title: Enhanced ex vivo stimulation of Mycobacterium tuberculosis-specific T cells in human immunodeficiency virus-infected persons via antigen delivery by the Bordetella pertussis adenylate cyclase vector.
abstract: The genetically detoxified Bordetella pertussis adenylate cyclase is a promising delivery system for immunodominant tuberculosis antigens in gamma interferon release assays. This system has not been evaluated in human immunodeficiency virus (HIV)-infected persons in high tuberculosis prevalence areas. A whole-blood gamma interferon release assay with Mycobacterium tuberculosis antigens (early-secreted antigenic target 6, culture filtrate protein 10, alpha-crystallin 2, and TB10.3) delivered by adenylate cyclase in addition to native tuberculosis antigens (without adenylate cyclase delivery) was evaluated in 119 adults in Khayelitsha Township, Cape Town, South Africa. Results were compared to tuberculin skin test results of 41 HIV-positive and 42 HIV-negative asymptomatic persons, in addition to 36 HIV-positive persons with recently diagnosed smear- or culture-positive pulmonary tuberculosis. Delivery of tuberculosis antigens by adenylate cyclase decreased by 10-fold the amount of antigen required to restimulate T cells. Furthermore, the responses of HIV-positive persons with a low response to native tuberculosis antigens were enhanced when these antigens were delivered by adenylate cyclase. When gamma interferon responses to the tuberculosis antigens (with or without delivery by adenylate cyclase) were combined, a significantly higher number of patients were scored positive than by tuberculin skin testing. Ex vivo responses to tuberculosis antigens delivered by adenylate cyclase are maintained in the context of HIV infection. Our findings suggest that the majority of those in this population are infected with tuberculosis, which is of significant public health importance.
authors.affiliation: Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Tom G
authors.initials: TG
authors.lastname: Connell
authors.forename: Muki S
authors.initials: MS
authors.lastname: Shey
authors.forename: Ronnett
authors.initials: R
authors.lastname: Seldon
authors.forename: Molebogeng X
authors.initials: MX
authors.lastname: Rangaka
authors.forename: Gilles
authors.initials: G
authors.lastname: van Cutsem
authors.forename: Marcela
authors.initials: M
authors.lastname: Simsova
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Marcekova
authors.forename: Peter
authors.initials: P
authors.lastname: Sebo
authors.forename: Nigel
authors.initials: N
authors.lastname: Curtis
authors.forename: Lavanya
authors.initials: L
authors.lastname: Diwakar
authors.forename: Graeme A
authors.initials: GA
authors.lastname: Meintjes
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000235:genetics / Q000276:immunology; D000328:Adult; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D001886:Bordetella pertussis / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D004306:Dose-Response Relationship, Immunologic; D016503:Drug Delivery Systems; D005260:Female; D015658:HIV Infections / Q000453:epidemiology / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology; D015994:Incidence; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D015995:Prevalence; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013019:South Africa / Q000453:epidemiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D014374:Tuberculin Test; D032581:Tuberculosis Vaccines / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis* / Q000453:epidemiology / Q000276:immunology
chemical_list: D037361:Adenylate Cyclase Toxin; D000942:Antigens, Bacterial; D016056:Immunodominant Epitopes; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma