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Journal of Virology, January 2001, p. 579-588, Vol. 75, No. 2
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.2.579-588.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Potent, Broad-Spectrum Inhibition of Human Immunodeficiency Virus Type 1 by the CCR5 Monoclonal Antibody PRO 140

Alexandra Trkola,^1, Thomas J. Ketas,² Kirsten A. Nagashima,² Lu Zhao,² Tonie Cilliers,³ Lynn Morris,³ John P. Moore,^1, Paul J. Maddon,² and William C. Olson^2,*

The Aaron Diamond AIDS Research Center, New York,¹ and Progenics Pharmaceuticals, Inc., Tarrytown,² New York, and National Institute for Virology, Johannesburg, South Africa³

Received 14 September 2000/Accepted 13 October 2000

CCR5 serves as a requisite fusion coreceptor for clinically relevant strains of human immunodeficiency virus type 1 (HIV-1) and provides a promising target for antiviral therapy. However, no study to date has examined whether monoclonal antibodies, small molecules, or other nonchemokine agents possess broad-spectrum activity against the major genetic subtypes of HIV-1. PRO 140 (PA14) is an anti-CCR5 monoclonal antibody that potently inhibits HIV-1 entry at concentrations that do not affect CCR5's chemokine receptor activity. In this study, PRO 140 was tested against a panel of primary HIV-1 isolates selected for their genotypic and geographic diversity. In quantitative assays of viral infectivity, PRO 140 was compared with RANTES, a natural CCR5 ligand that can inhibit HIV-1 entry by receptor downregulation as well as receptor blockade. Despite their divergent mechanisms of action and binding epitopes on CCR5, low nanomolar concentrations of both PRO 140 and RANTES inhibited infection of primary peripheral blood mononuclear cells (PBMC) by all CCR5-using (R5) viruses tested. This is consistent with there being a highly restricted pattern of CCR5 usage by R5 viruses. In addition, a panel of 25 subtype C South African R5 viruses were broadly inhibited by PRO 140, RANTES, and TAK-779, although ~30-fold-higher concentrations of the last compound were required. Interestingly, significant inhibition of a dualtropic subtype C virus was also observed. Whereas PRO 140 potently inhibited HIV-1 replication in both PBMC and primary macrophages, RANTES exhibited limited antiviral activity in macrophage cultures. Thus CCR5-targeting agents such as PRO 140 can demonstrate potent and genetic-subtype-independent anti-HIV-1 activity.

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^* Corresponding author. Mailing address: Progenics Pharmaceuticals, Inc., 777 Old Saw Mill River Rd., Tarrytown, NY 10591. Phone: (914) 789-2800. Fax: (914) 789-2807. E-mail: olson{at}progenics.com.

Present address: Division of Infectious Diseases, Department of Internal Medicine, University Hospital Zurich, U Pol 33, CH-8091 Zurich, Switzerland.

Present address: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, N.Y.

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Journal of Virology, January 2001, p. 579-588, Vol. 75, No. 2
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.2.579-588.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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