Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection
Open Access
- 14 March 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 108 (14), 5736-5741
- https://doi.org/10.1073/pnas.1016358108
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.Keywords
This publication has 53 references indexed in Scilit:
- Facilitation of KIR genotyping by a PCR‐SSP method that amplifies short DNA fragmentsTissue Antigens, 2007
- Increased frequencies of activating natural killer receptors are associated with liver injury in individuals who do not eliminate hepatitis C virusTissue Antigens, 2007
- Influence of inhibitory killer immunoglobulin‐like receptors and their HLA‐C ligands on resolving hepatitis C virus infectionTissue Antigens, 2007
- Donor–Recipient Combinations of Group A and B KIR Haplotypes and HLA class I Ligand Affect the Outcome of HLA-Matched, Sibling Donor Hematopoietic Cell TransplantationHuman Immunology, 2007
- Prognosis after unmanipulated HLA‐haploidentical blood and marrow transplantation is correlated to the numbers of KIR ligands in recipientsEuropean Journal of Haematology, 2007
- KIR haplotype content at the allele level in 77 Northern Irish familiesImmunogenetics, 2007
- Interferons α and λ Inhibit Hepatitis C Virus Replication With Distinct Signal Transduction and Gene Regulation KineticsGastroenterology, 2006
- Natural killer cells as an initial defense against pathogensCurrent Opinion in Immunology, 2006
- Natural killer cells: Primary target for hepatitis C virus immune evasion strategies?Liver Transplantation, 2006
- NK cells: Natural born killers in the conflict between humans and HCVHepatology, 2006