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

Annalise M. Martin, Coral Ann Almeida, Paul Cameron, Anthony W. Purcell, David Nolan, Ian James, James McCluskey, Elizabeth Phillips, Alan Landay, Simon Mallal

Research output: Contribution to journalArticleResearchpeer-review

42 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1233-1244
Number of pages12
JournalAIDS
Volume21
Issue number10
DOIs
Publication statusPublished - 1 Jun 2007
Externally publishedYes

Keywords

  • Abacavir hypersensitivity
  • Cell activation
  • HLA-B*5701
  • Interferon gamma
  • Monocytes

Cite this

Martin, A. M., Almeida, C. A., Cameron, P., Purcell, A. W., Nolan, D., James, I., ... Mallal, S. (2007). Immune responses to abacavir in antigen-presenting cells from hypersensitive patients. AIDS, 21(10), 1233-1244. https://doi.org/10.1097/QAD.0b013e3280119579
Martin, Annalise M. ; Almeida, Coral Ann ; Cameron, Paul ; Purcell, Anthony W. ; Nolan, David ; James, Ian ; McCluskey, James ; Phillips, Elizabeth ; Landay, Alan ; Mallal, Simon. / Immune responses to abacavir in antigen-presenting cells from hypersensitive patients. In: AIDS. 2007 ; Vol. 21, No. 10. pp. 1233-1244.
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Martin, AM, Almeida, CA, Cameron, P, Purcell, AW, Nolan, D, James, I, McCluskey, J, Phillips, E, Landay, A & Mallal, S 2007, 'Immune responses to abacavir in antigen-presenting cells from hypersensitive patients', AIDS, vol. 21, no. 10, pp. 1233-1244. https://doi.org/10.1097/QAD.0b013e3280119579

Immune responses to abacavir in antigen-presenting cells from hypersensitive patients. / Martin, Annalise M.; Almeida, Coral Ann; Cameron, Paul; Purcell, Anthony W.; Nolan, David; James, Ian; McCluskey, James; Phillips, Elizabeth; Landay, Alan; Mallal, Simon.

In: AIDS, Vol. 21, No. 10, 01.06.2007, p. 1233-1244.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Immune responses to abacavir in antigen-presenting cells from hypersensitive patients

AU - Martin, Annalise M.

AU - Almeida, Coral Ann

AU - Cameron, Paul

AU - Purcell, Anthony W.

AU - Nolan, David

AU - James, Ian

AU - McCluskey, James

AU - Phillips, Elizabeth

AU - Landay, Alan

AU - Mallal, Simon

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N2 - 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.

AB - 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.

KW - Abacavir hypersensitivity

KW - Cell activation

KW - HLA-B5701

KW - Interferon gamma

KW - Monocytes

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