title: HLA Class I restricted CD8+ and Class II restricted CD4+ T cells are implicated in the pathogenesis of nevirapine hypersensitivity.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: aInstitute for Immunology and Infectious Diseases, Murdoch University bDepartment of Paediatrics and Adolescent Medicine, Princess Margaret Hospital for Children cSchool of Paediatrics & Child Health dSchool of Medicine & Pharmacology and School of Pathology & Laboratory Medicine, The University of Western Australia, Perth, Western Australia, Australia eVanderbilt University School of Medicine, Nashville, Tennessee, USA. *Niamh M. Keane and Rebecca K. Parlos contributed equally to this study.
authors.forename: Niamh M
authors.initials: NM
authors.lastname: Keane
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Pavlos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McKinnon
authors.forename: Andrew
authors.initials: A
authors.lastname: Lucas
authors.forename: Craig
authors.initials: C
authors.lastname: Rive
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Blyth
authors.forename: David
authors.initials: D
authors.lastname: Dunn
authors.forename: Michaela
authors.initials: M
authors.lastname: Lucas
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Phillips
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D004342:Drug Hypersensitivity; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000009:adverse effects*; D012189:Retrospective Studies; D013194:Staining and Labeling; D055815:Young Adult
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D019829:Nevirapine