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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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