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Abacavir hypersensitivity in HLA-B57-positive individuals with HIV infection is dependent upon the conventional MHC-I Ag presentation pathway
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Abacavir hypersensitivity in HLA-B57-positive individuals with HIV infection is dependent upon the conventional MHC-I Ag presentation pathway

J. McCluskey, D. Chessman, T. Lethborg, L. Kostenko, A.W. Purcell, L. Kjer-Nielsen, N.A. Mifsud, B.D. Tait, R. Holdsworth, C. Almeida, …
4th International AIDS Conference on HIV Pathogenesis, Treatment and Prevention (Sydney, Australia, 22/07/2007–25/07/2007)
2007
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Abstract

Objectives: The chain terminator drug Abacavir triggers a serious hypersensitivity reaction in 8% of patients with HIV infection. This reaction is strongly associated with HLA-B*5701 and appears to be mediated by CD8+ T cells producing inflammatory cytokines. Methods: Abacavir-specific T cell responses were investigated by utilising the Intracellular Cytokine Staining Assay. Towards a better understanding of the HLA association with Abacavir hypersensitivity, mutant Antigen Presenting Cells expressing HLA-B*5701 and closely related alleles were generated and utilised re-stimulate Abacavir-specific T cells. Results: We show that CD8+T cell responses can be primed in vitro, in normal blood donors who are HLA-B*5701+, but not in non- B*5701+ donors. CD8 T cells, but not CD4 T cells, are expanded by abacavir pulsed autologous APC over a 13 day culture, producing IFN-gamma and TNF-alpha upon re-stimulation with APC expressing HLA-B*5701. Similar responses were detected in abacavir-hypersensitive HLA-B*5701+ patients. Responses were not detected using mutant APC deficient in TAP or tapasin, or when normal APC were aldehyde fixed before loading with abacavir, indicating a reliance on the conventional MHC-I Ag presentation. Responses were exquisitely restricted to HLA-B*5701 since they were undetectable using APC expressing closely related HLA-B57 or B58 allotypes. Responses to APC expressing mutants of HLA-B*5701 demonstrated a crucial role for residue 116. Conclusions: We propose that abacavir forms a conjugate with an endogenous peptide that is presented by HLA-B*5701 triggering CD8 T cells. We speculate that this form of altered self is highly immunogenic, behaving like a form of allogeneic MHC-I, contributing to the responses observed in abacavir-naive individuals. The molecular mechanisms underlying altered HLA-B*5701 may be relevant to the role of other disease-associated class I allotypes such as HLA-B27 and B51.

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