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Background Chronic obstructive pulmonary disease (COPD) is the third leading cause of global mortality. Therapeutic options that effectively attenuate airway remodelling and disease progression remain limited. Epstein-Barr virus (EBV) has been implicated in immune dysregulation and lymphoid neogenesis in COPD, yet the immunological consequences of antiviral suppression in the airway are poorly defined.Aims To determine whether antiviral therapy alters cellular composition and inflammatory signalling in the bronchial airway microenvironment of COPD patients.Methods Spatial transcriptomics (10x Genomics Visium SD) was performed on paired bronchial biopsies (n=5) collected at baseline and following 8 weeks of treatment from a subset of patients enrolled in the EViSCO trial ( NCT03699904), a randomised, placebo-controlled study of valaciclovir (1 g TID). Computational tools including Scanpy, Scanorama, and Cell2Location were used for cell type deconvolution and differential gene expression analysis.Results Unsupervised clustering identified distinct epithelial and immune populations with region-specific localisation. Enrichment analysis revealed global downregulation of prostaglandin transport and Toll-like receptor (TLR) pathways, indicative of reduced inflammatory signalling, particularly in T and NK cell-enriched regions. At individual patient level, we observed downregulation of genes associated with extracellular matrix components (e.g., collagen trimer, fibrillar matrix), immune activation pathways (e.g., leukocyte migration, chemotaxis), and epithelial remodelling processes (e.g., EMT, cell adhesion, proliferation). These changes suggest a transition from active inflammation and tissue remodelling toward a more quiescent, structurally resolved epithelial state. Reactome pathway analysis additionally showed downregulation of surfactant metabolism and related disease-associated genes post-treatment, potentially reflecting a resolution of inflammation-driven expression, restoring baseline levels of epithelial surfactant genes such as SFTPA-D, in alignment with broader suppression of immune and tissue remodelling pathways.Conclusions This study provides the first spatial transcriptomic characterisation of the airway response to EBV-targeted antiviral therapy in COPD. The findings suggest that treatment suppresses key inflammatory and remodelling pathways, offering mechanistic insight into virus-associated airway pathology and its resolution.