Structural Elements Recognized by Abacavir-Induced T Cells.

Daniel Yerly,Anette Strhyn,David Ostrov,Yuri Pompeu,Ryan Schutte,Austin. Bracey,Soren Buus,Klara. Eriksson

doi:10.3390/ijms18071464

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.

Highlights

There are relationships between viral infections and immune-mediated adverse reactions, the mechanistic roles of the viruses are complex and incompletely defined [1,2]
Advancements in understanding the structural mechanisms responsible for immunopathogenesis of abacavir hypersensitivity syndrome, an autoimmune response following treatment with the human immunodeficiency virus (HIV) drug strongly associated with Human leukocyte antigen (HLA)-B*57:01 [10,11], allows the abacavir T cell recognition system to serve as a model for assessing which peptide antigens are presented by HLA-B*57:01 [1]
Solved structures of peptides bound to HLA-B*57:01 in the presence of abacavir illustrate that the drug forms peptide/HLA-B*57:01 interactions by direct H bonds and van der Waals contacts with both elements

Summary

Introduction

There are relationships between viral infections and immune-mediated adverse reactions, the mechanistic roles of the viruses are complex and incompletely defined [1,2]. Cytomegalovirus (CMV) is associated with tribenoside-induced hypersensitivity syndrome [8] These data suggest that virus infection influences the initiation or perpetuation of drug hypersensitivity. One hypothesis to explain the role of viruses in drug hypersensitivity is that cytotoxic T cells specific for viral antigens cross-react with self peptides complexed to drugs and HLA molecules [9]. Advancements in understanding the structural mechanisms responsible for immunopathogenesis of abacavir hypersensitivity syndrome, an autoimmune response following treatment with the HIV drug strongly associated with HLA-B*57:01 [10,11], allows the abacavir T cell recognition system to serve as a model for assessing which peptide antigens are presented by HLA-B*57:01 [1]. We used a TCR transfection system to determine if identified homologous viral peptides could be recognized by drug reactive T cells

X-ray Crystallography and Structural Analysis

TCR-Transfectant Stimulation Assay

Results

Identification of Viral Peptides Similar to a Drug-Restricted Self Epitope