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Journal of Virology, October 2004, p. 10628-10635, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10628-10635.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Retroviruses Pseudotyped with the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Efficiently Infect Cells Expressing Angiotensin-Converting Enzyme 2

Michael J. Moore,1 Tatyana Dorfman,1 Wenhui Li,1 Swee Kee Wong,1 Yanhan Li,2 Jens H. Kuhn,1,3 James Coderre,4 Natalya Vasilieva,5 Zhongchao Han,2 Thomas C. Greenough,4 Michael Farzan,1* and Hyeryun Choe5*

Partners AIDS Research Center, Brigham and Women's Hospital, and Department of Medicine (Microbiology and Molecular Genetics),1 Perlmutter Laboratory, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston,5 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts,4 State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China,2 Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany3

Received 3 February 2004/ Accepted 28 May 2004

Infection of receptor-bearing cells by coronaviruses is mediated by their spike (S) proteins. The coronavirus (SARS-CoV) that causes severe acute respiratory syndrome (SARS) infects cells expressing the receptor angiotensin-converting enzyme 2 (ACE2). Here we show that codon optimization of the SARS-CoV S-protein gene substantially enhanced S-protein expression. We also found that two retroviruses, simian immunodeficiency virus (SIV) and murine leukemia virus, both expressing green fluorescent protein and pseudotyped with SARS-CoV S protein or S-protein variants, efficiently infected HEK293T cells stably expressing ACE2. Infection mediated by an S-protein variant whose cytoplasmic domain had been truncated and altered to include a fragment of the cytoplasmic tail of the human immunodeficiency virus type 1 envelope glycoprotein was, in both cases, substantially more efficient than that mediated by wild-type S protein. Using S-protein-pseudotyped SIV, we found that the enzymatic activity of ACE2 made no contribution to S-protein-mediated infection. Finally, we show that a soluble and catalytically inactive form of ACE2 potently blocked infection by S-protein-pseudotyped retrovirus and by SARS-CoV. These results permit studies of SARS-CoV entry inhibitors without the use of live virus and suggest a candidate therapy for SARS.

* Corresponding authors. Mailing address for Michael Farzan: Partners AIDS Research Center, 65 Landsdowne St., Cambridge, MA 02139. Phone: (617) 768-8372. Fax: (617) 768-8738. E-mail: farzan{at}mbcrr.harvard.edu. Mailing address for Hyeryun Choe: Perlmutter Laboratory, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Phone: (617) 355-7586. Fax: (617) 730-0240. E-mail: hyeryun.choe{at}tch.harvard.edu.

Journal of Virology, October 2004, p. 10628-10635, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10628-10635.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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