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Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1.

Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1.
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Martin MP, Naranbhai V, Shea PR, Qi Y, Ramsuran V, Vince N, Gao X, 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,


Martin MP, Naranbhai V, Shea PR, Qi Y, Ramsuran V, Vince N, Gao X, 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, (click to view)

Martin MP, Naranbhai V, Shea PR, Qi Y, Ramsuran V, Vince N, Gao X, 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,

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The Journal of clinical investigation 2018 04 03() doi 10.1172/JCI98463

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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