scRNA sequencing revealed HIV-associated inflammatory-mediated lung epithelial dysregulation and fibroblast remodeling

HIV infection is a well-recognized risk factor for a wide spectrum of pulmonary diseases, with incidence rates significantly higher in people living with HIV (PLWH). Despite antiretroviral therapy, persistent immune activation and recurrent injury continue to compromise lung integrity in this population. However, the mechanism through which HIV disrupts alveolar homeostasis and reshapes epithelial, immune, and stromal compartments in the lungs remain poorly defined. To characterize the cellular and molecular landscape of HIV infection within the lungs upon tobacco smoking, we performed single cell RNA sequencing (scRNA-seq) on human lung tissues from HIV non-smokers and smokers compared them with HIV positive subjects with and without a smoking history. Integration and Uniform Manifold Approximation and Projection (UMAP) clustering of 54,320 cells from all experimental groups identified 29 transcriptionally distinct clusters upon scRNA seq analyses. HIV infection profoundly altered lung cellular composition, marked by expansion of CD4+, CD8+ T-cells, B cells, and non-classical monocytes, alongside reduced fibroblast abundance. Alveolar Type I and Type II epithelial cells displayed robust HIV-associated transcriptional reprogramming. In AT1 cells,. Fibroblast and smooth muscle cells showed enhanced proinflammatory and stress responsiveness with suppression of extracellular matrix and contractile programs. EMT marker analysis revealed cell type specific shifts with: (a) AT1 cells exhibiting reduced E-cadherin and increased vimentin gene expression, (b) AT2 cells adopting a hybrid epithelial mesenchymal phenotype, and (c) myofibroblast cluster displaying amplified mesenchymal activation. These findings reveal HIV as a potent driver of epithelial dysregulation in the human lung, and suggest that targeting epithelial stress programs and fibroblast remodeling may offer new therapeutic avenues, supporting future efforts to develop therapeutic interventions tailored for PLWH.