin