KIR2DL3+ NKG2A- Natural Killer Cells Protect People who Inject Drugs against Productive Hepatitis C Virus Infection

C Thoens; C Berger; M Trippler; H Siemann; M Lutterbeck; R Broering; JF Schlaak; FM Heinemann; A Heinold; J Nattermann; N Scherbaum; G Alter; J Timm

doi:10.1055/s-0033-1361036

Zeitschrift für Gastroenterologie, Table of Contents

KIR2DL3+ NKG2A- Natural Killer Cells Protect People who Inject Drugs against Productive Hepatitis C Virus Infection

C Thoens ¹, C Berger ², M Trippler ³, H Siemann ⁴, M Lutterbeck ³, R Broering ³, JF Schlaak ³, FM Heinemann ⁵, A Heinold ⁵, J Nattermann ⁶, N Scherbaum ⁴, G Alter ², J Timm ¹

¹University of Duisburg-Essen, Institute of Virology, Essen, Germany
²The Ragon Institute of MGH, MIT and Harvard, Boston, USA
³University of Duisburg-Essen, Department for Gastroenterology and Hepatology, Essen, Germany
⁴University of Duisburg-Essen, Department of Psychiatry and Psychotherapy, Rhine State Hospital, Essen, Germany
⁵University of Duisburg-Essen, Institute for Transfusion Medicine, Essen, Germany
⁶University of Bonn, Department of Internal Medicine, Bonn, Germany

Abstract

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. In this study we aimed to address the role of NK cells in HCV seronegative PWID at high risk for infection. HCV seronegative PWID had increased levels of KIR2DL3+NKG2A- NK cells compared to healthy controls (p < 0.001) and patients with chronic infection (p < 0.001). There was a strong inverse correlation between the frequency of KIR2DL3+ and NKG2A+ NK cells (r =-0.53; p < 0.0001). The KIR2DL3+NKG2A- NK cell phenotype in seronegative PWID was independent of NK cell subset distribution and expression of the differentiation marker CD57 suggesting that it may be the consequence of genetically determined differential NK cell licensing/education. Importantly, expression of HLA-E, the ligand for NKG2A, was significantly upregulated in liver biopsies of HCV infected patients (n = 51) compared to patients with hepatitis B (n = 22; p < 0.01) and correlated with HCV viral load (r = 0.32; p < 0.0029). In functional analyses KIR2DL3-NKG2A+ NK cells were significantly inhibited by HLA-E ligation. As a consequence of this functional phenotype, interferon gamma secretion of total NK cells from PWID with chronic infection but not from HCV seronegative PWID was significantly suppressed in the presence of HLA-E.

Conclusions: Our data suggest that a distinct KIR2DL3+NKG2A- NK cell phenotype associated with less HLA-E-mediated inhibition may control early HCV infection prior to seroconversion and result in an apparent state of “natural resistance” to HCV in PWID.