This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nelson, J. D.
Right arrow Articles by Zwick, M. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nelson, J. D.
Right arrow Articles by Zwick, M. B.

 Previous Article  |  Next Article 

Journal of Virology, April 2007, p. 4033-4043, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02588-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

An Affinity-Enhanced Neutralizing Antibody against the Membrane-Proximal External Region of Human Immunodeficiency Virus Type 1 gp41 Recognizes an Epitope between Those of 2F5 and 4E10{triangledown}

Josh D. Nelson,1 Florence M. Brunel,2 Richard Jensen,1 Emma T. Crooks,5 Rosa M. F. Cardoso,3 Meng Wang,1 Ann Hessell,1 Ian A. Wilson,3,4 James M. Binley,5 Philip E. Dawson,2,4 Dennis R. Burton,1 and Michael B. Zwick1*

Department of Immunology,1 Departments of Chemistry and Cell Biology,2 Department of Molecular Biology,3 Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037,4 Torrey Pines Institute for Molecular Studies, San Diego, California 921215

Received 22 November 2006/ Accepted 27 January 2007

The membrane-proximal external region (MPER) of human immunodeficiency virus type 1 (HIV-1) gp41 bears the epitopes of two broadly neutralizing antibodies (Abs), 2F5 and 4E10, making it a target for vaccine design. A third Ab, Fab Z13, had previously been mapped to an epitope that overlaps those of 2F5 and 4E10 but only weakly neutralizes a limited set of primary isolates. Here, libraries of Fab Z13 variants displayed on phage were engineered and affinity selected against an MPER peptide and recombinant gp41. A high-affinity variant, designated Z13e1, was isolated and found to be ~100-fold improved over the parental Fab not only in binding affinity for the MPER antigens but also in neutralization potency against sensitive HIV-1. Alanine scanning of MPER residues 664 to 680 revealed that N671 and D674 are crucial for peptide recognition as well as for the neutralization of HIV-1 by Z13e1. Ab competition studies and truncation of MPER peptides indicate that Z13e1 binds with high affinity to an epitope between and overlapping with those of 2F5 and 4E10, with the minimal peptide epitope WASLWNWFDITN. Still, Z13e1 remained about an order of magnitude less potent than 4E10 against several isolates of pseudotyped HIV-1. The sum of our molecular analyses with Z13e1 suggests that the segment on the MPER of gp41 between the 2F5 and 4E10 epitopes is exposed on the functional envelope trimer but that access to the specific Z13e1 epitope within this segment is limited. Thus, the ability of MPER-bearing immunogens to elicit potent HIV-1-neutralizing Abs may depend in part on recapitulating the particular constraints that the functional envelope trimer imposes on the segment of the MPER to which Z13e1 binds.

* Corresponding author. Mailing address: 10550 North Torrey Pines Road (IMM-2), The Scripps Research Institute, La Jolla, CA 92037. Phone: (858) 784-2833. Fax: (858) 784-8360. E-mail: zwick{at}scripps.edu

{triangledown} Published ahead of print on 7 February 2007.

Journal of Virology, April 2007, p. 4033-4043, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02588-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bryson, S., Julien, J.-P., Hynes, R. C., Pai, E. F. (2009). Crystallographic Definition of the Epitope Promiscuity of the Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5: Vaccine Design Implications. J. Virol. 83: 11862-11875 [Abstract] [Full Text]  
  • Gray, E. S., Madiga, M. C., Moore, P. L., Mlisana, K., Abdool Karim, S. S., Binley, J. M., Shaw, G. M., Mascola, J. R., Morris, L. (2009). Broad Neutralization of Human Immunodeficiency Virus Type 1 Mediated by Plasma Antibodies against the gp41 Membrane Proximal External Region. J. Virol. 83: 11265-11274 [Abstract] [Full Text]  
  • Pejchal, R., Gach, J. S., Brunel, F. M., Cardoso, R. M., Stanfield, R. L., Dawson, P. E., Burton, D. R., Zwick, M. B., Wilson, I. A. (2009). A Conformational Switch in Human Immunodeficiency Virus gp41 Revealed by the Structures of Overlapping Epitopes Recognized by Neutralizing Antibodies. J. Virol. 83: 8451-8462 [Abstract] [Full Text]  
  • Gray, E. S., Taylor, N., Wycuff, D., Moore, P. L., Tomaras, G. D., Wibmer, C. K., Puren, A., DeCamp, A., Gilbert, P. B., Wood, B., Montefiori, D. C., Binley, J. M., Shaw, G. M., Haynes, B. F., Mascola, J. R., Morris, L. (2009). Antibody Specificities Associated with Neutralization Breadth in Plasma from Human Immunodeficiency Virus Type 1 Subtype C-Infected Blood Donors. J. Virol. 83: 8925-8937 [Abstract] [Full Text]  
  • 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]  
  • Shen, X., Parks, R. J., Montefiori, D. C., Kirchherr, J. L., Keele, B. F., Decker, J. M., Blattner, W. A., Gao, F., Weinhold, K. J., Hicks, C. B., Greenberg, M. L., Hahn, B. H., Shaw, G. M., Haynes, B. F., Tomaras, G. D. (2009). In Vivo gp41 Antibodies Targeting the 2F5 Monoclonal Antibody Epitope Mediate Human Immunodeficiency Virus Type 1 Neutralization Breadth. J. Virol. 83: 3617-3625 [Abstract] [Full Text]  
  • Binley, J. M., Lybarger, E. A., Crooks, E. T., Seaman, M. S., Gray, E., Davis, K. L., Decker, J. M., Wycuff, D., Harris, L., Hawkins, N., Wood, B., Nathe, C., Richman, D., Tomaras, G. D., Bibollet-Ruche, F., Robinson, J. E., Morris, L., Shaw, G. M., Montefiori, D. C., Mascola, J. R. (2008). Profiling the Specificity of Neutralizing Antibodies in a Large Panel of Plasmas from Patients Chronically Infected with Human Immunodeficiency Virus Type 1 Subtypes B and C. J. Virol. 82: 11651-11668 [Abstract] [Full Text]  
  • Rogers, J., Schoepp, R.J., Schroder, O., Clements, T.L., Holland, T.F., Li, J.Q., Li, J., Lewis, L.M., Dirmeier, R.P., Frey, G.J., Tan, X., Wong, K., Woodnutt, G., Keller, M., Reed, D.S., Kimmel, B.E., Tozer, E.C. (2008). Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases. Protein Eng Des Sel 21: 495-505 [Abstract] [Full Text]  
  • Zhang, M.-Y., Vu, B. K., Choudhary, A., Lu, H., Humbert, M., Ong, H., Alam, M., Ruprecht, R. M., Quinnan, G., Jiang, S., Montefiori, D. C., Mascola, J. R., Broder, C. C., Haynes, B. F., Dimitrov, D. S. (2008). Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Human Monoclonal Antibody That Recognizes a Novel Conformational Epitope on gp41 and Lacks Reactivity against Self-Antigens. J. Virol. 82: 6869-6879 [Abstract] [Full Text]  
  • Rockx, B., Corti, D., Donaldson, E., Sheahan, T., Stadler, K., Lanzavecchia, A., Baric, R. (2008). Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus Challenge. J. Virol. 82: 3220-3235 [Abstract] [Full Text]  
  • Montero, M., van Houten, N. E., Wang, X., Scott, J. K. (2008). The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design. Microbiol. Mol. Biol. Rev. 72: 54-84 [Abstract] [Full Text]  
  • Gray, E. S., Moore, P. L., Bibollet-Ruche, F., Li, H., Decker, J. M., Meyers, T., Shaw, G. M., Morris, L. (2008). 4E10-Resistant Variants in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Individual with an Anti-Membrane-Proximal External Region-Neutralizing Antibody Response. J. Virol. 82: 2367-2375 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»