Transferrin receptor 1 binds human parvovirus B19 VP1u to facilitate entry

Human parvovirus B19 (B19V) displays a strict tropism for erythroid progenitor cells, which is governed by the VP1 unique domain (VP1u). This domain mediates cell-specific uptake through interaction with an unknown cellular receptor, termed VP1uR. Proximity labeling in permissive erythroid cells identifies transferrin receptor 1 (TfR1/CD71) as a predominant membrane protein associated with VP1u. VP1u constructs colocalize with TfR1 at the cell surface of erythroid cells. Incubation with anti-TfR1 antibody OKT9 abolishes binding and uptake of recombinant VP1u. While OKT9 efficiently inhibits B19V uptake and infection, it does not block virus binding to host cells. Direct binding assays confirm interaction of VP1u with human TfR1. Using cryo-EM we solved the 2.4 Å structure of the TfR1-VP1u complex, mapping the binding site. These findings establish TfR1 as the previously unknown receptor, VP1uR, required for B19V uptake.