Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles. / Pavlos, Rebecca; McKinnon, Elizabeth J.; Ostrov, David A.; Peters, Bjoern; Buus, Soren; Koelle, David; Chopra, Abha; Schutte, Ryan; Rive, Craig; Redwood, Alec; Restrepo, Susana; Bracey, Austin; Kaever, Thomas; Myers, Paisley; Speers, Ellen; Malaker, Stacy A.; Shabanowitz, Jeffrey; Jing, Yuan; Gaudieri, Silvana; Hunt, Donald F.; Carrington, Mary; Haas, David W.; Mallal, Simon; Phillips, Elizabeth J.
I: Scientific Reports, Bind 7, 8653, 2017.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 182976116