TY - JOUR
T1 - Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells
AU - Ramsuran, Veron
AU - Naranbhai, Vivek
AU - Horowitz, Amir
AU - Qi, Ying
AU - Martin, Maureen P.
AU - Yuki, Yuko
AU - Gao, Xiaojiang
AU - Walker-Sperling, Victoria
AU - Del Prete, Gregory Q.
AU - Schneider, Douglas K.
AU - Lifson, Jeffrey D.
AU - Fellay, Jacques
AU - Deeks, Steven G.
AU - Martin, Jeffrey N.
AU - Goedert, James J.
AU - Wolinsky, Steven M.
AU - Michael, Nelson L.
AU - Kirk, Gregory D.
AU - Buchbinder, Susan
AU - Haas, David
AU - Ndung'u, Thumbi
AU - Goulder, Philip
AU - Parham, Peter
AU - Walker, Bruce D.
AU - Carlson, Jonathan M.
AU - Carrington, Mary
N1 - 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.
PY - 2018/1/5
Y1 - 2018/1/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040125991&partnerID=8YFLogxK
U2 - 10.1126/science.aam8825
DO - 10.1126/science.aam8825
M3 - Article
C2 - 29302013
AN - SCOPUS:85040125991
SN - 0036-8075
VL - 359
SP - 86
EP - 90
JO - Science
JF - Science
IS - 6371
ER -