Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells

Veron Ramsuran; Vivek Naranbhai; Amir Horowitz; Ying Qi; Maureen P Martin; Yuko Yuki; Xiaojiang Gao; Victoria Walker-Sperling; Gregory Q Del Prete; Douglas K Schneider; Jeffrey D Lifson; Jacques Fellay; Steven G Deeks; Jeffrey N Martin; James J Goedert; Steven M Wolinsky; Nelson L Michael; Gregory D Kirk; Susan Buchbinder; David Haas; Thumbi Ndung'u; Philip Goulder; Peter Parham; Bruce D Walker; Jonathan M Carlson; Mary Carrington

doi:10.1126/science.aam8825

Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells

Science. 2018 Jan 5;359(6371):86-90. doi: 10.1126/science.aam8825. Epub 2018 Jan 4.

Authors

Veron Ramsuran^{1

2

3

4}, Vivek Naranbhai^{1

2

4

5}, Amir Horowitz⁶, Ying Qi¹, Maureen P Martin¹, Yuko Yuki¹, Xiaojiang Gao¹, Victoria Walker-Sperling⁷, Gregory Q Del Prete⁸, Douglas K Schneider⁸, Jeffrey D Lifson⁸, Jacques Fellay⁹, Steven G Deeks¹⁰, Jeffrey N Martin¹¹, James J Goedert¹², Steven M Wolinsky¹³, Nelson L Michael¹⁴, Gregory D Kirk¹⁵, Susan Buchbinder^{10

11

16}, David Haas¹⁷, Thumbi Ndung'u^{2

18

19

20}, Philip Goulder^{18

21}, Peter Parham²², Bruce D Walker^{2

18

23}, Jonathan M Carlson²⁴, Mary Carrington^{25

2}

Affiliations

¹ Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
² Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
³ KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.
⁴ Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
⁵ Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁶ Department of Oncological Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
⁸ AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁹ School of Life Sciences, École Polytechnique Fédérale de Lausanne, and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
¹⁰ Department of Medicine University of California, San Francisco, CA 94143, USA.
¹¹ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143, USA.
¹² Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20850, USA.
¹³ Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
¹⁴ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
¹⁵ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
¹⁶ San Francisco Department of Public Health, HIV Research Section, San Francisco, CA 94102, USA.
¹⁷ Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
¹⁸ African Health Research Institute, Durban, South Africa.
¹⁹ HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
²⁰ Max Planck Institute for Infection Biology, Berlin, Germany.
²¹ Department of Paediatrics, University of Oxford, Oxford, UK.
²² Departments of Structural Biology and Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
²³ Institute for Medical and Engineering Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
²⁴ Microsoft Research, Redmond, WA 98052, USA.
²⁵ Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. carringm@mail.nih.gov.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
CD4 Lymphocyte Count
Cohort Studies
HIV / immunology*
HIV Infections / drug therapy
HIV Infections / genetics
HIV Infections / immunology*
HLA Antigens / genetics
HLA Antigens / metabolism*
Humans
Killer Cells, Natural / immunology*
Ligands
NK Cell Lectin-Like Receptor Subfamily C / antagonists & inhibitors
NK Cell Lectin-Like Receptor Subfamily C / genetics
NK Cell Lectin-Like Receptor Subfamily C / metabolism*
Protein Sorting Signals
Viremia / immunology

Substances

HLA Antigens
KLRC1 protein, human
Ligands
NK Cell Lectin-Like Receptor Subfamily C
Protein Sorting Signals

Abstract

Publication types

MeSH terms

Substances

Grants and funding