title: Activation-induced cell death drives profound lung CD4(+) T-cell depletion in HIV-associated chronic obstructive pulmonary disease.
abstract: BACKGROUND
  As overall survival improves, individuals with HIV infection become susceptible to other chronic diseases, including accelerated chronic obstructive pulmonary disease (COPD).
  
  
  OBJECTIVE
  To determine whether individuals with HIV-associated COPD exhibit dysregulated lung mucosal T-cell immunity compared with control subjects.
  
  
  METHODS
  Using flow cytometry, we evaluated peripheral blood and lung mucosal T-cell immunity in 14 HIV(+)COPD(+), 13 HIV(+)COPD(-), and 7 HIV(-)COPD(+) individuals.
  
  
  RESULTS
  HIV(+)COPD(+) individuals demonstrated profound CD4(+) T-cell depletion with reduced CD4/CD8 T-cell ratios in bronchoalveolar lavage-derived lung mononuclear cells, not observed in peripheral blood mononuclear cells, and diminished CD4(+) T cell absolute numbers, compared with control subjects. Furthermore, HIV(+)COPD(+) individuals demonstrated decreased pulmonary HIV-specific and staphylococcal enterotoxin B-reactive CD4(+) memory responses, including loss of multifunctionality, compared with HIV(+)COPD(-) control subjects. In contrast, lung mucosal HIV-specific CD8(+) T-cell responses were preserved. Lung CD4(+) T cells from HIV(+)COPD(+) individuals expressed increased surface Fas death receptor (CD95) and programmed death-1, but similar bronchoalveolar lavage viral loads as control subjects. However, programmed death-1 expression inversely correlated with HIV-specific lung CD4(+)IFN-γ(+) T-cell responses, suggesting functional exhaustion. Moreover, lung CD4(+) T cells from HIV(+)COPD(+) patients demonstrated increased basal and HIV antigen-induced expression of the early apoptosis marker annexin V compared with control subjects, which was significantly attenuated with anti-Fas blockade. Lastly, lung mucosal, but not blood, CD4(+)/CD8(+) ratios from HIV(+) patients significantly correlated with the FEV1, but not in HIV(-)COPD(+) patients.
  
  
  CONCLUSIONS
  Together, our results provide evidence for profound lung mucosal CD4(+) T-cell depletion via a Fas-dependent activation-induced cell death mechanism, along with impaired HIV-specific CD4(+) immunity as immunologic features of HIV-associated COPD.
authors.affiliation: 1 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Iulia
authors.initials: I
authors.lastname: Popescu
authors.forename: M Bradley
authors.initials: MB
authors.lastname: Drummond
authors.forename: Lucio
authors.initials: L
authors.lastname: Gama
authors.forename: Tiffany
authors.initials: T
authors.lastname: Coon
authors.forename: Christian A
authors.initials: CA
authors.lastname: Merlo
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.forename: Janice E
authors.initials: JE
authors.lastname: Clements
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.forename: John F
authors.initials: JF
authors.lastname: McDyer
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016923:Cell Death; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008137:Longitudinal Studies; D008168:Lung / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology*; D019562:Viral Load / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
chemical_list: D019014:fas Receptor
keywords: COPD; HIV; T cells; apoptosis; immune activation