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

doi:10.1128/JVI.75.24.12198-12208.2001

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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 immunodeficiencyvirus type 1 (HIV-1). Synergy between human MAbs b12, 2G12, 2F5,and 4E10 in neutralization of primary isolates is of particularinterest. Neutralization synergy of these MAbs, however, has notbeen studied extensively, and the mechanism of synergy remainsunclear. We investigated neutralization synergy among this humanantibody set by using the classical approach of titrating antibodiesmixed at a fixed ratio as well as by an alternative, variableratio approach in which the neutralization curve of one MAb isassessed in the presence and absence of a fixed, weakly neutralizingconcentration of a second antibody. The advantage of this secondapproach is that it does not require mathematical analysis toestablish synergy. No neutralization enhancement of any of theMAb combinations tested was detected for the T-cell-line-adaptedmolecular HIV-1 clone HxB2 using both assay formats. Studies ofprimary isolates (89.6, SF162, and JR-CSF) showed neutralizationsynergy which was relatively weak, with a maximum of two- to fourfoldenhancement between antibody pairs, thereby increasing neutralizationtiters about 10-fold in triple and quadruple antibody combinations.Analysis of b12 and 2G12 binding to oligomeric envelope glycoproteinby using flow cytometry failed to demonstrate cooperativity inbinding between these two antibodies. The mechanism by which theseantibodies synergize is, therefore, not yet understood. The resultslend some support to the notion that an HIV-1 vaccine that elicitsmoderate neutralizing antibodies to multiple epitopes may be moreeffective than hereto supposed, although considerable cautionin extrapolating to a vaccine situation isrequired.

^* 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.

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