Abstract
Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots, but observed no difference in either the conformations, nor degree of flexibility when compared to abacavir-unbound systems. Our results support hypersensitivity models in which abacavir-binding alters the conformational ensemble of neopeptides, so as to favour exposed peptide surfaces that are no longer recognized as self by circulating CD8+ T cells, and are conducive to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.
Highlights
Mass spectrometry data characterizing the peptides eluted from human leukocyte antigen (HLA)-B*57:01 cell lines treated with or without abacavir revealed abacavir alters the repertoire of peptides that are bound by HLA-B*57:017,8,13
We further show that the high levels of peptide dynamics, and partial dissociation of HLA-B*57:01-bound peptides may allow abacavir direct access to the antigen-binding cleft, and propose conformational dynamics to be a central tenet of all models of HLA-associated drug hypersensitivity
We show that whether or not abacavir or any of its analogue compounds are present in the HLA-B*57:01 antigen-binding cleft, the peptides exhibit high levels of conformational flexibility
Summary
Mass spectrometry data characterizing the peptides eluted from HLA-B*57:01 cell lines treated with or without abacavir revealed abacavir alters the repertoire of peptides that are bound by HLA-B*57:017,8,13. Peptides that eluted from abacavir-treated HLA-B*57:01 cells had smaller C-terminal F-pocket anchor residues, such as valine PDB ID: 3VRJ MHC + LTTKLTNTNI + abacavir MHC + LTTKLTNTNI + carbovir MHC + LTTKLTNTNI + didanosine MHC + LTTKLTNTNI + guanosine MHC + LTTKLTNTNI of the peptide binding cleft, preferencing smaller C-terminal peptide residues and thereby altering the repertoire of peptides that can be presented by HLA-B*57:01 and considered foreign to circulating CD8+ T cells. We performed MD simulations of three abacavir analogues (carbovir, didanosine, and guanosine) all bound to HLA-B*57:01, to serve as a comparison. These analogues are all chemically very similar to abacavir, but do not trigger a T-cell response[11]
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