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) cellassociated 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). 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.

IFN‐λ‐mediated IL‐12 production in macrophages induces IFN‐γ production in human NK cells

“…This is in contrast to previous reports suggesting that type III IFNs have an inhibitory effect on IFN-γ production upon IL-12/IL-15 stimulation [27,28]. Our study not only investigated the effects of types I and III IFNs on cytokine production, but also on NK-cell activation and cytotoxicity.…”

“…A previous study had described IFN-λ as being able to partially inhibit NK-cell-derived IFN-γ production upon IL-12/15 stimulation [27,28], but an effect of IFN-λ on NK cells could not be reproduced in an ensuing response to the original article [29]. To better understand the biological role of IFN-λ, we investigated the effects of IFN-λ on NK cells in both a direct and indirect capacity through its modulation of TLR-activated macrophages.…”

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

“…Conversely, susceptibility factors appear to increase susceptibility. This was found in an Irish cohort, but not a larger international study 20, 21. Similarly, considering viral genotype and the response to IFN‐based therapy, IFN‐λ3/4 and centromeric A KIR haplotypes are important for treatment‐induced resolution of patients infected with HCV G1, whereas the KIR2DL3 and HLA‐class I combination, but not IFN‐λ3/4, plays a dominant role in resolving HCV G2 and G3 infection.…”

“…Heterogeneity at a population level has continued to contribute to substantial variation seen between studies in HCV resolution. For example for KIR in the UK population, KIR2DL3:HLA‐C1 is protective 8, but this is not found in the cohort of Irish women infected from a single source 20. In a Swiss cohort, the rs8099917 IFN‐λ3/4 minor allele failed to show any association with treatment in patients infected with HCV G2/3, but this was not the case when later repeated in a cohort of over 1000 Australians, also of Caucasian ethnicity 6, 32.…”

“…In these studies it has been shown that for the SNPs associated with worse outcomes, KIR2DS3, HLA‐C2C2 and IFN‐λ3/4 (rs8099917 G allele and rs12979860 T allele), there appeared to be an interaction, as individuals with two susceptibility factors had significantly worse outcomes than those with only one 20, 21. Conversely no predictive benefit was found on combining the favorable IFN‐λ3/4 polymorphism with KIR2DL3:HLA‐C1 homozygosity for protection against viremia in seronegative exposed groups 12.…”