@article{674240574267411a82a5e382e00f4041,
title = "Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells",
abstract = "The highly polymorphic human leukocyte antigen (HLA) locus encodes cell surface proteins that are critical for immunity. HLA-A expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide-binding preference. Analysis of 9763 HIV-infected individuals from 21 cohorts shows that higher HLA-A levels confer poorer control of HIV. Elevated HLA-A expression provides enhanced levels of an HLA-A-derived signal peptide that specifically binds and determines expression levels of HLA-E, the ligand for the inhibitory NKG2A natural killer (NK) cell receptor. HLA-B haplotypes that favor NKG2A-mediated NK cell licensing (i.e., education) exacerbate the deleterious effect of high HLA-A on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets. Therapeutic blockade of HLA-E:NKG2A interaction may yield benefit in HIV disease.",
author = "Veron Ramsuran and Vivek Naranbhai and Amir Horowitz and Ying Qi and Martin, \{Maureen P.\} and Yuko Yuki and Xiaojiang Gao and Victoria Walker-Sperling and \{Del Prete\}, \{Gregory Q.\} and Schneider, \{Douglas K.\} and Lifson, \{Jeffrey D.\} and Jacques Fellay and Deeks, \{Steven G.\} and Martin, \{Jeffrey N.\} and Goedert, \{James J.\} and Wolinsky, \{Steven M.\} and Michael, \{Nelson L.\} and Kirk, \{Gregory D.\} and Susan Buchbinder and David Haas and Thumbi Ndung'u and Philip Goulder and Peter Parham and Walker, \{Bruce D.\} and Carlson, \{Jonathan M.\} and Mary Carrington",
note = "Funding Information: We thank the volunteers in the contributing cohorts, their health-care providers, and the investigators involved in data collection. This work was supported by the National Cancer Institute, National Institutes of Health, and the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation. Additional funding was provided by the Howard Hughes Medical Institute (T.N.), International AIDS Vaccine Initiative, and South Africa National Research Foundation. See the extended acknowledgments in the supplementary materials for full details. Data and code to understand and assess the conclusions of this research are available in the main text, supplementary materials, or upon request of the authors. Genotyping of samples was subject to materials transfer agreements and institutional review board approved protocols, full details of which have been supplied to Science. V.N., V.R., A.H., J.M.C, and M.C. conceived and designed the study. All authors contributed to the generation, acquisition, analysis, and/or interpretation of data. V.N., V.R., and M.C. drafted the manuscript. All authors critically reviewed the manuscript for important intellectual content and approved the final version of the manuscript. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http:// creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.",
year = "2018",
month = jan,
day = "5",
doi = "10.1126/science.aam8825",
language = "English",
volume = "359",
pages = "86--90",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6371",
}