Killer cell immunoglobulin–like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1
- Maureen P. Martin ,
- Vivek Naranbhai ,
- Patrick R. Shea ,
- Ying Qi ,
- Veron Ramsuran ,
- Nicolas Vince ,
- Xiaojiang Gao ,
- Rasmi Thomas ,
- Zabrina L. Brumme ,
- Jonathan M. Carlson ,
- Steven M. Wolinsky ,
- James J. Goedert ,
- Bruce D. Walker ,
- Florencia P. Segal ,
- Steven G. Deeks ,
- David W. Haas ,
- Stephen A. Migueles ,
- Mark Connors ,
- Nelson Michael ,
- Jacques Fellay ,
- Emma Gostick ,
- Sian Llewellyn-Lacey ,
- David A. Price ,
- Bernard A. Lafont ,
- Phillip Pymm ,
- Philippa M. Saunders ,
- Jacqueline Widjaja ,
- Shu Cheng Wong ,
- Julian P. Vivian ,
- Jamie Rossjohn ,
- Andrew G. Brooks, ,
- Mary Carrington
Journal of Clinical Investigation | , Vol 128(5): pp. 1903-1912
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-tovaline 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.