Role of IL28B gene polymorphism and cell-mediated immunity in spontaneous resolution of acute hepatitis C

Abstract

Background: A single-nucleotide polymorphism (SNP; rs12979860) near the IL28B gene has been associated with spontaneous and treatment-induced hepatitis C virus clearance. We investigated predictors of spontaneous disease resolution in a cohort of patients with acute hepatitis C (AHC), analyzing epidemiological, clinical and virological parameters together with IL28B.rs12979860 genotypes and cell-mediated immunity (CMI).

Methods: Fifty-six symptomatic AHC patients were enrolled and followed prospectively. CMI was measured in 31 patients at multiple time points by interferon-γ enzyme-linked immunospot assay and was correlated to the IL28B.rs12979860 SNP.

Results: Eighteen patients had a self-limiting AHC that was associated with female sex (P = .028), older age (P = .018), alanine aminotransferase level >1000 U/L (P = .027), total bilirubin level >7 mg/dL (P = .036), and IL28B.rs12979860 genotype CC (P = .030). In multivariate analysis, only CC genotype was independently associated with self-limiting AHC (odds ratio, 5.3; 95% confidence interval, 1.1-26.5). Patients with the CC genotype with self-limiting AHC had a stronger (P = .02) and broader (P = .013) CMI than patients with the CT genotype with chronically evolving AHC. In patients with chronically evolving disease, CC genotype was associated with a broader CMI compared to CT genotype (P = .028). A negative CMI was more frequently associated with CT genotype among persistently infected patients (P = .043) and with persistent infection among CT patients (P = .033).

Conclusions: . Self-limiting AHC was independently associated with CC genotype. The correlation between IL28B.rs12979860 genotypes and CMI is suggestive of a possible important role of CMI in favoring hepatitis C virus clearance in CC patients.

Keywords: acute hepatitis C; cell-mediated immunity; interleukin-28B; prognostic factors.

Figure 1.

Spontaneous acute hepatitis C resolution and clinical features at disease onset by CC versus non-CC IL28B genotype. The fractional number on top of each column represents the proportion of patients with the clinical characteristic. Abbreviation: ALT, alanine aminotransferase.

Figure 2.

Analysis of the magnitude and breadth of the T-cell response in subjects with acute self-limiting infection (A–C) and subjects with chronic evolution (D–F). Peripheral blood mononuclear cell (PBMC) samples were tested by interferon-γ enzyme-linked immunospot assay (ELISpot) at 3 representative time points after disease onset (0–1 month, A and D; 6 months, B and E); between 12 and 24 months (C and F) against 7 peptide pools corresponding to core, NS3 protease, NS3 helicase, NS4, NS5a, and NS5b (pool I and II) antigens. To simplify, only responses above the threshold are shown. For all remaining subjects, ELISpot responses were negative at all time points tested. Numbers represent spot-forming cells per10⁶ PBMCs. For each patient, IL28B genotype is reported. Abbreviations: NT, not tested; PBMC, peripheral blood mononuclear cell; SFC, spot-forming cell; SNP, single-nucleotide polymorphism.