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 & 12 others 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

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)1903-1912
Number of pages10
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Cite this

Martin, M. P., Naranbhai, V., Shea, P. R., Qi, Y., Ramsuran, V., Vince, 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
Martin, Maureen P. ; Naranbhai, Vivek ; Shea, Patrick R. ; Qi, Ying ; Ramsuran, Veron ; Vince, Nicolas ; Gao, Xiaojiang ; Thomas, Rasmi ; Brumme, Zabrina L. ; Carlson, Jonathan M. ; Wolinsky, Steven M. ; Goedert, James J. ; Walker, Bruce D. ; Segal, Florencia P. ; Deeks, Steven G. ; Haas, David W. ; Migueles, Stephen A. ; Connors, Mark ; Michael, Nelson ; Fellay, Jacques ; Gostick, Emma ; Llewellyn-Lacey, Sian ; Price, David A. ; Lafont, Bernard A. ; Pymm, Phillip ; Saunders, Philippa M. ; Widjaja, Jacqueline ; Wong, Shu Cheng ; Vivian, Julian P. ; Rossjohn, Jamie ; Brooks, Andrew G. ; Carrington, Mary. / Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 1903-1912.
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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",
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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

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

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 1903-1912.

Research output: Contribution to journalArticleResearchpeer-review

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

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JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

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