In vivo characterization of the integrin β₃ as a receptor for Hantaan virus cellular entry

Binding of viruses to cell surface molecules is an essential step in viral infection. In vitro studies suggested that the α_vβ ₃ integrin receptor is the epithelial cell receptor for Hantaan virus (HTNV). Whether β₃ is in vivo the only or central cellular receptor for HTNV infection is not known. To investigate the role of β₃ integrin for cellular entry of HTNV, we established an HTNV infection model in newborn murine pups. Infected pups died at an average age of 14.2 ± 1.1 days with high levels of viral antigen detected in their brain, lung, and kidney. Pre-injection of blocking monoclonal antibodies (mAb) specific for either β₃ or α_V prolonged survival significantly to a maximal average survival of 19.7 ± 1.5 days (P < 0.01) and 18.4 ± 0.9 days (P < 0.01), respectively. XT-199, a chemical blocker of the α_Vβ₃ receptor also prolonged survival to 19.5 ± 1.3 days (P < 0.01). In contrast to these receptor blockades, anti-HTNV antibody was not only able to prolong survival, but 20% of infected pups achieved long-term survival. An anti-murine β₁ antibody comparatively prolonged survival (19.0 ± 1.2 days), suggesting that HTNV infection is partly mediated through integrin β¹ receptors as well as through β₃ receptors in vivo. Our data demonstrate that the β₃ receptor is important for HTNV infection in vivo, but also suggest that HTNV may utilize additional receptors beyond β₃ for cellular entry within an organism.