Abstract
BackgroundFifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.MethodsTo determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.ResultsAbacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.ConclusionsWe propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.
Highlights
To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir hypersensitivity reaction (HSR) symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling
Abacavir hypersensitivity reaction (HSR) is a potentially life threatening CD8+ T cell mediated, HLA-BÃ57:01 restricted syndrome previously occurring in 5–8% of those treated with the drug, but prevented by HLA-BÃ57:01 screening prior to abacavir prescription [1,2,3,4,5,6,7,8,9,10,11]
Abacavir patch testing is a specific and highly sensitive research tool used to identify HLABÃ57:01 positive patients who have experienced immunologically-mediated abacavir HSR [3,11,22]
Summary
Abacavir hypersensitivity reaction (HSR) is a potentially life threatening CD8+ T cell mediated, HLA-BÃ57:01 restricted syndrome previously occurring in 5–8% of those treated with the drug, but prevented by HLA-BÃ57:01 screening prior to abacavir prescription [1,2,3,4,5,6,7,8,9,10,11]. Abacavir forms contacts within the deep hydrophobic F-pocket of the groove which effects the shape and chemistry of the antigen binding cleft and alters the repertoire of HLA-BÃ57:01-restricted peptides presented to CD8+ T cells [12,13] This abrupt change in the peptide repertoire is analogous to what occurs in organ transplantation where immune recognition of neo-antigen results in graft rejection. In this context, pre-existing Class I restricted effector memory CD8+ T cells which have specificities to prevalent or persistent viruses may cross recognize an HLA mismatched allograph [14]. Confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.
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