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

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.