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

Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5736-41. doi: 10.1073/pnas.1016358108. Epub 2011 Mar 14.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genotype
  • Hepacivirus / immunology*
  • Hepatitis C / genetics
  • Hepatitis C / immunology*
  • Humans
  • Immunity, Innate / genetics*
  • Interleukins / metabolism*
  • Ireland
  • Killer Cells, Natural / immunology*
  • Odds Ratio
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, KIR / genetics
  • Receptors, KIR / metabolism*
  • Risk Factors

Substances

  • interferon-lambda, human
  • Interleukins
  • KIR2DS3 protein, human
  • Receptors, KIR