Transferrin receptor 1 binds human parvovirus B19 VP1u to facilitate entry

Summary Human parvovirus B19 (B19V) exhibits a strict tropism for erythroid progenitor cells, which is governed by the VP1 unique region (VP1u). This region mediates cell-specific uptake by interacting with an unknown cellular receptor, termed VP1uR. Proximity labeling in permissive erythroid cells identified transferrin receptor 1 (TfR1/CD71) as the predominant membrane protein associated with VP1u. VP1u constructs colocalized with TfR1 at the cell surface of erythroid cells. Incubation with anti-TfR1 antibody OKT9 abolished binding and uptake of recombinant VP1u. While OKT9 efficiently inhibited B19V uptake and infection, it did not block virus binding to host cells. Direct binding assays confirmed interaction of VP1u to human TfR1. Using cryoEM we solved the 2.4 Å structure of the TfR1-VP1u complex, mapping the binding site and identifying the specific interactions. These findings establish TfR1 as the previously unknown receptor, VP1uR, required for B19V uptake.