@article{19f02d10172643419d92a618a80228d7,
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",
note = "Funding Information: This article is dedicated to the memory of Dr. Bonnie Mathieson, a longtime friend and colleague who dedicated her career to the advancement of HIV research. We would like to thank Victoria Walker-Sperling for her assistance with the figures. This work was supported by federal funds from the NCI, NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Departments of the Army and Defense or Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research, and the National Health and Medical Research Council of Australia. Data in this manuscript were collected by the MACS and/or the Women{\textquoteright}s Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the NIH. Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS). MACS (Principal Investigators): Johns Hopkins University Bloomberg School of Public Health (Joseph Margolick, Todd Brown), U01-AI35042; Northwestern University (Steven Wolinsky), U01-AI35039; University of California, Los Angeles (Roger Detels, Otoniel Martinez-Maza, Otto Yang), U01-AI35040; University of Pittsburgh (Charles Rinaldo, Lawrence Kingsley, Jeremy Martinson), U01-AI35041; the Center for Analysis and Management of MACS, Johns Hopkins University Bloomberg School of Public Health (Lisa Jacobson, Gypsyamber D{\textquoteright}Souza), UM1-AI35043. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR001079 (Johns Hopkins University Institute for Clinical and Translational Research [ICTR]) from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), Johns Hopkins ICTR, or NCATS. The MACS website is located at http:// aidscohortstudy.org/. The ACTG was supported by the NIAID under NIH grants AI068636, AI038858, AI068634, AI106701 and AI038855, and grants to Clinical Research Sites that participated in ACTG protocols and collected DNA under protocol A5128: AI069477, AI027675, AI073961, AI069474, AI069432, AI069513, AI069423, AI050410, AI069452, AI69450, AI054907, AI069428, AI045008, AI069495, AI069415, AI069556, AI069484, AI069424, AI069532, AI069419, AI069471, AI025859, AI069418, AI050409, AI069501, AI069502, AI069511, AI069434, AI069465, AI069494, AI069472, AI069470, AI046376, AI072626, AI027661, AI034853, AI069447, AI032782, AI027658, AI27666, AI058740, AI046370, TR000445, RR00051, RR00046, RR025747, RR025777, RR024160, RR024996, and RR024156. Abbott Laboratories, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline provided study medications. DWH is also supported by NIH grants AI077505, AI110527, and TR000445. JR is supported by the National Health and Medical Research Council of Australia, the Anti-cancer Council, the Austra- lian Research Council, and by an ARC Laureate Fellowship. ZLB is supported by a Scholar Award from the Michael Smith Foundation for Health Research. DAP is a Wellcome Trust Senior Investigator. Publisher Copyright: {\textcopyright} 2018 Academic Press. All rights reserved.",
year = "2018",
month = may,
day = "1",
doi = "10.1172/JCI98463",
language = "English (US)",
volume = "128",
pages = "1903--1912",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",
}
