TUPDA0103 - Poster Discussion
Inhibitory KIR/HLA incompatibility between sexual partners confers protection against HIV-1 transmission
Presented by Wim Jennes (Belgium).
W. Jennes1, S. Verheyden2, J.W. Mertens1, M. Camara3, M. Seydi4, T.N. Dieye3, S. Mboup3, C. Demanet2, L. Kestens1
1Institute of Tropical Medicine, Department of Biomedical Sciences, Antwerpen, Belgium, 2Universitair Ziekenhuis Brussel, HLA and Molecular Hematology Laboratory, Brussels, Belgium, 3Centre Hospitalier Universitaire Le Dantec, Department of Bacteriology-Virology, Dakar, Senegal, 4Centre Hospitalier Universitaire Fann, Department of Infectious Diseases, Dakar, Senegal
Background: Natural killer (NK) cells play an important role in the innate response to viruses and cancer. NK cells are regulated by killer immunoglobulin-like receptors (KIR) that sense human leukocyte antigen (HLA) expression on potential target cells. KIR/HLA mismatched hematopoietic stem cell transplants help cure acute myeloid leukemia by inducing alloreactive NK cells. Certain KIR/HLA combinations influence HIV-1 infection and disease, but whether KIR/HLA mismatches between sexual partners protect against HIV-1 transmission has not been investigated. In this study, we analyzed the effect of KIR/HLA mismatches and alloreactive NK cells on HIV-1 transmission in a West African population of HIV-1 discordant and concordant couples.
Methods: 108 couples, of which 35 HIV-1 discordant (1 partner HIV-negative, other partner HIV-1 positive), 35 HIV-1 concordant (both partners HIV-1 positive with phylogenetically confirmed transmission) and 38 HIV-negative (both partners HIV-negative), were enrolled at the Centre Hospitalier Universitaire Fann, Dakar, Senegal. All subjects were genotyped for KIR, HLA-B and HLA-C genes by PCR and frequencies of KIR genes and KIR/HLA gene combinations were compared between couple groups by Chi-squared tests. Fresh NK cells were purified from healthy blood donors and co-cultured with CD4+ T cells purified from HIV-1 patients to assess NK cell-mediated CD4+ T cell killing as a function of sample KIR/HLA incompatibility.
Results: HIV-1 discordant couples were characterized by recipient partners with homozygous KIR2DL2 (p=0.009), and by a mismatched recipient partner KIR2DL1/HLA-C2 with index partner HLA-C1/C1 combination (p=0.028) expected to allow licensed missing self NK cell killing of index partners' cells. HIV-1 concordant couples on the other hand were characterized by KIR2DL3 homozygous recipient partners (p=0.008) who most frequently had HLA-C1/C2 bearing index partners (p=0.001), resulting in a matched KIR/HLA combination expected to inhibit NK cell killing of index partners' cells. In vitro co-cultures of healthy donor-derived NK cells and HIV-1 patient-derived CD4+ T-cells confirmed the involvement of missing self allogeneic KIR/HLA combinations in NK cell-mediated CD4+ T-cell killing (p=0.006).
Conclusion: Our data suggest that KIR/HLA incompatibility between sexual partners confers protection against HIV-1 transmission and that this may be due to alloreactive NK cells killing incoming HIV-infected partner cells.
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