Journal article
Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles
Scientific Reports, Vol.7(1)
2017
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.
Details
- Title
- Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles
- Authors/Creators
- R. Pavlos (Author/Creator) - Murdoch UniversityE.J. McKinnon (Author/Creator) - Murdoch UniversityD.A. Ostrov (Author/Creator) - Florida CollegeB. Peters (Author/Creator) - La Jolla Institute for ImmunologyS. Buus (Author/Creator) - University of CopenhagenD. Koelle (Author/Creator) - University of WashingtonA. Chopra (Author/Creator) - Murdoch UniversityR. Schutte (Author/Creator) - Florida CollegeC. Rive (Author/Creator) - Murdoch UniversityA. Redwood (Author/Creator) - Murdoch UniversityS. Restrepo (Author/Creator) - Florida CollegeA. Bracey (Author/Creator) - Florida CollegeT. Kaever (Author/Creator) - La Jolla Institute for ImmunologyP. Myers (Author/Creator) - University of VirginiaE. Speers (Author/Creator) - University of VirginiaS.A. Malaker (Author/Creator) - University of VirginiaJ. Shabanowitz (Author/Creator) - University of VirginiaY. Jing (Author/Creator) - Boehringer Ingelheim Pharmaceuticals Inc. , Ridgefield , CT , 06877 , USAS. Gaudieri (Author/Creator) - Murdoch UniversityD.F. Hunt (Author/Creator) - University of VirginiaM. Carrington (Author/Creator) - Leidos (United States)D.W. Haas (Author/Creator) - Vanderbilt UniversityS. Mallal (Author/Creator) - Murdoch UniversityE.J. Phillips (Author/Creator) - Murdoch University
- Publication Details
- Scientific Reports, Vol.7(1)
- Publisher
- Springer Nature
- Identifiers
- 991005541218407891
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.265 Dermatology - Skin Allergies
- 1.265.1140 Drug Hypersensitivity
- Web Of Science research areas
- Immunology
- ESI research areas
- Immunology