KIR2DL3+NKG2A- natural killer cells are associated with protection from productive hepatitis C virus infection in people who inject drugs

Background & Aims: Despite continuous high-risk behavior, a subgroup among people who inject drugs (PWID) remains seronegative for hepatitis C virus (HCV) suggesting that a state of natural resistance'' to HCV Infection may exist. Homozygosity for KIR2DL3 and its ligand HLA-C1 group alleles has been associated with control of HCV infection, however, the mechanism mediating this protective effect remained unclear. Methods: Peripheral NK cells from PWID (n = 104) were phenotypically and functionally characterized by multicolor flow cytometry. Expression levels of the NK cell receptor ligands were analysed in liver biopsies and primary human hepatocytes. Results: HCV seronegative PWID (n = 34) had increased levels of KIR2DL3(+)NKG2A(-) NK cells compared to healthy controls (n = 10; p < 0.001) and PWID with chronic (n = 38; p < 0.001) or resolved infection (n = 37; p < 0.001). There was an inverse correlation between the frequency of KIR2DL3(+) and NKG2A(+) NK cells (r = -0.53; p < 0.0001). Importantly, expression of HLA-E, the ligand for NKG2A, was significantly upregulated in liver biopsies of HCV infected patients (n = 51) compared to HBV infected patients (n = 22; p < 0.01) and correlated with HCV viral load (r = 0.32; p < 0.0029). In functional analyses KIR2DL3(-)NKG2A(+) NK cells but not KIR2DL3(+) NKG2A(-) NK cells were significantly inhibited by HLA-E ligation. Accordingly, interferon gamma secretion of NK cells from PWID with chronic infection but not from HCV seronegative PWID was significantly suppressed in the presence of HLA-E. Conclusions: KIR2DL3(+)NKG2A(-) NK cells are not sensitive to HLA-E-mediated inhibition and may thereby control early HCV infection prior to seroconversion and result in an apparent state of natural resistance'' to HCV in PWID. (C) 2014 Published by Elsevier B.V.