Sulfated glycosaminoglycans inhibit LCMV entry and modulate antiviral immunity and pathology.

Viral infections remain a major challenge due to the limited availability and efficacy of current treatments. Existing antivirals primarily target viral replication but are often virus-specific and can lead to drug resistance. Sulfated glycosaminoglycans (GAGs) have emerged as promising broad-spectrum agents that block viral binding and entry into host cells. Here, we show that highly sulfated GAGs restrict the infectivity of both pathogenic and non-pathogenic Arenaviruses. Using the lymphocytic choriomeningitis virus (LCMV) model, we demonstrate that GAG exposure reduces viral entry and infection in cell lines and bone marrow-derived dendritic cells, impairing their ability to activate antiviral T cells. In vivo, early exposure of LCMV to dextran sulfate suppressed immune activation, leading to diminished T-cell responses, prolonged infection, and increased immunopathology. By contrast, administering dextran sulfate during the acute infection phase decreased viral load, improved effector T-cell function, and reduced liver pathology. These findings highlight the therapeutic potential of sulfated GAGs against Arenavirus infections and the importance of treatment timing for clinical efficacy.