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 beta(3) and beta(1) integrins, respectively, to enter endothelial cells. beta(3) integrins were recently reported to bind receptors that regulate vascular permeability suggesting that hantavirus beta(3) 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 beta(3) and beta(1) integrin directed endothelial cell functions. We found that pathogenic NY-1, SNV, HTN, SEO and PUU viruses blocked endothelial cell migration on beta(3), but not beta(1), integrin ligands. Migration is similarly inhibited by antibodies to beta(3) 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 beta(3) or beta(1) integrin ligands from 1 to 5 days post-infection. These findings indicate that only hantaviruses which use 3 integrins, and are associated with HPS and HFRS diseases, functionally dysregulate endothelial cell migration. These findings further demonstrate that hantaviruses regulate only beta(3) integrin directed endothelial cell functions and have no effect on beta(1) integrin functions. Since beta(3) 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 beta(3) integrins may contribute to hantavirus pathogenesis.