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Journal of Virology, September 2008, p. 8986-8996, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00846-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 4E10 Monoclonal Antibody Is Better Adapted to Membrane-Bound Epitope Recognition and Blocking than 2F5{triangledown} ,{dagger}

Nerea Huarte,1 Maier Lorizate,1,{ddagger} Rubén Maeso,1 Renate Kunert,2 Rocio Arranz,3 José M. Valpuesta,3 and José L. Nieva1*

Biophysics Unit (CSIC-UPV/EHU) and Biochemistry and Molecular Biology Department, University of the Basque Country, P.O. Box 644, 48080 Bilbao, Spain,1 Institute of Applied Microbiology, University of Agriculture, A-1190 Vienna, Austria,2 Department of Macromolecular Structures, National Center for Biotechnology (CSIC), Cantoblanco, 28049 Madrid, Spain3

Received 22 April 2008/ Accepted 24 June 2008

The broadly neutralizing 2F5 and 4E10 monoclonal antibodies (MAbs) recognize epitopes within the membrane-proximal external region (MPER) that connects the human immunodeficiency virus type 1 (HIV-1) envelope gp41 ectodomain with the transmembrane anchor. By adopting different conformations that stably insert into the virion external membrane interface, such as helical structures, a conserved aromatic-rich sequence within the MPER is thought to participate in HIV-1-cell fusion. Recent experimental evidence suggests that the neutralizing activity of 2F5 and 4E10 might correlate with the MAbs' capacity to recognize epitopes inserted into the viral membrane, thereby impairing MPER fusogenic activity. To gain new insights into the molecular mechanism underlying viral neutralization by these antibodies, we have compared the capacities of 2F5 and 4E10 to block the membrane-disorganizing activity of MPER peptides inserted into the surface bilayer of solution-diffusing unilamellar vesicles. Both MAbs inhibited leakage of vesicular aqueous contents (membrane permeabilization) and intervesicular lipid mixing (membrane fusion) promoted by MPER-derived peptides. Thus, our data support the idea that antibody binding to a membrane-inserted epitope may interfere with the function of the MPER during gp41-induced fusion. Antibody insertion into a cholesterol-containing, uncharged virion-like membrane is mediated by specific epitope recognition, and moreover, partitioning-coupled folding into a helix reduces the efficiency of 2F5 MAb binding to its epitope in the membrane. We conclude that the capacity to interfere with the membrane activity of conserved MPER sequences is best correlated with the broad neutralization of the 4E10 MAb.

* Corresponding author. Mailing address: Unidad de Biofísica (CSIC-UPV/EHU), Universidad del País Vasco, Aptdo 644, 48080 Bilbao, Spain. Phone: 34 94 6013353. Fax: 34 94 6013360. E-mail: gbpniesj{at}lg.ehu.es

{triangledown} Published ahead of print on 2 July 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: Abteilung Virologie, Universitätsklinikum Heidelberg, im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.

Journal of Virology, September 2008, p. 8986-8996, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00846-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Song, L., Sun, Z.-Y. J., Coleman, K. E., Zwick, M. B., Gach, J. S., Wang, J.-h., Reinherz, E. L., Wagner, G., Kim, M. (2009). Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface. Proc. Natl. Acad. Sci. USA 106: 9057-9062 [Abstract] [Full Text]  


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