Abstract
The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B⁎57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between the α 1 and α 2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B⁎58:01-restricted allopurinol hypersensitivity reactions.
Highlights
Administration of particular drugs sometimes causes drug hypersensitivity reactions (DHRs)
Conformational changes of the four investigated selfpeptides bound to human leukocyte antigen (HLA)-B∗57:01 were calculated by Root Mean Square Deviation (RMSD)
Increasing simulation times are being used for molecular dynamics (MD) simulation studies [20, 21], and at least 10 ns to 400 ns MD simulation lengths are needed to monitor the dynamics of pHLA [22]
Summary
Administration of particular drugs sometimes causes drug hypersensitivity reactions (DHRs). DHRs, named abacavir hypersensitivity reactions (AHRs), abacavir’s safety profile has been questioned especially for use in children [1, 2]. A relationship between AHRs and certain alleles of human leukocyte antigen (HLA) has been reported. AHRs occur in approximately 5 to 8% individuals carrying an HLAB∗57:01 allele, which is a higher rate than the observed in people carrying other alleles [3,4,5]. Three distinct models have been reported: the hapten/prohapten model, the pharmacological interaction (p-i) model, and the altered repertoire model [6, 7]. Recent studies revealed that abacavir forms noncovalent bonds with
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