Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1
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| Authors: | Martin, MP; Naranbhai, V; Shea, PR; Qi, Y; Ramsuran, V; Vince, N; Gao, XJ; Thomas, R; Brumme, ZL; Carlson, JM; Wolinsky, SM; Goedert, JJ; Walker, BD; Segal, FP; Deeks, SG; Haas, DW; Migueles, SA; Connors, M; Michael, N; Fellay, J; Gostick, E; Llewellyn-Lacey, S; Price, DA; Lafont, BA; Pymm, P; Saunders, PM; Widjaja, J; Wong, SC; Vivian, JP; Rossjohn, J; Brooks, AG; Carrington, M |
| Year: | 2018 |
| Journal: | J. Clin. Invest. 128 Article Link (DOI) PubMed |
| Title: | Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1 |
| Abstract: | HLA-B*57 control of HIV involves enhanced CD8(+) T cell responses against infected cells, but extensive heterogeneity exists in the level of HIV control among B*57(+) individuals. Using whole-genome sequencing of untreated B*57(+) HIV-1-infected controllers and noncontrollers, we identified a single variant (rs643347A/G) encoding an isoleucine-to-valine substitution at position 47 (I47V) of the inhibitory killer cell immunoglobulin-like receptor KIR3DL1 as the only significant modifier of B*57 protection. The association was replicated in an independent cohort and across multiple outcomes. The modifying effect of I47V was confined to B*57:01 and was not observed for the closely related B*57:03. Positions 2, 47, and 54 tracked one another nearly perfectly, and 2 KIR3DL1 allotypes differing only at these 3 positions showed significant differences in binding B*57:01 tetramers, whereas the protective allotype showed lower binding. Thus, variation in an immune NK cell receptor that binds B*57:01 modifies its protection. These data highlight the exquisite specificity of KIR-HLA interactions in human health and disease. |
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