Pathogenic hantaviruses bind plexin-semaphorin-integrin domains present at the apex of inactive, bent αvβ3 integrin conformers

The αvβ3 integrins are linked to human bleeding disorders, and pathogenic hantaviruses regulate the function of αvβ3 integrins and cause acute vascular diseases. αvβ3 integrins are present in either extended (active) or dramatically bent (inactive) structures, and interconversion of αvβ3 conformers dynamically regulates integrin functions. Here, we show that hantaviruses bind human αvβ3 integrins and that binding maps to the plexin-semaphorin-integrin (PSI) domain present at the apex of inactive, bent, αvβ3-integrin structures. Pathogenic hantaviruses [New York-1 virus (NY-1V) and Hantaan virus (HTNV)] bind immobilized β3 polypeptides containing the PSI domain, and human (but not murine) β3 polypeptides inhibit hantavirus infectivity. Substitution of human β3 residues 1-39 for murine β3 residues directed pathogenic hantavirus infection of nonpermissive CHO cells expressing chimeric αvβ3 receptors. Mutation of murine β3 Asn-39 to Asp-39 present in human β3 homologues (N39D) permitted hantavirus infection of cells and specified PSI domain residue interactions with pathogenic hantaviruses. In addition, cell-surface expression of αvβ3 locked in an inactive bent conformation conferred hantavirus infectivity of CHO cells. Our findings indicate that hantaviruses bind to a unique domain exposed on inactive integrins and, together with prior findings, suggest that this interaction restricts αvβ3 functions that regulate vascular permeability. Our findings suggest mechanisms for viruses to direct hemorrhagic or vascular diseases and provide a distinct target for modulating αvβ3-integrin functions.