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Sci Rep. 2017 Aug 17;7(1):8653. doi: 10.1038/s41598-017-08876-0.

Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles.

Author information

1
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, 6150, Australia.
2
University of Florida College of Medicine, Gainesville, FL, 32610, USA.
3
La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
4
Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, DK-2200, Denmark.
5
Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
6
Department of Global Health, University of Washington, Seattle, WA, 98195, USA.
7
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
8
Department of Laboratory Medicine, University of Washington, Seattle, WA, 98195, USA.
9
Benaroya Research Institute, Seattle, WA, 98195, USA.
10
Departments of Chemistry and Pathology, University of Virginia, Charlottesville, VA, 222904, USA.
11
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 06877, USA.
12
School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, WA, 6009, Australia.
13
Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
14
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Nashville, TN, 37232, USA.
15
Frederick National Laboratory for Cancer Research, Frederick, MD, 21702-1201, USA.
16
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA.
17
Meharry Medical College, Nashville, TN, 37208, USA.
18
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, 6150, Australia. elizabeth.j.phillips@vanderbilt.edu.
19
Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. elizabeth.j.phillips@vanderbilt.edu.

Abstract

Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that primary predisposition to cutaneous NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C alleles sharing a common binding groove F pocket with HLA-C*04:01. An independent association with a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA-B alleles defined by a characteristic peptide binding groove B pocket. The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets. We thereby provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms.

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