KIR2DL3⁺NKG2A⁻ natural killer cells are associated with protection from productive hepatitis C virus infection in people who inject drugs.
OBJECTIVE
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.
Institute of Virology, University of Duisburg-Essen, University Hospital, Essen, Germany.
Christine
C
Thoens
The Ragon Institute of MGH, MIT and Harvard, Boston, USA.
Christoph
C
Berger
Department for Gastroenterology and Hepatology, University of Duisburg-Essen, University Hospital, Essen, Germany.
Martin
M
Trippler
Addiction Research Group, Department of Psychiatry and Psychotherapy, Rhine State Hospital, Hospital of the University of Duisburg-Essen, Essen, Germany.
Holger
H
Siemann
Department for Gastroenterology and Hepatology, University of Duisburg-Essen, University Hospital, Essen, Germany.
Melanie
M
Lutterbeck
Department for Gastroenterology and Hepatology, University of Duisburg-Essen, University Hospital, Essen, Germany.
Ruth
R
Broering
Department for Gastroenterology and Hepatology, University of Duisburg-Essen, University Hospital, Essen, Germany.
Jörg
J
Schlaak
Institute for Transfusion Medicine, University of Duisburg-Essen, University Hospital, Essen, Germany.
Falko M
FM
Heinemann
Institute for Transfusion Medicine, University of Duisburg-Essen, University Hospital, Essen, Germany.
Andreas
A
Heinold
Department of Internal Medicine, University of Bonn, Bonn, Germany.
Jacob
J
Nattermann
Addiction Research Group, Department of Psychiatry and Psychotherapy, Rhine State Hospital, Hospital of the University of Duisburg-Essen, Essen, Germany.
Norbert
N
Scherbaum
The Ragon Institute of MGH, MIT and Harvard, Boston, USA.
Galit
G
Alter
Institute of Virology, University of Duisburg-Essen, University Hospital, Essen, Germany. Electronic address: joerg.timm@uni-due.de.
Joerg
J
Timm
D000328:Adult; D000483:Alleles; D001706:Biopsy; D016022:Case-Control Studies; D005260:Female; D016174:Hepacivirus / Q000502:physiology; D006526:Hepatitis C / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000378:metabolism* / Q000473:pathology*; D008099:Liver / Q000473:pathology; D008297:Male; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000172:deficiency*; D010641:Phenotype; D054344:Receptors, KIR2DL3 / Q000378:metabolism*; D012309:Risk-Taking; D015819:Substance Abuse, Intravenous; D014779:Virus Replication; D000097625:HLA-E Antigens
D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; D054344:Receptors, KIR2DL3; D000097625:HLA-E Antigens; C515078:KIR2DL3 protein, human; C527054:KLRC1 protein, human
HCV; Injection drug user; KIR2DL3; NKG2A