Journal article
Immune responses to abacavir in antigen-presenting cells from hypersensitive patients
AIDS, Vol.21(10), pp.1233-1244
06/2007
Abstract
OBJECTIVES: A potentially life-threatening hypersensitive reaction accompanies the use of HIV nucleoside analogue abacavir (ABC) in 4-8% of Caucasian individuals. HLA-B*5701 and Hsp70 493T alleles have been shown to predict susceptibility to this hypersensitivity. DESIGN AND METHODS: This study was undertaken to provide a mechanistic understanding of the highly significant genetic association of HLA Class I and Hsp70 alleles with ABC hypersensitivity. RESULTS: In this study an ABC-induced localization of intracellular HSP70 to endosomal vesicles of antigen-presenting cells was demonstrated. This ABC-stimulated redistribution of endogenous HSP70 was substantially higher in the genetically homogenous HLA-B*5701, Hsp70 493T ABC-hypersensitive individuals and ABC-naive individuals in comparison with the heterogenous tolerant patients (P = 0.023). Increased expression of HSP70 was also detected in the hypersensitive group as measured by flow cytometry (P = 0.032). Blocking of HSP70 and HSP70 cell surface receptors CD14 and TLR2 abrogated ABC-stimulated HSP70 redistribution in sensitized individuals to basal levels (P < 0.004). In addition, the use of TcRαβ and HLA-B57/58 antibodies also ablated the expression of HSP70. Cells expressing the activation markers CD40 were increased after ABC stimulation in the hypersensitive patients (P = 0.006). ABC-stimulated interferon-gamma levels were higher in hypersensitive patients in comparison with ABC-tolerant individuals with a mean of 123.54 versus 0 pg/ml (P = 0.001). CONCLUSION: The present data indicates that ABC stimulates an innate immune response and activates antigen-presenting cells via the endogenous HSP70-mediated Toll-like receptor pathway in genetically susceptible individuals potentially initiating the immuno-pathological hypersensitive response.
Details
- Title
- Immune responses to abacavir in antigen-presenting cells from hypersensitive patients
- Authors/Creators
- A. Martin (Author/Creator)C.M. Almeida (Author/Creator)P.U. Cameron (Author/Creator)Anthony W Purcell (Author/Creator)D. Nolan (Author/Creator)I. James (Author/Creator)J. McCluskey (Author/Creator)E.J. Phillips (Author/Creator)Alan Landay (Author/Creator)S. Mallal (Author/Creator)
- Publication Details
- AIDS, Vol.21(10), pp.1233-1244
- Publisher
- Lippincott Williams & Wilkins Ltd.
- Identifiers
- 991005544638307891
- Copyright
- © 2007 Lippincott Williams & Wilkins, Inc.
- Murdoch Affiliation
- Centre for Clinical Immunology and Biomedical Statistics
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.265 Dermatology - Skin Allergies
- 1.265.1140 Drug Hypersensitivity
- Web Of Science research areas
- Immunology
- Infectious Diseases
- Virology
- ESI research areas
- Immunology