Abstract
Abacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life-threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLA-B*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature.
Highlights
Major histocompatibility complex class I (MHC I) molecules acquire peptide antigens in the endoplasmic reticulum (ER) and present their peptide cargo at the cell surface for scrutiny by cytotoxic T lymphocytes (CTLs)
We previously characterised the impact of abacavir exposure on the immunopeptidome of Human Leukocyte Antigen (HLA)-B*57:01 molecules isolated from C1R.B*57:01 cells and determined the sequences of novel drug induced ligands by liquid chromatography-tandem mass spectrometry (LC-MS/MS) [25]
We and others have shown that abacavir exclusively binds within the HLA-B*57:01 antigen binding groove, altering the preference for the C-terminal amino acid residue of the bound peptide, and changing the immunopeptidome in a process dependent on tapasin and the conventional MHC I antigen presentation pathway [23,24,25,26]
Summary
Major histocompatibility complex class I (MHC I) molecules acquire peptide antigens in the endoplasmic reticulum (ER) and present their peptide cargo at the cell surface for scrutiny by cytotoxic T lymphocytes (CTLs). These peptide antigens are derived from the degradation of intracellular proteins along with other sources, including peptides derived from defective ribosomal. Virus infected or cancerous cells can be detected when novel peptides, such as those derived from the viral proteome or neo-epitopes generated during oncogenesis, are presented on the cell surface. Their recognition by CTLs stimulates cytotoxicity against the antigen presenting cells, facilitating elimination of the infected or transformed cells
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