title: Natural killer cell activation distinguishes Mycobacterium tuberculosis-mediated immune reconstitution syndrome from chronic HIV and HIV/MTB coinfection.
abstract: BACKGROUND
  With increased access to antiretroviral treatment (ART), immune reconstitution inflammatory syndrome (IRIS) in Mycobacterium tuberculosis (MTB)-infected populations remains a clinical challenge. We studied a cross-sectional cohort of HIV-infected subjects in Johannesburg (South Africa) to help define the immune correlates that best distinguish IRIS from ongoing MTB cases.
  
  
  METHODS
  We studied HIV+ subjects developing MTB-related unmasking tuberculosis-related immune reconstitution inflammatory syndrome (uTB-IRIS) after ART initiation; control groups were subjects with HIV and HIV/tuberculosis-coinfected subjects with comparable ART treatment. Testing was conducted with whole blood-based 4-color flow cytometry and plasma-based Luminex cytokine assessment.
  
  
  RESULTS
  Natural killer cell activation, C-reactive protein, and interleukin 8 serum concentration were significantly higher in uTB-IRIS subjects compared with both control groups. In addition, all MTB-coinfected subjects, independent of clinical presentation, had higher neutrophils and T-cell activation, together with lower lymphocytes, CD4⁺ T-cell, and myeloid dendritic cell counts. Using conditional inference tree analysis, we show that elevated natural killer cell activation in combination with lymphocyte count characterizes the immunological profile of uTB-IRIS.
  
  
  CONCLUSIONS
  Our results support a role for innate immune effectors in the immunopathogenesis of unmasking MTB-related IRIS and identify new immune parameters defining this pathology.
authors.affiliation: Clinical HIV Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Francesca
authors.initials: F
authors.lastname: Conradie
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Foulkes
authors.forename: Prudence
authors.initials: P
authors.lastname: Ive
authors.forename: Xiangfan
authors.initials: X
authors.lastname: Yin
authors.forename: Katerina
authors.initials: K
authors.lastname: Roussos
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Glencross
authors.forename: Denise
authors.initials: D
authors.lastname: Lawrie
authors.forename: Wendy
authors.initials: W
authors.lastname: Stevens
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
authors.forename: Ian
authors.initials: I
authors.lastname: Sanne
authors.forename: Livio
authors.initials: L
authors.lastname: Azzoni
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000175:diagnosis* / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D013019:South Africa; D014376:Tuberculosis / Q000150:complications / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; D016207:Cytokines