title: Effect of Antiretroviral Therapy on HIV-mediated Impairment of the Neutrophil Antimycobacterial Response.
abstract: BACKGROUND
  Experimental and epidemiological evidence suggests that neutrophils are important in the host response to tuberculosis. HIV infection, which increases the risk of tuberculosis, adversely affects neutrophil function.
  
  
  OBJECTIVE
  To determine the impact of HIV and antiretroviral therapy on neutrophil antimycobacterial activity.
  
  
  METHODS
  We performed a cross-sectional comparison of neutrophil functions in 20 antiretroviral-naive HIV-infected and 20 HIV-uninfected individuals using luminescence-, flow cytometry-, and ELISA-based assays. We then conducted a prospective study in the HIV-infected individuals investigating these parameters during the first 6 months of antiretroviral therapy. Surface markers of neutrophil activation were investigated in a separate cohort using flow cytometry.
  
  
  RESULTS
  HIV infection impaired control of Mycobacterium tuberculosis by neutrophils (mean ratio of mycobacterial luminescence in neutrophil samples vs. serum controls at 1 hour in HIV-infected participants, 0.88 ± 0.13 vs. HIV-uninfected participants, 0.76 ± 0.14; P = 0.01; at 24 hours, 0.82 ± 0.13 vs. 0.71 ± 0.13; P = 0.01). The extent of impairment correlated with log[HIV viral load]. Neutrophil cell death after 24 hours' incubation with M. tuberculosis was higher in the HIV-infected cohort (85.3 ± 11.8% vs. 57.9 ± 22.4% necrotic cells; P < 0.0001). Neutrophils from HIV-infected participants demonstrated significantly more CD62L-negative cells (median, 23.0 vs. 8.5%; P = 0.008) and CD16-negative cells (3.2 vs. 1.3%, P = 0.03). Antiretroviral therapy restored mycobacterial restriction and pattern of neutrophil death toward levels seen in HIV-uninfected persons.
  
  
  CONCLUSIONS
  Neutrophils in antiretroviral-naive HIV-infected persons are hyperactivated, eliminate M. tuberculosis less effectively than in HIV-uninfected individuals, and progress rapidly to necrotic cell death. These factors are ameliorated by antiretroviral therapy.
authors.affiliation: 1 Clinical Infectious Diseases Research Initiative, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.|2 Department of Medicine, Imperial College London, London, United Kingdom.|3 Institute of Immunity and Transplantation, University College London, Royal Free Hospital Campus, London, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Lowe
authors.affiliation: 1 Clinical Infectious Diseases Research Initiative, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Nonzwakazi
authors.initials: N
authors.lastname: Bangani
authors.affiliation: 1 Clinical Infectious Diseases Research Initiative, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Rene
authors.initials: R
authors.lastname: Goliath
authors.affiliation: 2 Department of Medicine, Imperial College London, London, United Kingdom.|4 Vaccines and Immunity Theme, Medical Research Council Unit, The Gambia, West Africa.
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.affiliation: 1 Clinical Infectious Diseases Research Initiative, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.|5 Francis Crick Institute Mill Hill Laboratory, London, United Kingdom; and.
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.affiliation: 1 Clinical Infectious Diseases Research Initiative, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.|2 Department of Medicine, Imperial College London, London, United Kingdom.|5 Francis Crick Institute Mill Hill Laboratory, London, United Kingdom; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.affiliation: 2 Department of Medicine, Imperial College London, London, United Kingdom.|5 Francis Crick Institute Mill Hill Laboratory, London, United Kingdom; and.|6 Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Martineau
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011446:Prospective Studies; D012307:Risk Factors; D013019:South Africa; D014376:Tuberculosis / Q000276:immunology*; D019562:Viral Load; D055815:Young Adult
keywords: granulocyte; necrosis; tuberculosis