Hyeryun Choe, PhD
|Hospital Title||Research Associate|
|Academic Title||Associate Professor of Medicine|
300 Longwood Avenue
Boston MA 02115
The Choe laboratory focuses on processes by which enveloped viruses enter their target cells. Dr. Choe’s work has led to the identification of a few key factors essential for entry of HIV-1, SARS coronavirus (SARS-CoV), and New World arenaviruses. These key factors include (1) HIV-1 coreceptor CCR5 (2) a post-translational modification, tyrosine sulfation, as the key common feature for all HIV-1 coreceptors, (3) SARS-CoV receptor, (4) lysosomal enzyme cathepsins as essential host factors for SARS-CoV infection, and (5) transferrin receptor 1 (TfR1) as the receptor for New World hemorrhagic fever arenaviruses. These studies are described below in detail.
HIV-1. In parallel with several other groups, we were involved in identifying CCR5 as an obligate coreceptor for most primary HIV-1 isolates in 1996 (ref 1). Following this initial observation, we identified other G-protein-coupled receptors (GPCRs) that serve as HIV-1 or SIV coreceptors. Identification of these molecules led us to notice a common property of coreceptors, which is important for their role as coreceptors; the amino-termini of CCR5, CXCR4, and all other HIV-1 and SIV coreceptors are modified by tyrosine sulfation, and these sulfate moieties on tyrosines are critical for HIV-1 infection. We have followed this initial observation with a series of studies of characteriing the important role of tyrosine sulfation of chemokine receptors and other G-protein coupled receptors; most, if not all, chemokine receptors and related molecules contain functionally important sulfate moieties on their N-terminal tyrosines. This work also led to another important observation described below.
The Choe lab made another interesting observation in 2003; that a number of antibodies, derived from AIDS patients' B cells, which recognize the coreceptor-binding site of HIV-1 envelope glycoprotein, are also modified by tyrosine sulfation, and their recognition of HIV-1 envelope glycoprotein is depended on these sulfate groups (ref 2). This work was carried out in collaboration with Dr. Michael Farzan (NEPRC, Dept. of Microbiology, Harvard Medical School). Soon after this observation, importance of tyrosine sulfation of these antibodies was confirmed by structural studies. Currently, we are designing and developing tyrosine-sulfated peptides, derived from these antibodies, which potently inhibit infection of various strains of HIV-1.
Hemorrhagic-fever arenaviruses. In 2007, the Choe laboratory identified transferrin receptor 1 (TfR1) as the receptor for pathogenic New World arenaviruses, Machupo, Junin, Guanarito, and Sabia (ref 4). These viruses cause hemorrhagic fever with high mortality in various regions of South America. This is the second virus receptor identified by the Choe lab, following the first in 2003 for SARS coronavirus (ref 3), in collaboration with the Farzan lab. In this arenavirus work, the lab was also able to show that iron depletion enhances, and iron supplementation slows, infection by these viruses, suggesting iron supplement as a possible treatment for these hemorrhagic fevers. We have followed this work with crystallographic study (ref 5) of arenavirus entry protein GP complexed with human TfR1 to better understand how these hemorrhagic fever viruses with low similarity in their entry protens can utilize the same receptor. This study was carried out in collaboration with Dr. Stephen Harrison's laboratory (Children's Hospital, Boston). We have also shown that with only small changes, non-pathogenic arenaviruses that are quite similar to pathogenic ones, can gain the ability to use human TfR1 and might cause diseases in humans (ref 6). Currently, there is no small animal model for these viruses, because murine TfR1 does not support their infection. We are, therefore, in the process of designing and producing knock-in mice that express a small portion of human TfR1, but sufficient to support pathogenic virus infection. This knock-in mice generation is funded by the Centers for Disease Control and Prevention (CDC) and being carried out in collaboration with Dr. Christina Spiropoulou (CDC). When available, these mice will be used to study disease pathology and also to test vaccines and therapeutic candidates, including an humanized anti-hTfR1 antibody, we characterized in collaboration with Dr. Manuel Penichet (UCLA), which potently inhibits in vitro all five hemorrhagic fever arenaviruses (ref 7).
- Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard NP, Gerard C, Sodroski J. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996 Jun;85(7):1135-48.
- Farzan M, Mirzakov T, Kolchinsky P, Wyatt R, Cayabyab M, Gerard NP, Gerard C, Sodroski J, Choe H. Tyrosine Sulfation of N-terminal CCR5 facilitates HIV-1 Entry. Cell. 1999 Mar;96(5):667-76.
- Abraham J, Corbett KD, Farzan M, Choe H, Harrison SC. Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses. Nat Struct Mol Biol. 2010 Apr;17(4):438-44.
- Helguera G, Jemielity S, Abraham J, Cordo SM, Martinez MG, Rodríguez JA, Bregni C, Wang JJ, Farzan M, Penichet ML, Candurra NA, Choe H. An antibody recognizing the apical domain of human transferrin receptor 1 efficiently inhibits the entry of all New World hemorrhagic fever arenaviruses. J Virol. 2012 Apr;86(7):4024-8.
- Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting Enzyme 2 is a Functional Receptor for the SARS coronavirus. Nature. 2003 Nov;426(6965): 450-4.
- Radoshitzky SR, Abraham J, Spiropoulou CF, Kuhn JH, Nguyen D, Li W, Nagel J, Schmidt PJ, Nunberg JH, Andrews NC, Farzan M, Choe H. Transferrin receptor 1 is a cellular receptor for New World hemorrhagic fever arenaviruses. Nature. 2007 Mar 1;446(7131):92-6.
- Abraham J, Kwong JA, Albariño CG, Lu JG, Radoshitzky SR, Salazar-Bravo J, Farzan M, Spiropoulou CF, Choe H. Host-species transferrin receptor 1 orthologs are cellular receptors for nonpathogenic New World clade B arenaviruses. PLoS Pathog. 2009 Apr;5(4):e1000358.