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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.

SUBMITTER: Martin MP 

PROVIDER: S-EPMC5919796 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Martin Maureen P MP   Naranbhai Vivek V   Shea Patrick R PR   Qi Ying Y   Ramsuran Veron V   Vince Nicolas N   Gao Xiaojiang X   Thomas Rasmi R   Brumme Zabrina L ZL   Carlson Jonathan M JM   Wolinsky Steven M SM   Goedert James J JJ   Walker Bruce D BD   Segal Florencia P FP   Deeks Steven G SG   Haas David W DW   Migueles Stephen A SA   Connors Mark M   Michael Nelson N   Fellay Jacques J   Gostick Emma E   Llewellyn-Lacey Sian S   Price David A DA   Lafont Bernard A BA   Pymm Phillip P   Saunders Philippa M PM   Widjaja Jacqueline J   Wong Shu Cheng SC   Vivian Julian P JP   Rossjohn Jamie J   Brooks Andrew G AG   Carrington Mary M  

The Journal of clinical investigation 20180403 5


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 protect  ...[more]

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