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 Ofek, G.
Right arrow Articles by Kwong, P. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ofek, G.
Right arrow Articles by Kwong, P. D.

 Previous Article  |  Next Article 

Journal of Virology, October 2004, p. 10724-10737, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10724-10737.2004

Structure and Mechanistic Analysis of the Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5 in Complex with Its gp41 Epitope

Gilad Ofek,1 Min Tang,1 Anna Sambor,1 Hermann Katinger,2 John R. Mascola,1 Richard Wyatt,1 and Peter D. Kwong1*

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,1 Institute of Applied Microbiology, University of Agricultural Sciences, Vienna, Austria2

Received 6 February 2004/ Accepted 15 June 2004

The membrane-proximal region of the ectodomain of the gp41 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) is the target of three of the five broadly neutralizing anti-HIV-1 antibodies thus far isolated. We have determined crystal structures of the antigen-binding fragment for one of these antibodies, 2F5, in complex with 7-mer, 11-mer, and 17-mer peptides of the gp41 membrane-proximal region, at 2.0-, 2.1-, and 2.2-Å resolutions, respectively. The structures reveal an extended gp41 conformation, which stretches over 30 Å in length. Contacts are made with five complementarity-determining regions of the antibody as well as with nonpolymorphic regions. Only one exclusive charged face of the gp41 epitope is bound by 2F5, while the nonbound face, which is hydrophobic, may be hidden due to occlusion by other portions of the ectodomain. The structures reveal that the 2F5 antibody is uniquely built to bind to an epitope that is proximal to a membrane surface and in a manner mostly unaffected by large-scale steric hindrance. Biochemical studies with proteoliposomes confirm the importance of lipid membrane and hydrophobic context in the binding of 2F5 as well as in the binding of 4E10, another broadly neutralizing antibody that recognizes the membrane-proximal region of gp41. Based on these structural and biochemical results, immunization strategies for eliciting 2F5- and 4E10-like broadly neutralizing anti-HIV-1 antibodies are proposed.

* Corresponding author. Mailing address: Vaccine Research Center, NIAID/NIH, 40 Convent Dr., Building 40, Room 4508, Bethesda, MD 20892. Phone: (301) 594-8439. Fax: (301) 480-0274. E-mail: pdkwong{at}nih.gov.

Journal of Virology, October 2004, p. 10724-10737, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10724-10737.2004




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]  
  • Dennison, S. M., Stewart, S. M., Stempel, K. C., Liao, H.-X., Haynes, B. F., Alam, S. M. (2009). Stable Docking of Neutralizing Human Immunodeficiency Virus Type 1 gp41 Membrane-Proximal External Region Monoclonal Antibodies 2F5 and 4E10 Is Dependent on the Membrane Immersion Depth of Their Epitope Regions. J. Virol. 83: 10211-10223 [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]  
  • Perez, L. G., Costa, M. R., Todd, C. A., Haynes, B. F., Montefiori, D. C. (2009). Utilization of Immunoglobulin G Fc Receptors by Human Immunodeficiency Virus Type 1: a Specific Role for Antibodies against the Membrane-Proximal External Region of gp41. J. Virol. 83: 7397-7410 [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]  
  • Arnold, G. F., Velasco, P. K., Holmes, A. K., Wrin, T., Geisler, S. C., Phung, P., Tian, Y., Resnick, D. A., Ma, X., Mariano, T. M., Petropoulos, C. J., Taylor, J. W., Katinger, H., Arnold, E. (2009). Broad Neutralization of Human Immunodeficiency Virus Type 1 (HIV-1) Elicited from Human Rhinoviruses That Display the HIV-1 gp41 ELDKWA Epitope. J. Virol. 83: 5087-5100 [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]  
  • Davis, K. L., Bibollet-Ruche, F., Li, H., Decker, J. M., Kutsch, O., Morris, L., Salomon, A., Pinter, A., Hoxie, J. A., Hahn, B. H., Kwong, P. D., Shaw, G. M. (2009). Human Immunodeficiency Virus Type 2 (HIV-2)/HIV-1 Envelope Chimeras Detect High Titers of Broadly Reactive HIV-1 V3-Specific Antibodies in Human Plasma. J. Virol. 83: 1240-1259 [Abstract] [Full Text]  
  • Chen, S. S.-L., Yang, P., Ke, P.-Y., Li, H.-F., Chan, W.-E., Chang, D.-K., Chuang, C.-K., Tsai, Y., Huang, S.-C. (2009). Identification of the LWYIK Motif Located in the Human Immunodeficiency Virus Type 1 Transmembrane gp41 Protein as a Distinct Determinant for Viral Infection. J. Virol. 83: 870-883 [Abstract] [Full Text]  
  • Schelonka, R. L., Zemlin, M., Kobayashi, R., Ippolito, G. C., Zhuang, Y., Gartland, G. L., Szalai, A., Fujihashi, K., Rajewsky, K., Schroeder, H. W. Jr. (2008). Preferential Use of DH Reading Frame 2 Alters B Cell Development and Antigen-Specific Antibody Production. J. Immunol. 181: 8409-8415 [Abstract] [Full Text]  
  • Coutant, J., Yu, H., Clement, M.-J., Alfsen, A., Toma, F., Curmi, P. A., Bomsel, M. (2008). Both lipid environment and pH are critical for determining physiological solution structure of 3-D-conserved epitopes of the HIV-1 gp41-MPER peptide P1. FASEB J. 22: 4338-4351 [Abstract] [Full Text]  
  • Joyce, J. G., Krauss, I. J., Song, H. C., Opalka, D. W., Grimm, K. M., Nahas, D. D., Esser, M. T., Hrin, R., Feng, M., Dudkin, V. Y., Chastain, M., Shiver, J. W., Danishefsky, S. J. (2008). An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions. Proc. Natl. Acad. Sci. USA 105: 15684-15689 [Abstract] [Full Text]  
  • Huarte, N., Lorizate, M., Maeso, R., Kunert, R., Arranz, R., Valpuesta, J. M., Nieva, J. L. (2008). The Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 4E10 Monoclonal Antibody Is Better Adapted to Membrane-Bound Epitope Recognition and Blocking than 2F5. J. Virol. 82: 8986-8996 [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]  
  • Vishwanathan, S. A., Hunter, E. (2008). Importance of the Membrane-Perturbing Properties of the Membrane-Proximal External Region of Human Immunodeficiency Virus Type 1 gp41 to Viral Fusion. J. Virol. 82: 5118-5126 [Abstract] [Full Text]  
  • Frey, G., Peng, H., Rits-Volloch, S., Morelli, M., Cheng, Y., Chen, B. (2008). A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies. Proc. Natl. Acad. Sci. USA 105: 3739-3744 [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]  
  • Alam, S. M., Scearce, R. M., Parks, R. J., Plonk, K., Plonk, S. G., Sutherland, L. L., Gorny, M. K., Zolla-Pazner, S., VanLeeuwen, S., Moody, M. A., Xia, S.-M., Montefiori, D. C., Tomaras, G. D., Weinhold, K. J., Karim, S. A., Hicks, C. B., Liao, H.-X., Robinson, J., Shaw, G. M., Haynes, B. F. (2008). Human Immunodeficiency Virus Type 1 gp41 Antibodies That Mask Membrane Proximal Region Epitopes: Antibody Binding Kinetics, Induction, and Potential for Regulation in Acute Infection. J. Virol. 82: 115-125 [Abstract] [Full Text]  
  • Manrique, A., Rusert, P., Joos, B., Fischer, M., Kuster, H., Leemann, C., Niederost, B., Weber, R., Stiegler, G., Katinger, H., Gunthard, H. F., Trkola, A. (2007). In Vivo and In Vitro Escape from Neutralizing Antibodies 2G12, 2F5, and 4E10. J. Virol. 81: 8793-8808 [Abstract] [Full Text]  
  • Bellamy-McIntyre, A. K., Lay, C.-S., Baar, S., Maerz, A. L., Talbo, G. H., Drummer, H. E., Poumbourios, P. (2007). Functional Links between the Fusion Peptide-proximal Polar Segment and Membrane-proximal Region of Human Immunodeficiency Virus gp41 in Distinct Phases of Membrane Fusion. J. Biol. Chem. 282: 23104-23116 [Abstract] [Full Text]  
  • Giannecchini, S., D'Ursi, A. M., Esposito, C., Scrima, M., Zabogli, E., Freer, G., Rovero, P., Bendinelli, M. (2007). Antibodies Generated in Cats by a Lipopeptide Reproducing the Membrane-Proximal External Region of the Feline Immunodeficiency Virus Transmembrane Enhance Virus Infectivity. CVI 14: 944-951 [Abstract] [Full Text]  
  • Dey, B., Pancera, M., Svehla, K., Shu, Y., Xiang, S.-H., Vainshtein, J., Li, Y., Sodroski, J., Kwong, P. D., Mascola, J. R., Wyatt, R. (2007). Characterization of Human Immunodeficiency Virus Type 1 Monomeric and Trimeric gp120 Glycoproteins Stabilized in the CD4-Bound State: Antigenicity, Biophysics, and Immunogenicity. J. Virol. 81: 5579-5593 [Abstract] [Full Text]  
  • Miranda, L. R., Duval, M., Doherty, H., Seaman, M. S., Posner, M. R., Cavacini, L. A. (2007). The Neutralization Properties of a HIV-Specific Antibody Are Markedly Altered by Glycosylation Events Outside the Antigen-Binding Domain. J. Immunol. 178: 7132-7138 [Abstract] [Full Text]  
  • Law, M., Cardoso, R. M. F., Wilson, I. A., Burton, D. R. (2007). Antigenic and Immunogenic Study of Membrane-Proximal External Region-Grafted gp120 Antigens by a DNA Prime-Protein Boost Immunization Strategy. J. Virol. 81: 4272-4285 [Abstract] [Full Text]  
  • Nelson, J. D., Brunel, F. M., Jensen, R., Crooks, E. T., Cardoso, R. M. F., Wang, M., Hessell, A., Wilson, I. A., Binley, J. M., Dawson, P. E., Burton, D. R., Zwick, M. B. (2007). 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. J. Virol. 81: 4033-4043 [Abstract] [Full Text]  
  • Alam, S. M., McAdams, M., Boren, D., Rak, M., Scearce, R. M., Gao, F., Camacho, Z. T., Gewirth, D., Kelsoe, G., Chen, P., Haynes, B. F. (2007). The Role of Antibody Polyspecificity and Lipid Reactivity in Binding of Broadly Neutralizing Anti-HIV-1 Envelope Human Monoclonal Antibodies 2F5 and 4E10 to Glycoprotein 41 Membrane Proximal Envelope Epitopes. J. Immunol. 178: 4424-4435 [Abstract] [Full Text]  
  • Sheppard, N. C., Davies, S. L., Jeffs, S. A., Vieira, S. M., Sattentau, Q. J. (2007). Production and Characterization of High-Affinity Human Monoclonal Antibodies to Human Immunodeficiency Virus Type 1 Envelope Glycoproteins in a Mouse Model Expressing Human Immunoglobulins. CVI 14: 157-167 [Abstract] [Full Text]  
  • Steger, H. K., Root, M. J. (2006). Kinetic Dependence to HIV-1 Entry Inhibition. J. Biol. Chem. 281: 25813-25821 [Abstract] [Full Text]  
  • Eda, Y., Takizawa, M., Murakami, T., Maeda, H., Kimachi, K., Yonemura, H., Koyanagi, S., Shiosaki, K., Higuchi, H., Makizumi, K., Nakashima, T., Osatomi, K., Tokiyoshi, S., Matsushita, S., Yamamoto, N., Honda, M. (2006). Sequential Immunization with V3 Peptides from Primary Human Immunodeficiency Virus Type 1 Produces Cross-Neutralizing Antibodies against Primary Isolates with a Matching Narrow-Neutralization Sequence Motif.. J. Virol. 80: 5552-5562 [Abstract] [Full Text]  
  • Yuste, E., Sanford, H. B., Carmody, J., Bixby, J., Little, S., Zwick, M. B., Greenough, T., Burton, D. R., Richman, D. D., Desrosiers, R. C., Johnson, W. E. (2006). Simian Immunodeficiency Virus Engrafted with Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Epitopes: Replication, Neutralization, and Survey of HIV-1-Positive Plasma. J. Virol. 80: 3030-3041 [Abstract] [Full Text]  
  • Ou, W., Lu, N., Yu, S. S., Silver, J. (2006). Effect of Epitope Position on Neutralization by Anti-Human Immunodeficiency Virus Monoclonal Antibody 2F5. J. Virol. 80: 2539-2547 [Abstract] [Full Text]  
  • Brunel, F. M., Zwick, M. B., Cardoso, R. M. F., Nelson, J. D., Wilson, I. A., Burton, D. R., Dawson, P. E. (2006). Structure-Function Analysis of the Epitope for 4E10, a Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody. J. Virol. 80: 1680-1687 [Abstract] [Full Text]  
  • Burton, D. R., Stanfield, R. L., Wilson, I. A. (2005). Antibody vs. HIV in a clash of evolutionary titans. Proc. Natl. Acad. Sci. USA 102: 14943-14948 [Abstract] [Full Text]  
  • Zhou, T., Hamer, D. H., Hendrickson, W. A., Sattentau, Q. J., Kwong, P. D. (2005). Interfacial metal and antibody recognition. Proc. Natl. Acad. Sci. USA 102: 14575-14580 [Abstract] [Full Text]  
  • Rao, S., Hu, S., McHugh, L., Lueders, K., Henry, K., Zhao, Q., Fekete, R. A., Kar, S., Adhya, S., Hamer, D. H. (2005). From the Cover: Toward a live microbial microbicide for HIV: Commensal bacteria secreting an HIV fusion inhibitor peptide. Proc. Natl. Acad. Sci. USA 102: 11993-11998 [Abstract] [Full Text]  
  • Qiao, Z.-S., Kim, M., Reinhold, B., Montefiori, D., Wang, J.-h., Reinherz, E. L. (2005). Design, Expression, and Immunogenicity of a Soluble HIV Trimeric Envelope Fragment Adopting a Prefusion gp41 Configuration. J. Biol. Chem. 280: 23138-23146 [Abstract] [Full Text]  
  • Decker, J. M., Bibollet-Ruche, F., Wei, X., Wang, S., Levy, D. N., Wang, W., Delaporte, E., Peeters, M., Derdeyn, C. A., Allen, S., Hunter, E., Saag, M. S., Hoxie, J. A., Hahn, B. H., Kwong, P. D., Robinson, J. E., Shaw, G. M. (2005). Antigenic conservation and immunogenicity of the HIV coreceptor binding site. JEM 201: 1407-1419 [Abstract] [Full Text]  
  • Lenz, O., Dittmar, M. T., Wagner, A., Ferko, B., Vorauer-Uhl, K., Stiegler, G., Weissenhorn, W. (2005). Trimeric Membrane-anchored gp41 Inhibits HIV Membrane Fusion. J. Biol. Chem. 280: 4095-4101 [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»