HLA Class I restricted CD8+ and Class II restricted CD4+ T cells are implicated in the pathogenesis of nevirapine hypersensitivity
Keane, N.M., Pavlos, R.K., McKinnon, E., Lucas, A., Rive, C., Blyth, C.C., Dunn, D., Lucas, M., Mallal, S. and Phillips, E. (2014) HLA Class I restricted CD8+ and Class II restricted CD4+ T cells are implicated in the pathogenesis of nevirapine hypersensitivity. AIDS, 28 (13). pp. 1891-1901.
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Objectives: This study sought to examine nevirapine hypersensitivity (NVP HSR) phenotypes and their relationship with differing major histocompatibility complex (MHC) Class I and Class II alleles and the associated CD4+ and CD8+ T-cell NVP-specific responses and their durability over time.
Methods: A retrospective cohort study compared HIV-positive patients with NVP HSR, defined by fever and hepatitis and/or rash, with those tolerant of NVP for more than 3 months. Covariates included class I (HLA-A, B, C) and class II (HLA-DR) alleles. Cellular studies examined NVP-specific CD4+ and CD8+ T-cell responses by interferon-gamma (IFNγ) ELISpot assay and intracellular cytokine staining (ICS).
Results: NVP HSR occurred in 19 out of 451 (4%) NVP-exposed individuals between March 1993 and December 2011. HLA associations were phenotype dependent with HLA-DRB1∗01 : 01 associated with hepatitis (P = 0.02); HLA-B∗35 : 01 and HLA-Cw4 associated with cutaneous NVP HSR (P = 0.001, P = 0.01), and HLA-Cw∗08 was associated with NVP HSR with eosinophilia (P = 0.04) and multisystemic NVP HSR (P = 0.02). NVP-specific INFγ responses waned significantly more than 3 months from the original reaction and were diminished or completely abrogated when either CD4+ or CD8+ T cells were depleted from the peripheral blood mononuclear cells culture.
Conclusion: The association of specific class I and II allele pairings with specific phenotypes of NVP HSR, and cellular studies showing both CD4+ and CD8+ T-cell NVP-specific responses suggest that specific combinations of NVP reactive class I restricted CD8+ and class II restricted CD4+ T cells contribute to the immunopathogenesis of NVP HSR.
|Publication Type:||Journal Article|
|Murdoch Affiliation:||Institute for Immunology and Infectious Diseases|
|Publisher:||Lippincott Williams & Wilkins Ltd.|
|Copyright:||© 2014 Wolters Kluwer Health|
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