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.