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.
Highlights
Adverse drug reactions are associated with considerable global morbidity and mortality and pose a substantial challenge in drug development and implementation
The analyses revealed that, despite marked variation in the observed human leukocyte antigen (HLA) allele repertoire across the representative ethnicities, the alleles associated with cutaneous NVP hypersensitivity reactions (HSRs) share the structure of specific binding pockets within the antigen-binding groove
While certain drug HSR syndromes show clear associations with only one specific allele, such as abacavir with HLA-B*57:01, such single allele associations with 100% negative predictive values are the exception rather than the rule; the approach described provides a potential means for exploring more complex drug HSRs or immune-based pathologies with multiple risk HLA alleles such as is observed for cutaneous NVP HSR
Summary
Adverse drug reactions are associated with considerable global morbidity and mortality and pose a substantial challenge in drug development and implementation. It is well established that patients carrying these related alleles tolerate abacavir and in vitro functional assays are negative This illustrates the importance of allele-specific sites within the HLA peptide binding groove, where single amino acid changes seen between risk and control alleles can alter the chemistry of HLA-drug interaction. Abacavir binds directly to a unique combination of polymorphic residues within the F pocket of the HLA binding groove present only in HLA-B*57:01 and not in other B17 serotype alleles[8, 9] This results in presentation of self-peptides not previously exposed to patient T cells as neoantigens[8,9,10]. The HLA alleles most often associated with cutaneous manifestations of NVP HSR are HLA-C*04, commonly carried across ethnicities, as well as HLA-B*35 in Asians and Caucasian patients[19, 21,22,23,24]
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