Arenavirus

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Host-Species Transferrin Receptor 1 Orthologs Are Cellular Receptors for Nonpathogenic New World Clade B Arenaviruses
´ ˜ Jonathan Abraham1,2,3., Jo Ann Kwong1., Cesar G. Albarino4, Jiajie G. Lu1, Sheli R. Radoshitzky5, Jorge 6 5 4 Salazar-Bravo , Michael Farzan , Christina F. Spiropoulou *, Hyeryun Choe1*
1 Department of Medicine, Children’s Hospital, Harvard Medical School, Boston,Massachusetts, United States of America, 2 Laboratory of Molecular Medicine, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 3 Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America, 4 Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America, 5 Department ofMicrobiology and Molecular Genetics, Harvard Medical School, New England Primate Center, Southborough, Massachusetts, United States of America, 6 Department of Biological Sciences, Texas Tech University, Lubbock, Texas, United States of America

Abstract
The ability of a New World (NW) clade B arenavirus to enter cells using human transferrin receptor 1 (TfR1) strictly correlates with itsability 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 theirrespective 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 intheir GPs the nonpathogenic arenaviruses could use human TfR1 and emerge as human pathogens.
˜ Citation: Abraham J, Kwong JA, Albarino CG, Lu JG, Radoshitzky SR, et al. (2009) Host-Species Transferrin Receptor 1 Orthologs Are Cellular Receptors for Nonpathogenic New World Clade B Arenaviruses. PLoS Pathog 5(4): e1000358. doi:10.1371/journal.ppat.1000358 Editor: Michael J. Buchmeier, University ofCalifornia Irvine, United States of America Received October 15, 2008; Accepted March 1, 2009; Published April 3, 2009 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone forany lawful purpose. Funding: This work was supported by a grant from the National Institute for Allergy and Infectious Diseases to HC (R01 AI07487). JA is a Howard Hughes Medical Institute Gilliam fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competinginterests exist. * E-mail: ccs8@cdc.gov (CFS); hyeryun.choe@childrens.harvard.edu (HC) . These authors contributed equally to this manuscript.

Introduction
Arenaviruses are enveloped viruses that carry single-stranded, bi-segmented, RNA genomes [1]. The family Arenaviridae comprises a single genus (Arenavirus) that contains at least 25 members [2–4]. Arenaviruses have been classified into twoantigenically and geographically distinct groups, the Lassa-lymphocytic choriomeningitis serocomplex (‘‘Old World arenaviruses’’) and the Tacaribe serocomplex (‘‘New World arenaviruses’’) [5–7]. The New World (NW) arenavirus cluster is subdivided into clades A, B, and C. In addition, several North American viruses are recombination products of clades A and B (A/B) (Figure 1). All NW arenaviruses...
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