Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2001 Dec;75(24):12198-208.
doi: 10.1128/JVI.75.24.12198-12208.2001.

Neutralization synergy of human immunodeficiency virus type 1 primary isolates by cocktails of broadly neutralizing antibodies

M B Zwick  1 , M Wang, P Poignard, G Stiegler, H Katinger, D R Burton, P W Parren
Affiliations

Neutralization synergy of human immunodeficiency virus type 1 primary isolates by cocktails of broadly neutralizing antibodies

M B Zwick et al. J Virol. 2001 Dec.

Abstract

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.

PubMed Disclaimer

Figures

FIG. 1
FIG. 1
Analysis of cooperativity of MAb binding to HIV-1 envelope spikes. Binding of MAb 2G12 to HIV-1 envelope expressed on the surface of HIV-1HxB2-infected H9 cells (A) or BHK cells infected with a recombinant vaccinia virus expressing HIV-189.6 envelope (B) was detected by using flow cytometry. Dose-response curves of MAb 2G12 binding were assessed in the absence or presence of a subsaturating amount of F(ab′)2 fragments of MAb b12. Detection of bound antibody was performed with a fluorochrome-labeled antibody against Fc (A and B). (C and D) Binding of MAb b12, MAb 2G12, and F(ab′)2 b12 and their combinations to HIV-1HxB2-infected H9 cells and BHK cells infected with a recombinant vaccinia virus expressing HIV-189.6 envelope, respectively. Antibody binding was detected with a fluorochrome-labeled antibody against the Fc or Fab fragment as indicated above the bars. The primary antibody (dark bars, or indicated first in the antibody pair described below the hatched bars) was tested at 10 μg/ml, whereas the secondary antibody (shown as the second antibody below the hatched bars) was tested at a subsaturating concentration (resulting in 50 to 75% of maximal binding). The results in the third pair of bars correspond to the data in panels A and B and are shown for comparison.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Allaway G P, Ryder A M, Beaudry G A, Maddon P J. Synergistic inhibition of HIV-1 envelope-mediated cell fusion by CD4-based molecules in combination with antibodies to gp120 or gp41. AIDS Res Hum Retrovir. 1993;9:581–587. - PubMed
    1. Baba T W, Liska V, Hofmann-Lehmann R, Vlasak J, Xu W, Ayehunie S, Cavacini L A, Posner M R, Katinger H, Stiegler G, Bernacky B J, Rizvi T A, Schmidt R, Hill L R, Keeling M E, Lu Y, Wright J E, Chou T C, Ruprecht R M. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med. 2000;6:200–206. - PubMed
    1. Bjorndal A, Deng H, Jansson M, Fiore R R, Colognesi C, Karlsson A, Albert J, Scarlatti G, Littman D R, Fenyö E-M. Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype. J Virol. 1997;71:7478–7487. - PMC - PubMed
    1. Buchacher A, Predl R, Strutzenberger K, Steinfellner W, Trkola A, Purtscher M, Gruber G, Tauer C, Steindl F, Jungbauder A, Katinger H. Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and Epstein-Barr virus transformation for peripheral blood lymphocyte immortalization. AIDS Res Hum Retrovir. 1994;10:359–369. - PubMed
    1. Bunow B, Weinstein J N. COMBO: a new approach to the analysis of drug combinations in vitro. Ann NY Acad Sci. 1990;616:490–494. - PubMed

Publication types

LinkOut - more resources