TY - JOUR

T1 - Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles

AU - Pavlos, Rebecca

AU - McKinnon, Elizabeth J.

AU - Ostrov, David A.

AU - Peters, Bjoern

AU - Buus, Soren

AU - Koelle, David

AU - Chopra, Abha

AU - Schutte, Ryan

AU - Rive, Craig

AU - Redwood, Alec

AU - Restrepo, Susana

AU - Bracey, Austin

AU - Kaever, Thomas

AU - Myers, Paisley

AU - Speers, Ellen

AU - Malaker, Stacy A.

AU - Shabanowitz, Jeffrey

AU - Jing, Yuan

AU - Gaudieri, Silvana

AU - Hunt, Donald F.

AU - Carrington, Mary

AU - Haas, David W.

AU - Mallal, Simon

AU - Phillips, Elizabeth J.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-017-08876-0

DO - 10.1038/s41598-017-08876-0

M3 - Journal article

C2 - 28819312

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 8653

ER -