Pathogenic hantaviruses selectively inhibit β₃ integrin directed endothelial cell migration

Hantaviruses cause two diseases of man, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Pathogenic and non-pathogenic hantaviruses use β₃ and β₁ integrins, respectively, to enter endothelial cells. β₃ integrins were recently reported to bind receptors that regulate vascular permeability suggesting that hantavirus β₃ integrin interactions may regulate endothelial cell function and contribute to viral pathogenesis. In this study we investigated the ability of pathogenic and non-pathogenic hantaviruses to regulate β₃ and β₁ integrin directed endothelial cell functions. We found that pathogenic NY-1, SNV, HTN, SEO and PUU viruses blocked endothelial cell migration on β₃, but not β₁, integrin ligands. Migration is similarly inhibited by antibodies to β₃ integrins which selectively block vitronectin directed endothelial cell migration. As a result, the ability of endothelial cells to migrate on integrin ligands was selectively inhibited by only pathogenic hantaviruses. Infection by NY-1 virus inhibited endothelial cell migration as early as 24-48 h post-infection. In contrast, non-pathogenic PH and TUL viruses had no effect on the ability of endothelial cells to migrate on either β₃ or β₁ integrin ligands from 1 to 5 days post-infection. These findings indicate that only hantaviruses which use β₃ integrins, and are associated with HPS and HFRS diseases, functionally dysregulate endothelial cell migration. These findings further demonstrate that hantaviruses regulate only β₃ integrin directed endothelial cell functions and have no effect on β₁ integrin functions. Since β₃ integrins are linked to changes in vascular permeability and the maintenance of vascular integrity, these findings suggest a means by which hantavirus usage and regulation of β₃ integrins may contribute to hantavirus pathogenesis.