Consistent Beneficial Effects of Killer Cell Immunoglobulin-Like Receptor 2DL3 and Group 1 Human Leukocyte Antigen-C Following Exposure to Hepatitis C Virus

Department of Hepatology, Division of Medicine, Imperial College London, UK.
Hepatology (Impact Factor: 11.06). 04/2010; 51(4):1168-75. DOI: 10.1002/hep.23477
Source: PubMed


Natural killer cells are a key component in the immune control of viral infections. Their functions are controlled by inhibitory receptors for major histocompatability complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIR). KIR2DL3 in combination with its cognate human leukocyte antigen (HLA)-C ligand has been shown to be associated with spontaneous resolution of viremia following hepatitis C virus (HCV) infection. In order to determine if this gene combination is advantageous across all potential outcomes following HCV exposure, we studied individuals with apparent resistance to HCV infection who remain seronegative and aviremic despite long-term injection drug use and also individuals chronically infected with HCV who successfully clear HCV with treatment. Homozygosity for KIR2DL3 in combination with group 1 HLA-C allotypes was more frequent in exposed seronegative aviremic individuals as compared to those with chronic HCV (25.0% versus 9.7%, P = 0.003, odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.3-7.1) in a model similar to that found for those spontaneously resolving HCV. In individuals undergoing treatment for HCV, those with KIR2DL3 and group 1 HLA-C were more likely to make a sustained virological response (SVR) (P = 0.013, OR = 2.3, 95% CI = 1.1-4.5). KIR and HLA-C protection in both treatment response and spontaneously resolving HCV was validated at the allelic level, in which KIR2DL3-HLA-Cw*03 was associated with SVR (P = 0.004, OR = 3.4, 95% CI = 1.5-8.7) and KIR2DL3/KIR2DL3-HLA-Cw*03 was associated with spontaneous resolution of HCV infection (P = 0.01, OR = 2.3, 95% CI = 1.2-4.4). Conclusion: KIR and HLA-C genes are consistently beneficial determinants in the outcome of HCV infection. This advantage extends to the allelic level for both gene families.

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Available from: Ann-Margaret Little, Oct 16, 2014
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    • "However, as NK cells are the first immunological walls against HCV, much evidence has been uncovered. An NK-cell activating and inhibitory receptor gene polymorphism has been discovered to have roles in the course of HCV infection [54, 55]. As IFN-α is the basic treatment for chronic hepatitis C, IFN-producing NK cells have been defined as key immune cells. "
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    • "To maintain functional recognition of rapidly evolving class I HLA complexes, the NK cell KIR genes must also evolve under pathogen-mediated pressure [59, 60]. Genotyping of those exposed to HCV demonstrated that coordinate expression of NK cell receptor KIR2DL3 and its cognate class I HLA C group 1 (HLA-C1) ligand confers an increased likelihood of spontaneous HCV clearance or of a sustained virological response (SVR) to treatment when spontaneous HCV clearance is not achieved [14, 56, 61]. One functional interpretation of this association is that as the interaction between KIR2DL3 and HLA-C1 is relatively low affinity, it generates a weaker inhibitory signal than other KIR/ligand interactions allowing a greater functional response by NK cells [57, 58]. "
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    • "In addition, the homozygous genotype is correlated with apparent resistance to infection in i.v. drug users (prolonged seronegativity despite continual exposure) and positive responses to treatment after HCV infection (166). "
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