Activation-induced cell death drives profound lung CD4+ T-cell depletion in HIV-associated chronic obstructive pulmonary disease

Iulia Popescu, Michael Drummond, Lucio Gama, Tiffany Coon, Christian A. Merlo, Robert A. Wise, Janice E. Clements, Gregory D. Kirk, John F. McDyer

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: As overall survival improves, individuals with HIV infection become susceptible to other chronic diseases, including accelerated chronic obstructive pulmonary disease (COPD). Objectives: To determine whether individuals with HIV-associated COPDexhibit 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. Measurements and Main 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 responseswere preserved. LungCD4+ 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 CD41 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 FEV+, but not in HIV-COPD+ patients. Conclusions: Together, our results provide evidence for profound lung mucosal CD4+ T-cell depletion via a Fas-dependent activationinduced cell death mechanism, along with impaired HIV-specific CD4+ immunity as immunologic features of HIV-associated COPD.

Original languageEnglish (US)
Pages (from-to)744-755
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume190
Issue number7
DOIs
StatePublished - Oct 1 2014

Keywords

  • Apoptosis
  • COPD
  • HIV
  • Immune activation
  • T cells

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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