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HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs

HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs
HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs

BACKGROUND AND AIMS: 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). KIR/KIR-ligand genotypes associated with spontaneous clearance of HCV infection were identified in a cohort of PWID from Germany (n=266) and further validated in a second anti-HCV positive cohort of PWID recruited in North America (n=342). Moreover, NK cells of PWID and healthy donors were functionally characterized according to their KIR/KIR-ligand genotype by flow cytometry.

RESULTS: Multivariate logistic regression analysis revealed that KIR3DL1/HLA-Bw4 80(T) was associated with spontaneous clearance of HCV infection in PWID, which was confirmed in the PWID cohort from North America. Moreover, compared with PWID with detectable HCV-RNA the frequency of individuals with multiple HLA-Bw4 alleles was significantly higher in anti-HCV positive PWID with resolved HCV infection (29.7% vs. 15.2%; p=0.0229) and in anti-HCV seronegative PWID (39.2%; p=0.0006). KIR3DL1(+) NK cells from HLA-Bw4 80(T)-positive PWID showed superior functionality compared to HLA-Bw4 80(I)-positive PWID. This differential impact was not observed in healthy donors; however 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. Lay summary NK cells are part of the innate immune system and are regulated by a complex network of activating and inhibiting receptors. The regulating receptor-ligand pairs of an individual are genetically determined. Here, we identified a particular set of ligand and receptor genes that associated with better functionality of NK cells and better outcome upon exposure to HCV in a high risk group.

Journal Article
0168-8278
462-470
Thöns, Christine
548cad74-b55a-4f6f-8367-3c84ea2e85d7
Senff, Tina
60ec8661-c990-4630-bfdc-89cc380d0ee7
Hydes, Theresa J.
d842d1ec-c64a-4934-a5a2-7316fea65767
Manser, Angela R.
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Heinemann, Falko M.
ab999502-0b82-4f4f-b43d-d98d6777d689
Heinold, Andreas
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Heilmann, Martin
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Kim, Arthur Y.
c1677b18-8300-4e04-b0d1-8636b66c8ff8
Uhrberg, Markus
3e577d7a-9513-48de-8dc9-313a547e2821
Scherbaum, Norbert
495503bc-576d-4b0b-8f86-a941cab0204b
Lauer, Georg M.
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Khakoo, Salim I.
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Timm, Jörg
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Thöns, Christine
548cad74-b55a-4f6f-8367-3c84ea2e85d7
Senff, Tina
60ec8661-c990-4630-bfdc-89cc380d0ee7
Hydes, Theresa J.
d842d1ec-c64a-4934-a5a2-7316fea65767
Manser, Angela R.
541b6d74-a5ec-425e-95a7-a41149e474f0
Heinemann, Falko M.
ab999502-0b82-4f4f-b43d-d98d6777d689
Heinold, Andreas
e867d829-0b0b-4abd-b1d1-57f8d8035282
Heilmann, Martin
562c250b-eb02-4b55-a17d-4b055bd13cb6
Kim, Arthur Y.
c1677b18-8300-4e04-b0d1-8636b66c8ff8
Uhrberg, Markus
3e577d7a-9513-48de-8dc9-313a547e2821
Scherbaum, Norbert
495503bc-576d-4b0b-8f86-a941cab0204b
Lauer, Georg M.
e7217e36-9234-4134-9c18-e95da7fb4a4a
Khakoo, Salim I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273
Timm, Jörg
fc58af7a-12c4-4545-b5ac-ce866cb4d3c9

Thöns, Christine, Senff, Tina, Hydes, Theresa J., Manser, Angela R., Heinemann, Falko M., Heinold, Andreas, Heilmann, Martin, Kim, Arthur Y., Uhrberg, Markus, Scherbaum, Norbert, Lauer, Georg M., Khakoo, Salim I. and Timm, Jörg (2017) HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs. Journal of Hepatology, 67 (3), 462-470. (doi:10.1016/j.jhep.2017.03.040).

Record type: Article

Abstract

BACKGROUND AND AIMS: 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). KIR/KIR-ligand genotypes associated with spontaneous clearance of HCV infection were identified in a cohort of PWID from Germany (n=266) and further validated in a second anti-HCV positive cohort of PWID recruited in North America (n=342). Moreover, NK cells of PWID and healthy donors were functionally characterized according to their KIR/KIR-ligand genotype by flow cytometry.

RESULTS: Multivariate logistic regression analysis revealed that KIR3DL1/HLA-Bw4 80(T) was associated with spontaneous clearance of HCV infection in PWID, which was confirmed in the PWID cohort from North America. Moreover, compared with PWID with detectable HCV-RNA the frequency of individuals with multiple HLA-Bw4 alleles was significantly higher in anti-HCV positive PWID with resolved HCV infection (29.7% vs. 15.2%; p=0.0229) and in anti-HCV seronegative PWID (39.2%; p=0.0006). KIR3DL1(+) NK cells from HLA-Bw4 80(T)-positive PWID showed superior functionality compared to HLA-Bw4 80(I)-positive PWID. This differential impact was not observed in healthy donors; however 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. Lay summary NK cells are part of the innate immune system and are regulated by a complex network of activating and inhibiting receptors. The regulating receptor-ligand pairs of an individual are genetically determined. Here, we identified a particular set of ligand and receptor genes that associated with better functionality of NK cells and better outcome upon exposure to HCV in a high risk group.

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Accepted/In Press date: 31 March 2017
e-pub ahead of print date: 13 April 2017
Published date: September 2017
Keywords: Journal Article
Organisations: Faculty of Medicine, Tissue Infection & Repair

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Local EPrints ID: 407951
URI: http://eprints.soton.ac.uk/id/eprint/407951
ISSN: 0168-8278
PURE UUID: 38bb2e97-04a2-423f-9fe1-46fda9182d56

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Date deposited: 05 May 2017 01:03
Last modified: 07 Oct 2020 05:49

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