HLA Class I restricted CD8+ and Class II restricted CD4 + T cells are implicated in the pathogenesis of nevirapine hypersensitivity

Abstract

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 NVPspecific 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 (IFNg) 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 INFg 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. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.