title: Interferon γ responses to mycobacterial antigens protect against subsequent HIV-associated tuberculosis.
abstract: BACKGROUND
  The cellular immune responses that protect against tuberculosis have not been identified.
  
  
  METHODS
  We assessed baseline interferon γ (IFN‐γ) and lymphocyte proliferation assay (LPA) responses to antigen 85 (Ag85), early secretory antigenic target 6 (ESAT‐6), and Mycobacterium tuberculosis whole cell lysate (WCL) in human immunodeficiency virus (HIV)-infected and bacille Calmette‐Guérin (BCG)-immunized adults with CD4 cell counts of >or= 200 cells/μL who received placebo in the DarDar tuberculosis vaccine trial in Tanzania. Subjects were followed prospectively to diagnose definite or probable tuberculosis.
  
  
  RESULTS
  Tuberculosis was diagnosed in 92 of 979 subjects during a mean follow‐up of 3.2 years. The relative risk of tuberculosis among subjects with positive IFN‐γ responses to Ag85 was 0.51 (95% confidence interval [CI], 0.26-0.99; P = .049), to ESAT‐6 was 0.44 (95% CI, 0.23-0.85; P = .004), and to WCL was 0.67 (95% CI, 0.49-0.88; P = .002). The relative risk of tuberculosis was not significantly associated with baseline LPA responses. In a multivariate Cox regression model, subjects with IFN‐γ responses to ESAT‐6 and WCL had a lower hazard of developing tuberculosis, with a hazard ratio for ESAT‐6 of 0.35 (95% CI, 0.16–0.77; P = .009) and a hazard ratio for WCL of 0.30 (95% CI, 0.16-0.56; P < .001).
  
  
  CONCLUSIONS
  Baseline IFN‐γ responses to ESAT-6 and WCL were associated with protection from subsequent tuberculosis among HIV-infected subjects with childhood BCG immunization in a region of high tuberculosis prevalence. Trial registration. ClinicalTrials.gov identifier: NCT00052195.
authors.affiliation: Dartmouth Medical School, Lebanon, New Hampshire, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lahey
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sheth
authors.forename: Mecky
authors.initials: M
authors.lastname: Matee
authors.forename: Robert
authors.initials: R
authors.lastname: Arbeit
authors.forename: C Robert
authors.initials: CR
authors.lastname: Horsburgh
authors.forename: Lillian
authors.initials: L
authors.lastname: Mtei
authors.forename: Todd
authors.initials: T
authors.lastname: Mackenzie
authors.forename: Muhammad
authors.initials: M
authors.lastname: Bakari
authors.forename: Jenni M
authors.initials: JM
authors.lastname: Vuola
authors.forename: Kisali
authors.initials: K
authors.lastname: Pallangyo
authors.forename: C Fordham
authors.initials: CF
authors.lastname: von Reyn
mesh_terms: D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D001500:BCG Vaccine / Q000276:immunology; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D012307:Risk Factors; D013636:Tanzania; D014376:Tuberculosis / Q000150:complications* / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D007371:Interferon-gamma
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