Differential PCDH1 usage by Laguna Negra and Black Creek Canal hantaviruses

Laguna Negra virus and Black Creek Canal virus are two hantaviruses that cause hantavirus cardiopulmonary syndrome (HCPS), but the receptors they use to enter cells have not been identified. Researchers employed replication-competent recombinant vesicular stomatitis viruses (rVSVs) carrying hantavirus Gn/Gc glycoprotein complexes to investigate entry mechanisms, comparing them to Dabieshan virus, Tigray virus, Cao Bang virus, and Amga virus.

All six Gn/Gc complexes successfully infected human pulmonary microvascular endothelial cells, exhibiting varying levels of infection efficiency and kinetics.

Genetic removal of protocadherin-1 (PCDH1) impaired infection caused by Laguna Negra virus and Black Creek Canal virus Gn/Gc, while reintroducing PCDH1 restored susceptibility in human osteosarcoma and endothelial cells. Both viruses were bound by a soluble PCDH1 protein containing the first two extracellular cadherin domains, and their entry was also blocked by a soluble decoy containing the first cadherin domain and an antibody targeting that domain, suggesting that the first PCDH1 cadherin domain facilitates viral attachment.

However, Black Creek Canal Gn/Gc-bearing rVSVs bound less Gn/Gc and showed lower apparent capture by PCDH1 compared to Laguna Negra virus and Andes virus Gn/Gc-bearing particles, even when adjusted for glycoprotein abundance. Notably, PCDH1 depletion did not significantly affect infection mediated by the remaining four hantavirus Gn/Gc complexes.

Consequently, Laguna Negra virus and Black Creek Canal virus employ PCDH1 for efficient entry but display differences in receptor engagement and sensitivity to PCDH1-directed inhibitors, while all six viruses are effectively neutralized by the broad-spectrum Gn/Gc-directed antibody ADI-42898.