, a bio/informatics shared resource is still "open for business" - Visit the CDS website

Immune responses to abacavir in antigen-presenting cells from hypersensitive patients.

Martin AM, Almeida CA, Cameron P, Purcell AW, Nolan D, James I, McCluskey J, Phillips E, Landay A, Mallal S
AIDS. 2007 21 (10): 1233-44

PMID: 17545699 · DOI:10.1097/QAD.0b013e3280119579

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 heterogeneous 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 TcRalphabeta 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.

MeSH Terms (19)

Antigen-Presenting Cells CD40 Antigens Cells, Cultured Dideoxynucleosides Drug Hypersensitivity Endoplasmic Reticulum Endosomes Fluorescent Antibody Technique Histocompatibility Antigens Class I HIV Seropositivity HLA-B Antigens HSP70 Heat-Shock Proteins Humans Immunophenotyping Interferon-gamma Microscopy, Confocal Monocytes Receptors, Cell Surface Reverse Transcriptase Inhibitors

Connections (1)

This publication is referenced by other Labnodes entities: