title: Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant.
abstract: Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8(+) T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to abacavir.
authors.affiliation: Centre for Clinical Immunology and Biomedical Statistics, Murdoch University, Second Floor, North Block, Royal Perth Hospital, Perth 6000, Australia.
authors.forename: Annalise M
authors.initials: AM
authors.lastname: Martin
authors.forename: David
authors.initials: D
authors.lastname: Nolan
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.forename: Coral Ann
authors.initials: CA
authors.lastname: Almeida
authors.forename: Richard
authors.initials: R
authors.lastname: Nolan
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Filipa
authors.initials: F
authors.lastname: Carvalho
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Phillips
authors.forename: Frank T
authors.initials: FT
authors.lastname: Christiansen
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
mesh_terms: D002874:Chromosome Mapping; D015224:Dideoxynucleosides / Q000276:immunology*; D004342:Drug Hypersensitivity / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D005819:Genetic Markers; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006239:Haplotypes / Q000276:immunology; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008969:Molecular Sequence Data; D015995:Prevalence; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099227:Abacavir
chemical_list: D015224:Dideoxynucleosides; D005819:Genetic Markers; D015235:HLA-B Antigens; D018840:HSP70 Heat-Shock Proteins; D014409:Tumor Necrosis Factor-alpha; D000099227:Abacavir; C484830:HLA-B*57:01 antigen