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

Maureen Martin 1 Vivek Naranbhai 2, 3 Patrick Shea 4 Ying Qi 1 Veron Ramsuran 1, 3, 5 Nicolas Vince 1, 6, 7, 8, * Xiaojiang Gao 1 Rasmi Thomas 9, 10 Zabrina Brumme 11, 12 Jonathan Carlson 13 Steven Wolinsky 14 James Goedert 15 Bruce D. Walker 2 Florencia Segal 16 Steven G Deeks 17 David Haas 18 Stephen Migueles 19 Mark Connors 19 Nelson Michael 9, 10 Jacques Fellay 20 Emma Gostick 21, 22 Sian Llewellyn-Lacey 21, 22 David A. Price 21, 23 Bernard Lafont 24 Phillip Pymm 25 Philippa Saunders 26 Jacqueline Widjaja 26 Shu Wong 26 Julian Vivian 25 Jamie Rossjohn 21, 22, 25 Andrew Brooks 26 Mary Carrington 1, 2
* Corresponding author
8 Team 5 - U1064 Inserm - CRTI - Translational ImmunoGenetic in AutoImmunity and Transplantation
U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
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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Maureen Martin, Vivek Naranbhai, Patrick Shea, Ying Qi, Veron Ramsuran, et al.. Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1. Journal of Clinical Investigation, American Society for Clinical Investigation, 2018, 128 (5). ⟨inserm-02156536⟩

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