Structural Elements Recognized by Abacavir-Induced T Cells

Abstract

Adverse drug reactions are one of the leading causes of morbidity and mortality in health care worldwide. Human leukocyte antigen (HLA) alleles have been strongly associated with drug hypersensitivities, and the causative drugs have been shown to stimulate specific T cells at the sites of autoimmune destruction. The structural elements recognized by drug-specific T cell receptors (TCRs) in vivo are poorly defined. Drug-stimulated T cells express TCRs specific for peptide/HLA complexes, but the characteristics of peptides (sequence, or endogenous or exogenous origin) presented in the context of small molecule drugs are not well studied. Using HLA-B*57:01 mediated hypersensitivity to abacavir as a model system, this study examines structural similarities of HLA presented peptides recognized by drug-specific TCRs. Using the crystal structure of HLA-B*57:01 complexed with abacavir and an immunogenic self peptide, VTTDIQVKV SPT5a 976-984, peptide side chains exhibiting flexibility and solvent exposure were identified as potential drug-specific T cell recognition motifs. Viral sequences with structural motifs similar to the immunogenic self peptide were identified. Abacavir-specific T cell clones were used to determine if virus peptides presented in the context of abacavir stimulate T cell responsiveness. An abacavir-specific T cell clone was stimulated by VTQQAQVRL, corresponding to HSV1/2 230-238, in the context of HLA-B*57:01. These data suggest the T cell polyclonal response to abacavir consists of multiple subsets, including T cells that recognize self peptide/HLA-B*57:01 complexes and crossreact with viral peptide/HLA-B*57:01 complexes due to similarity in TCR contact residues.

Mechanisms leading to T-cell activation in drug hypersensitivity

“…Here, tiny modifications of the restricting presenting HLA allele were shown to abolish the reactivity [35]. In the case of abacavir, crystals could be generated and revealed the drug-binding site within the peptide-binding groove of the HLA-BÃ57:01 [36][37][38]. Of note, the interactions between abacavir, the HLA molecule and the peptide were purely noncovalent, demonstrating the pharmacological interaction properties of this association.…”

“…It is hypothesized that pharmacological interaction reacting T cells could be cross-reactive with antigenic peptides from microorganisms representing the infectious history of the drug hypersensitive patients. Although a recent study tackled this hypothesis [38], a formal proof has not been discovered yet. Nevertheless, drug reacting cells can be generated from the memory as well as from the naïve pool of T cells in drug-naïve individuals.…”

A transgenic mouse model for HLA-B*57:01–linked abacavir drug tolerance and reactivity

“…These results prompted models for autoimmunity, in which ABC favored the loading of novel self-peptides containing carboxyl-terminal valine, isoleucine, or leucine into HLA-B*57:01. Crystal structures of peptide-HLA-B*57:01 complexes with ABC revealed drug bound in the vicinity of the F pocket of the HLA groove beneath the peptide (19)(20)(21). These structural results, however, failed to explain why, while 100% of HLA-B*57:01 + human T cell cultures from drug-naive donors respond to ABC (13), only 55% of individuals carrying HLA-B*57:01 develop AHR (16,17).…”

Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions

“…As there are multiple crystal structures available for B*57:01 in complex with Abacavir (3VRI ( Illing et al, 2012 ), 3UPR ( Ostrov et al, 2012 ), 3VRJ ( Illing et al, 2012 ) and 5U98 ( Yerly et al, 2017 )) these were compared to ensure there were no major differences between docking results using each of the starting structures (Supplementary Fig. 1).…”