β₃ integrins mediate the cellular entry of hantaviruses that cause respiratory failure

Newly emerged hantaviruses replicate primarily in the pulmonary endothelium, cause acute platelet loss, and result in hantavirus pulmonary syndrome (HPS). We now report that specific integrins expressed on platelets and endothelial cells permit the cellular entry of HPS-associated hantaviruses. Infection with HPS-associated hantaviruses, NY-1 and Sin Nombre virus (SNV), is inhibited by antibodies to β₃ integrins and by the β₃- integrin ligand, vitronectin. In contrast, infection with the nonpathogenic (no associated human disease) Prospect Hill virus was inhibited by fibronectin and β₁-specific antibodies but not by β₃-specific antibodies or vitronectin. Transfection with recombinant α(iib)β₃ orα(v)β₃ integrins rendered cells permissive to NY-1 and SNV but not Prospect Hill virus infection, indicating that α(iib)β₃ and α(v)β₃ integrins mediate the entry of NY-1 and SNV hantaviruses. Furthermore, entry is divalent cation independent, not blocked by arginine-glycine-aspartic acid peptides and still mediated by, ligand-binding defective, α(iib)β₃-integrin mutants. Hence, NY-1 and SNV entry is independent of β₃ integrin binding to physiologic ligands. These findings implicate integrins as cellular receptors for hantaviruses and indicate that hantavirus pathogenicity correlates with integrin usage.