Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597517
5. Virus Immunology
Georg Thieme Verlag KG Stuttgart · New York

HLA-Bw4 80(T) and high HLA-Bw4 copy numbers in combination with KIR3DL1 are associated with superior immune control of HCV infection in people who inject drugs

C Thöns
1   Heinrich-Heine-University, University Hospital, Institute for Virology, Düsseldorf, Germany
,
T Senff
1   Heinrich-Heine-University, University Hospital, Institute for Virology, Düsseldorf, Germany
,
TJ Hydes
2   University of Southampton, Clinical and Experimental Academic Sciences, Southampton, UK
,
AR Manser
3   Heinrich-Heine-University, University Hospital, Institute for Transplantation Diagnostics and Cell Therapeutics, Düsseldorf, Germany
,
FM Heinemann
4   University of Duisburg-Essen, University Hospital, Institute for Transfusion Medicine, Essen, Germany
,
A Heinold
4   University of Duisburg-Essen, University Hospital, Institute for Transfusion Medicine, Essen, Germany
,
M Heilmann
5   LVR-Hospital Essen, Faculty of Medicine, University of Duisburg-Essen, Department for Addiction Medicine and Addictive Behavior, Essen, Germany
,
M Uhrberg
3   Heinrich-Heine-University, University Hospital, Institute for Transplantation Diagnostics and Cell Therapeutics, Düsseldorf, Germany
,
N Scherbaum
5   LVR-Hospital Essen, Faculty of Medicine, University of Duisburg-Essen, Department for Addiction Medicine and Addictive Behavior, Essen, Germany
,
SI Khakoo
2   University of Southampton, Clinical and Experimental Academic Sciences, Southampton, UK
,
J Timm
1   Heinrich-Heine-University, University Hospital, Institute for Virology, Düsseldorf, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2016 (online)

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Objective: 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).

Design: The KIR/KIR-ligand genotype was determined in 266 therapy-naïve PWID including 215 anti-HCV positive PWID (151 HCV-RNA positive and 64 HCV-RNA negative) and 51 anti-HCV seronegative PWID with high risk behavior. NK cells of 90 PWID (30 of each group) and 120 healthy donors were functionally characterized by flow cytometry.

Results: Multivariate logistic regression analysis revealed that KIR3DL1/HLA-Bw4 80(T) was associated with an HCV-RNA negative status in anti-HCV seropositive PWID. Moreover, the frequency of individuals with multiple HLA-Bw4 alleles was significantly higher among anti-HCV seropositive PWID with undetectable HCV-RNA (29.7%; p = 0.0229) and even more pronounced in anti-HCV seronegative PWID (39.2%; p = 0.0006) compared with HCV-RNA positive individuals (15.2%). In line with the genetic association KIR3DL1+ NK cells from HLA-Bw4 80(T)-positive PWID showed superior functionality compared to HLA-Bw4 80(I)-positive PWID. This differential impact of HLA-Bw4 80(T) on NK cell function was not observed in healthy donors, however, here, 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.