Hypersensitivity is a major complication of certain drug treatments. In the Proceedings of the National Academy of Sciences, Peters et al. shine light on the mechanistic basis of hypersensitivity responses triggered by the antiviral drug abacavir. Some patients treated with abacavir go on to develop sensitivity reactions, but only in the presence of an allele encoding HLA-B*57:01. Peptide scanning in the presence of abacavir shows that the drug enhances the affinity of certain peptides, especially those with small amino acids such as valine or isoleucine at the carboxy terminus. Structural analysis finds abacavir nestled in the F-pocket binding groove of HLA-B*57:01, where it is able to exclude certain peptides yet accept others. Peptide elution of abacavir-bound HLA-B*57:01 demonstrates skewing of the peptide repertoire and in effect generates an allogenic antigen complex. Finally, T cells from people sensitized to abacavir show a bias of memory responses to peptides with a carboxy-terminal valine, which supports the structural and biochemical findings.

Proc. Natl. Acad. Sci. USA (19 June 2012) doi:10.1073/pnas.1207934109