D101-21 Chronic Hiv-1 Tat Expression in Alveolar Epithelium Induces Lung Inflammation and Remodeling

Abstract Introduction Even with suppressive ART, people living with HIV (PLWH) have higher rates of non-infectious chronic lung diseases (e.g., COPD, pulmonary hypertension) than uninfected individuals, suggesting persistent viral factors contribute to lung injury. HIV-1 Tat is one such factor that continues to be produced under ART and can drive inflammation. We hypothesized that chronic expression of Tat in lung alveolar epithelium would disrupt normal lung homeostasis. We tested this using the SPC-Tat transgenic mouse, in which HIV-1 Tat is selectively expressed in alveolar type II (AT2) cells under the surfactant protein C promoter. Methods SPC-Tat transgenic mice and wild-type littermates were studied at 6 and 12 months of age. Lungs were analyzed by single-cell RNA sequencing (scRNA-seq) to profile transcriptional changes across cell types. Alveolar epithelial subsets (AT2, transitional Club/AT2, and AT1 cells) and immune cells were identified to assess Tat-induced alterations in surfactant and secretoglobin gene expression, inflammatory pathways, and fibrotic/EMT markers. Results 6 months old Tat-tg mice showed early alveolar epithelial abnormalities. AT2 cells had markedly reduced surfactant protein and secretoglobin gene expression, along with upregulation of stress and inflammatory markers (e.g., NF-κB target genes). A persistent subset of transitional Club/AT2 cells was present, suggesting aberrant progenitor activation. By one year of age, chronic Tat expression led to severe lung remodeling. The AT2 cell population had essentially collapsed, with near-complete loss of normal AT2 cells. Lungs exhibited dense inflammatory cell infiltration and sustained upregulation of pro-inflammatory cytokine signals. The transitional Club/AT2 cell compartment was significantly expanded and exhibited a pronounced EMT/fibrotic gene signature, indicating a shift toward a mesenchymal phenotype. Alveolar repair was ineffective: AT2 cells could no longer differentiate into AT1 cells, resulting in an absence of mature AT1 epithelium and loss of normal alveolar structure. Conclusion Chronic expression of HIV-1 Tat in AT2 cells disrupts alveolar cell differentiation and drives a persistent pro-inflammatory, pro-fibrotic state in the lungs. This epithelial-intrinsic effect of Tat recapitulates key features of HIV-associated non-infectious pulmonary disease, highlighting the contribution of alveolar epithelial injury in PLWH. The SPC-Tat model provides a valuable platform for mechanistic insight and for testing interventions targeting HIV-related lung comorbidities. This abstract is funded by: R01 HL158316, HL167655, HL147715 , R01HL176254