Host-Species Transferrin Receptor 1 Orthologs Are Cellular Receptors for Nonpathogenic New World Clade B Arenaviruses

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Abstract
The ability of a New World (NW) clade B arenavirus to enter cells using human transferrin receptor 1 (TfR1) strictly correlates with its ability to cause hemorrhagic fever. Amapari (AMAV) and Tacaribe (TCRV), two nonpathogenic NW clade B arenaviruses that do not use human TfR1, are closely related to the NW arenaviruses that cause hemorrhagic fevers. Here we show that pseudotyped viruses bearing the surface glycoprotein (GP) of AMAV or TCRV can infect cells using the TfR1 orthologs of several mammalian species, including those of their respective natural hosts, the small rodent Neacomys spinosus and the fruit bat Artibeus jamaicensis. Mutation of one residue in human TfR1 makes it a functional receptor for TCRV, and mutation of four residues makes it a functional receptor for AMAV. Our data support an in vivo role for TfR1 in the replication of most, if not all, NW clade B arenaviruses, and suggest that with modest changes in their GPs the nonpathogenic arenaviruses could use human TfR1 and emerge as human pathogens. Several arenaviruses found in the New World cause hemorrhagic fever when they are transmitted from their natural reservoirs to humans. These pathogenic arenaviruses use human transferrin receptor 1 (TfR1), a protein involved in cellular iron uptake, to infect human cells. The nonpathogenic New World arenaviruses characterized thus far do not use human TfR1. We show here that two of these nonpathogenic viruses, Amapari and Tacaribe, can use animal orthologs of TfR1 to infect cells. We observe that recombinant viruses coated with the entry proteins of Amapari and Tacaribe viruses use the TfR1 orthologs of their natural reservoirs. Modest alteration of human TfR1 converts it to an efficient receptor for Amapari and Tacaribe viruses. Our findings provide insight into the potential of Amapari and Tacaribe viruses to adapt to use human TfR1 and perhaps emerge as human pathogens.