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Journal of Virology, December 2001, p. 12198-12208, Vol. 75, No. 24
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.24.12198-12208.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Neutralization Synergy of Human Immunodeficiency Virus Type 1 Primary Isolates by Cocktails of Broadly Neutralizing Antibodies

Michael B. Zwick,1 Meng Wang,1 Pascal Poignard,1 Gabriela Stiegler,2 Hermann Katinger,2 Dennis R. Burton,1 and Paul W. H. I. Parren1,*

Departments of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037,1 and Institute for Applied Microbiology, University of Agriculture, Vienna, Austria2

Received 6 July 2001/Accepted 17 September 2001

Several reports have described the existence of synergy between neutralizing monoclonal antibodies (MAbs) against human immunodeficiency virus type 1 (HIV-1). Synergy between human MAbs b12, 2G12, 2F5, and 4E10 in neutralization of primary isolates is of particular interest. Neutralization synergy of these MAbs, however, has not been studied extensively, and the mechanism of synergy remains unclear. We investigated neutralization synergy among this human antibody set by using the classical approach of titrating antibodies mixed at a fixed ratio as well as by an alternative, variable ratio approach in which the neutralization curve of one MAb is assessed in the presence and absence of a fixed, weakly neutralizing concentration of a second antibody. The advantage of this second approach is that it does not require mathematical analysis to establish synergy. No neutralization enhancement of any of the MAb combinations tested was detected for the T-cell-line-adapted molecular HIV-1 clone HxB2 using both assay formats. Studies of primary isolates (89.6, SF162, and JR-CSF) showed neutralization synergy which was relatively weak, with a maximum of two- to fourfold enhancement between antibody pairs, thereby increasing neutralization titers about 10-fold in triple and quadruple antibody combinations. Analysis of b12 and 2G12 binding to oligomeric envelope glycoprotein by using flow cytometry failed to demonstrate cooperativity in binding between these two antibodies. The mechanism by which these antibodies synergize is, therefore, not yet understood. The results lend some support to the notion that an HIV-1 vaccine that elicits moderate neutralizing antibodies to multiple epitopes may be more effective than hereto supposed, although considerable caution in extrapolating to a vaccine situation is required.


* Corresponding author. Mailing address: The Scripps Research Institute, Department of Immunology, 10550 N. Torrey Pines Rd., IMM2, La Jolla, CA 92037. Phone: (858) 784-8602. Fax: (858) 784-8360. E-mail: parren{at}scripps.edu.


Journal of Virology, December 2001, p. 12198-12208, Vol. 75, No. 24
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.24.12198-12208.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.



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Copyright © 2001 by the American Society for Microbiology. All rights reserved.