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leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T\u2009cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs\u20096, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.","bibjson":{"author":[{"initials":"PT","lastname":"Illing","name":"Illing PT"},{"initials":"JP","lastname":"Vivian","name":"Vivian JP"},{"initials":"NL","lastname":"Dudek","name":"Dudek NL"},{"initials":"L","lastname":"Kostenko","name":"Kostenko L"},{"initials":"Z","lastname":"Chen","name":"Chen Z"},{"initials":"M","lastname":"Bharadwaj","name":"Bharadwaj M"},{"initials":"JJ","lastname":"Miles","name":"Miles JJ"},{"initials":"L","lastname":"Kjer-Nielsen","name":"Kjer-Nielsen L"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"NA","lastname":"Williamson","name":"Williamson NA"},{"initials":"SR","lastname":"Burrows","name":"Burrows SR"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"}],"identifier":[{"id":"10.1038/nature11147","type":"doi"},{"id":"22722860","type":"pubmed"}],"issue":["7404"],"journal":{"iso_abbreviation":"Nature","name":""},"pages":["554-8"],"title":"Immune self-reactivity triggered by drug-modified HLA-peptide repertoire.","type":"article","url":"http://www.nature.com/articles/nature11147","volume":["486"],"year":[2012]},"in_pmc":"N","in_pmce":"N","open_access":"N"},"resolution":"1.60","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/3vri"},"rcsb":{"url":"https://www.rcsb.org/structure/3vri"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-B*57:01 binding \"RVAQLEQVYI\" at 1.60Å resolution","unique_chain_count":3}}