Research Faculty

Hyeryun Choe, PhD

Department Respiratory Diseases
Hospital Title Research Associate
Academic Title Associate Professor of Medicine
Phone 617-355-7586
Fax 617-738-1752
Email Hyeryun Choe
Location 300 Longwood Avenue
Enders-1
Boston MA 02115

Research Overview

Hyeryun Choe’s 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, Dr. Choe’s laboratory identified CCR5 as an obligate coreceptor for most primary HIV-1 isolates in 1996. Following this initial observation, they worked to identify other G-protein-coupled receptors (GPCRs) that served as HIV-1 or SIV coreceptors. The physiological relevance of these other receptors is still not established, but their identification led the lab 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. They have followed this initial observation with a series of studies of characterizing the important role of tyrosine sulfation of chemokine receptors and other G-protein coupled receptors, and learned that 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 2003-2003; 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 envelope glycoprotein is dependent on these sulfate groups. This work was carried out in collaboration with Dr. Michael Farzan (New England Primate Center, Dept. of Microbiology, Harvard Medical School). Soon after this observation, structural basis of these tyrosine-sulfated antibodies was shown by Dr. Peter Kwong (Vaccine Research Center, NIH). Because the diversity-chain genes of immunoglobulin heavy chains encode many sequences that can be considered motifs for tyrosine sulfation, the lab expects tyrosine-sulfated antibodies to play a role in the control of a number of pathogens in addition to HIV-1. Currently, they 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 a receptor for a group of viruses; we showed transferrin receptor 1 (TfR1) as the receptor for pathogenic New World arenaviruses, Machupo, Junin, Guanarito, and Sabia. These viruses cause hemorrhagic fever with high mortality in various regions of South America. This is their second receptor identification following the first in 2003 for SARS coronavirus. 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. Recently they have described the molecular determinants of TfR1 usage, and characterized the ability of these viruses to utilize the TfR1 orthologs of several species including the host species of these viruses. They are now pursuing two directions for this project. One is to study the interaction between arenaviral entry protein and TfR1 through crystallography to better understand how these four hemorrhagic fever viruses with low similarity in their entry protein can utilize the same receptor. This work is being carried out in collaboration with Dr. Stephen Harrison’s lab (Children’s Hospital, Boston). The other is to assess the probability that currently non-pathogenic arenaviruses could gain the ability to utilize human TfR1 and cause diseases in humans. Currently, there is no small animal model for these viruses, because murine TfR1 does not support their infection. They are, therefore, in the process of designing and producing knock-in mice that expresses a small portion of human TfR1, but sufficient to support pathogenic virus infection. This work and all infectious virus work are being carried out in collaboration with Dr. Christina Spiropoulou (Center for Disease Control). These mice will be valuable to study disease pathology and also to test vaccines and therapeutics.

Key Publications

  • 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.
  • Choe H, Li W, Wright PL, Vasilieva N, Venturi M, Huang CC, Grundner C, Dorfman T, Zwick MB, Wang L, Rosenberg ES, Kwong PD, Burton DR, Robinson JE, Sodroski JG, Farzan M. Tyrosine Sulfation of Human Antibodies Contributes to Recognition of the CCR5 Binding Region of HIV-1 gp120. Cell. 2003 Jul;114(2): 161-70.
  • Huang CC, Venturi M, Majeed S, Moore MJ, Phogat S, Zhang MY, Dimitrov DS, Hendrickson WA, Robinson J, Sodroski J, Wyatt R, Choe H, Farzan M, Kwong PD. Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120. Proc Natl Acad Sci. 2004 Mar;101(9):2706-11.
  • Dorfman T, Moore MJ, Guth AC, Choe H, Farzan M. A tyrosine-sulfated peptide derived from the heavy-chain CDR3 region of an HIV-1-neutralizing antibody binds gp120 and inhibits HIV-1 infection. J Biol Chem. 2006 Sep 29;281(39):28529-35.
  • 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.