Decreased interferon-γ production by NK cells from KIR haplotype B carriers in hepatitis C virus infection

Background and Aims: Different population genetics studies showed that interactions between killer-cell immunoglobulin-like receptors (KIR) and HLA play a role in viral disease outcome, but functional correlates are missing. Building upon our previous work pointing to a regulatory role for KIR3DL1/DS1 in hepatitis C virus (HCV) infection, we analysed whether its expression may affect natural killer (NK) cell function in the presence or absence of its principal ligand HLA-Bw4 in KIR haplotype A and B carriers, which are characterized by a different representation of activating and inhibitory KIRs. Methods: We performed KIR and HLA class I genotypic analysis in 54 healthy donors (HD) and 50 HCV+ subjects and examined NK cell cytokine secretion and degranulation in the context of KIR3DL1-HLA-Bw4 match stratified by KIR haplotype. Results: KIR3DL1-HLA-Bw4 match induced functional NK cell modulation, reflected by reduced interferon (IFN)γ production in haplotype B HCV+ patients compared to HD. This functional impairment could be ascribed to the KIR3DS1 negative HCV-infected patient population, whose NK cells also showed a significantly decreased proportion of KIR3DL1. Haplotype A HCV-infected patients showed increased NK cell degranulation compared with HD in the absence of KIR-HLA-Bw4 match and this activity was associated with increased phosphorylation of signal transducer and activator of transcription (STAT) 1. Conclusions: Our data show that NK cells from HCV+ patients have an unbalanced ability to produce IFNγ and to kill target cells in haplotype A and B carriers, suggesting the existence of complex functional differences governed by KIR-HLA interaction, particularly on KIR3DL1 expressing NK cells.