ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is increasingly prevalent among people infected with human immunodeficiency virus (HIV) in sub-Saharan Africa, yet the ecological and immunological mechanisms linking airway microbes to mucosal inflammation remain unclear. We performed multi-omics profiling in adults from rural Uganda stratified by their HIV and COPD status, integrating sputum microbiome sequencing, outer membrane vesicle quantification, cytokine profiling, cytometry by time-of flight immunophenotyping, and bulk and single-cell transcriptomics with bronchoalveolar lavage-guided deconvolution. Temporal ecological dynamics predominantly shaped airway microbial structure, although disease-modified instability patterns, particularly Haemophilus enrichment and altered trajectories of Staphylococcus, Gemella, and Moraxella, were detectable in HIV+/COPD+ individuals. In contrast, host immune phenotypes showed disease-linked remodeling: HIV and COPD were associated with activation of NF-κB, IL-17, chemokine, TLR, NOD, and antiviral pathways and with compartment-specific transcriptional shifts across sputum, bronchoalveolar lavage, and blood. Integrative modeling revealed discrete, non-linear microbe-immune interaction modules rather than broad dysbiosis, indicating that specific taxa engage defined inflammatory circuits. Together, these findings suggest that HIV-associated COPD reflects immune-skewed mucosal remodeling in which the airway microbiome functions as a selective, temporally dynamic modulator of inflammatory states rather than a globally disrupted community.
