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


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).


CONCLUSIONS
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.
Martin
Annalise M
AM
Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Western Australia 6000, Australia.
Almeida
Coral-Ann
CA
Cameron
Paul
P
Purcell
Anthony W
AW
Nolan
David
D
James
Ian
I
McCluskey
James
J
Phillips
Elizabeth
E
Landay
Alan
A
Mallal
Simon
S
D000938:Antigen-Presenting Cells / Q000276:immunology*; D019013:CD40 Antigens / Q000032:analysis / Q000276:immunology; D002478:Cells, Cultured; D015224:Dideoxynucleosides / Q000276:immunology*; D004342:Drug Hypersensitivity / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology; D011992:Endosomes / Q000235:genetics / Q000276:immunology; D005455:Fluorescent Antibody Technique / Q000379:methods; D006679:HIV Seropositivity / Q000188:drug therapy / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D018613:Microscopy, Confocal / Q000379:methods; D009000:Monocytes / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D018894:Reverse Transcriptase Inhibitors / Q000276:immunology*; D000099227:Abacavir
D019013:CD40 Antigens; D015224:Dideoxynucleosides; D015235:HLA-B Antigens; D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D011956:Receptors, Cell Surface; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir; C103707:HLA-B57 antigen