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

doi:10.1172/JCI98463

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 FellayEmma 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

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.

Original language	English
Pages (from-to)	1903-1912
Number of pages	10
Journal	Journal of Clinical Investigation
Volume	128
Issue number	5
DOIs	https://doi.org/10.1172/JCI98463
State	Published - 1 May 2018
Externally published	Yes

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Martin, M. P., Naranbhai, V., Shea, P. R., Qi, Y., Ramsuran, V., Vince, N., Gao, X., Thomas, R., Brumme, Z. L., Carlson, J. M., Wolinsky, S. M., Goedert, J. J., Walker, B. D., Segal, F. P., Deeks, S. G., Haas, D. W., Migueles, S. A., Connors, M., Michael, N., ... Carrington, M. (2018). Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1. Journal of Clinical Investigation, 128(5), 1903-1912. https://doi.org/10.1172/JCI98463

@article{b8d42879effa41b9b8752ad2dd8841ef,

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.",

author = "Martin, {Maureen P.} and Vivek Naranbhai and Shea, {Patrick R.} and Ying Qi and Veron Ramsuran and Nicolas Vince and Xiaojiang Gao and Rasmi Thomas and Brumme, {Zabrina L.} and Carlson, {Jonathan M.} and Wolinsky, {Steven M.} and Goedert, {James J.} and Walker, {Bruce D.} and Segal, {Florencia P.} and Deeks, {Steven G.} and Haas, {David W.} and Migueles, {Stephen A.} and Mark Connors and Nelson Michael and Jacques Fellay and Emma Gostick and Sian Llewellyn-Lacey and Price, {David A.} and Lafont, {Bernard A.} and Phillip Pymm and Saunders, {Philippa M.} and Jacqueline Widjaja and Wong, {Shu Cheng} and Vivian, {Julian P.} and Jamie Rossjohn and Brooks, {Andrew G.} and Mary Carrington",

year = "2018",

month = may,

day = "1",

doi = "10.1172/JCI98463",

language = "English",

volume = "128",

pages = "1903--1912",

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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 2018, 'Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1', Journal of Clinical Investigation, vol. 128, no. 5, pp. 1903-1912. https://doi.org/10.1172/JCI98463

TY - JOUR

T1 - Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1

AU - Martin, Maureen P.

AU - Naranbhai, Vivek

AU - Shea, Patrick R.

AU - Qi, Ying

AU - Ramsuran, Veron

AU - Vince, Nicolas

AU - Gao, Xiaojiang

AU - Thomas, Rasmi

AU - Brumme, Zabrina L.

AU - Carlson, Jonathan M.

AU - Wolinsky, Steven M.

AU - Goedert, James J.

AU - Walker, Bruce D.

AU - Segal, Florencia P.

AU - Deeks, Steven G.

AU - Haas, David W.

AU - Migueles, Stephen A.

AU - Connors, Mark

AU - Michael, Nelson

AU - Fellay, Jacques

AU - Gostick, Emma

AU - Llewellyn-Lacey, Sian

AU - Price, David A.

AU - Lafont, Bernard A.

AU - Pymm, Phillip

AU - Saunders, Philippa M.

AU - Widjaja, Jacqueline

AU - Wong, Shu Cheng

AU - Vivian, Julian P.

AU - Rossjohn, Jamie

AU - Brooks, Andrew G.

AU - Carrington, Mary

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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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U2 - 10.1172/JCI98463

DO - 10.1172/JCI98463

M3 - Article

C2 - 29461980

AN - SCOPUS:85046437844

SN - 0021-9738

VL - 128

SP - 1903

EP - 1912

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 5

ER -

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

Abstract

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