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Journal of Virology, May 1999, p. 4145-4155, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Differential Inhibition of Human Immunodeficiency Virus Type 1 Fusion, gp120 Binding, and CC-Chemokine Activity by Monoclonal Antibodies to CCR5

William C. Olson,1 Gwénaël E. E. Rabut,2 Kirsten A. Nagashima,1 Diep N. H. Tran,1 Deborah J. Anselma,1 Simon P. Monard,2 Jeremy P. Segal,2 Daniah A. D. Thompson,2 Francis Kajumo,2 Yong Guo,2 John P. Moore,2 Paul J. Maddon,1 and Tatjana Dragic2,*

Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016,2 and Progenics Pharmaceuticals, Inc., Tarrytown, New York 105911

Received 28 December 1998/Accepted 12 February 1999

The CC-chemokine receptor CCR5 mediates fusion and entry of the most commonly transmitted human immunodeficiency virus type 1 (HIV-1) strains. We have isolated six new anti-CCR5 murine monoclonal antibodies (MAbs), designated PA8, PA9, PA10, PA11, PA12, and PA14. A panel of CCR5 alanine point mutants was used to map the epitopes of these MAbs and the previously described MAb 2D7 to specific amino acid residues in the N terminus and/or second extracellular loop regions of CCR5. This structural information was correlated with the MAbs' abilities to inhibit (i) HIV-1 entry, (ii) HIV-1 envelope glycoprotein-mediated membrane fusion, (iii) gp120 binding to CCR5, and (iv) CC-chemokine activity. Surprisingly, there was no correlation between the ability of a MAb to inhibit HIV-1 fusion-entry and its ability to inhibit either the binding of a gp120-soluble CD4 complex to CCR5 or CC-chemokine activity. MAbs PA9 to PA12, whose epitopes include residues in the CCR5 N terminus, strongly inhibited gp120 binding but only moderately inhibited HIV-1 fusion and entry and had no effect on RANTES-induced calcium mobilization. MAbs PA14 and 2D7, the most potent inhibitors of HIV-1 entry and fusion, were less effective at inhibiting gp120 binding and were variably potent at inhibiting RANTES-induced signaling. With respect to inhibiting HIV-1 entry and fusion, PA12 but not PA14 was potently synergistic when used in combination with 2D7, RANTES, and CD4-immunoglobulin G2, which inhibits HIV-1 attachment. The data support a model wherein HIV-1 entry occurs in three stages: receptor (CD4) binding, coreceptor (CCR5) binding, and coreceptor-mediated membrane fusion. The antibodies described will be useful for further dissecting these events.

* Corresponding author. Mailing address: Aaron Diamond AIDS Research Center, 455 1st Ave., 7th Floor, New York, NY 10016. Phone: (212) 448-5053. Fax: (212) 725-1126. E-mail: tdragic{at}adarc.org.

Journal of Virology, May 1999, p. 4145-4155, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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