Research ArticleKIR2DL3+NKG2A− natural killer cells are associated with protection from productive hepatitis C virus infection in people who inject drugs

Background & AimsDespite 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.MethodsPeripheral 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.ResultsHCV 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.ConclusionsKIR2DL3+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.