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

Rebecca Pavlos, Elizabeth J. McKinnon, David A. Ostrov, Bjoern Peters, Soren Buus, David Koelle, Abha Chopra, Ryan Schutte, Craig Rive, Alec Redwood, Susana Restrepo, Austin Bracey, Thomas Kaever, Paisley Myers, Ellen Speers, Stacy A. Malaker, Jeffrey Shabanowitz, Yuan Jing, Silvana Gaudieri, Donald F. HuntMary Carrington, David W. Haas, Simon Mallal, Elizabeth J. Phillips

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

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.

Original languageEnglish
Article number8653
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

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