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.