A Tissue Virus Microenvironment with Activated Stress Responses Underlies Durable SIV Persistence [Visium]

These features co-occurred with immunosuppressive cellular architectures resembling tertiary lymphoid structures enriched for Treg cells, innate lymphoid cells, and mast cells, regulated by Treg-centered cell-cell interaction networks. In contrast, transient reservoirs displayed enhanced translational and metabolic activity and were embedded within immune-active environments enriched for CD8+ T cells, Th17, Tfh, and activated CD4+ T cells.

Machine learning identified stress adaptation, hypoxia, metabolic rewiring, and cytoskeletal remodeling pathways as dominant predictors of viral density within persistent VMEs, with strong convergence on programs observed in tumor microenvironments (TME). Orthogonal validation confirmed activation of the integrated stress response (ISR) at sites of viral production in concurrence with results of immunofluorescent microscopy revealing SIV gag expression in two populations primarily in the mucosa, differentiated by the phosphorylation of eIF2a.

Together, these findings establish the VME as a critical determinant of reservoir persistence, integrating immune regulation, tissue remodeling, and translational control to enable viral survival.