HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs

Abstract

BACKGROUND AND AIMS: NK cell function is regulated by inhibitory and activating receptors including killer-cell immunoglobulin-like receptors (KIRs). Here, we analyzed the impact of different KIR/KIR-ligand genotypes on the outcome of HCV infection in people who inject drugs (PWID). KIR/KIR-ligand genotypes associated with spontaneous clearance of HCV infection were identified in a cohort of PWID from Germany (n=266) and further validated in a second anti-HCV positive cohort of PWID recruited in North America (n=342). Moreover, NK cells of PWID and healthy donors were functionally characterized according to their KIR/KIR-ligand genotype by flow cytometry.

RESULTS: Multivariate logistic regression analysis revealed that KIR3DL1/HLA-Bw4 80(T) was associated with spontaneous clearance of HCV infection in PWID, which was confirmed in the PWID cohort from North America. Moreover, compared with PWID with detectable HCV-RNA the frequency of individuals with multiple HLA-Bw4 alleles was significantly higher in anti-HCV positive PWID with resolved HCV infection (29.7% vs. 15.2%; p=0.0229) and in anti-HCV seronegative PWID (39.2%; p=0.0006). KIR3DL1(+) NK cells from HLA-Bw4 80(T)-positive PWID showed superior functionality compared to HLA-Bw4 80(I)-positive PWID. This differential impact was not observed in healthy donors; however the HLA-Bw4 copy number strongly correlated with the functionality of KIR3DL1(+) NK cells.

CONCLUSIONS: HLA-Bw4-80(T) and multiple HLA-Bw4 copies in combination with KIR3DL1 are associated with protection against chronic hepatitis C in PWID by distinct mechanisms. Better licensing of KIR3DL1(+) NK cells in the presence of multiple HLA-Bw4 copies is beneficial prior to seroconversion whereas HLA-Bw4 80(T) may be beneficial during acute hepatitis C. Lay summary NK cells are part of the innate immune system and are regulated by a complex network of activating and inhibiting receptors. The regulating receptor-ligand pairs of an individual are genetically determined. Here, we identified a particular set of ligand and receptor genes that associated with better functionality of NK cells and better outcome upon exposure to HCV in a high risk group.

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