Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses

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Abstract
The transferrin receptor 1 (TfR1) has been identified as the cellular receptor for four New World arenaviruses — the Junin, Machupo, Guanarito and Sabia viruses. This class of arenaviruses is important because they cause fatal haemorrhagic fevers. Treating cultured cells with an antibody against TfR1 blocks viral entry and replication. Antibodies that limit arenavirus replication without interfering with host iron metabolism may be effective in controlling outbreaks of New World haemorrhagic fever. At least five arenaviruses cause viral haemorrhagic fevers in humans. Lassa virus, an Old World arenavirus, uses the cellular receptor α-dystroglycan to infect cells1. Machupo, Guanarito, Junin and Sabia viruses are New World haemorrhagic fever viruses that do not use α-dystroglycan2. Here we show a specific, high-affinity association between transferrin receptor 1 (TfR1) and the entry glycoprotein (GP) of Machupo virus. Expression of human TfR1, but not human transferrin receptor 2, in hamster cell lines markedly enhanced the infection of viruses pseudotyped with the GP of Machupo, Guanarito and Junin viruses, but not with those of Lassa or lymphocytic choriomeningitis viruses. An anti-TfR1 antibody efficiently inhibited the replication of Machupo, Guanarito, Junin and Sabia viruses, but not that of Lassa virus. Iron depletion of culture medium enhanced, and iron supplementation decreased, the efficiency of infection by Junin and Machupo but not Lassa pseudoviruses. These data indicate that TfR1 is a cellular receptor for New World haemorrhagic fever arenaviruses.