Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Abstract

Hepatitis C is a common infection with significant morbidity and mortality, and only a minority of patients successfully clear the infection. Identification of factors that influence disease progression in HCV infection is difficult owing to the lack of well-defined patient cohorts. However, recent evidence supports a role for the innate immune system in virus clearance. In this study, we investigated innate immune genes for their contribution to disease progression in a unique cohort of well-controlled HCV-infected patients. The Irish cohort of HCV patients is uniquely homogenous; patients were infected with a single genotype of HCV from contaminated anti-D Ig. We genotyped 543 infected patients, including 247 patients who spontaneously resolved infection, for natural killer (NK) cell-associated killer cell Ig-like receptors (KIR) genes and the recently reported IL28B (IFNλ3) SNP. The NK cell gene KIR2DS3 was significantly increased in patients with chronic infection [odds ratio (OR) 1.90, 95% confidence interval (CI) 1.25-2.90, P < 0.002]. The IL28B "T" allele was also significantly increased in chronically infected patients (OR 7.38, 95% CI 4.93-11.07, P < 10(-8)). The presence of both markers synergized to significantly increase the risk of chronic infection over either factor alone (OR 20.11, 95% CI 9.05-44.68, P < 10(-7)). In functional experiments, we found that IL28A significantly inhibited IFN-γ production by NK cells. Thus, we demonstrate a functional link between NK cells and type 3 IFN. Our findings may contribute to the development of a prognostic test for HCV and identify therapeutic strategies for the clinical management of HCV-infected patients.

Fig. 1.

Presence of both KIR2DS3 and IL28B-T synergize to increase the risk of developing chronic HCV infection. ORs for KIR2DS3 alone, IL28B-T carriers (CT or TT) alone, and KIR2DS3 with IL28B-T compared with neither risk factor present were calculated from multinomial logistic regression and used to calculate S and AP. The contribution of individual and combined risk factors to the ORs is graphically represented in the bar chart. Positive OR indicates an association with increased risk for chronic HCV. ^aOdds ratio (95% confidence interval). ^bSynergy index (95% confidence interval). ^cAttributable proportion for interaction (95% confidence interval).

Fig. 2.

IL28A inhibits IFN-γ production by human NK cells. Peripheral blood mononuclear cells (n = 11) from healthy normal donors were stimulated with PBS or IL12 (30 ng/mL)/IL15 (100 ng/mL) in the presence or absence of IL28A (500 ng/mL). Percentage of CD56⁺ CD3⁻ NK cells expressing IFN-γ as measured by intracellular staining is shown. Horizontal lines indicate the median percentages, and vertical lines indicate the range of values. A paired Student t test was used to compare data.