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
Google Scholar
Right arrow Articles by Bryson, S.
Right arrow Articles by Pai, E. F.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bryson, S.
Right arrow Articles by Pai, E. F.

 Previous Article  |  Next Article 

Journal of Virology, November 2009, p. 11862-11875, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01604-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Crystallographic Definition of the Epitope Promiscuity of the Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5: Vaccine Design Implications{triangledown}

Steve Bryson,1,3,{dagger} Jean-Philippe Julien,1,{dagger} Rosemary C. Hynes,1 and Emil F. Pai1,2,3*

Departments of Biochemistry,1 Medical Biophysics and Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8,2 Ontario Cancer Institute/Princess Margaret Hospital, Division of Cancer Genomics and Proteomics, 101 College Street, MaRS/TMDT, Toronto, Ontario, Canada M5G 1L73

Received 2 August 2009/ Accepted 25 August 2009

The quest to create a human immunodeficiency virus type 1 (HIV-1) vaccine capable of eliciting broadly neutralizing antibodies against Env has been challenging. Among other problems, one difficulty in creating a potent immunogen resides in the substantial overall sequence variability of the HIV envelope protein. The membrane-proximal region (MPER) of gp41 is a particularly conserved tryptophan-rich region spanning residues 659 to 683, which is recognized by three broadly neutralizing monoclonal antibodies (bnMAbs), 2F5, Z13, and 4E10. In this study, we first describe the variability of residues in the gp41 MPER and report on the invariant nature of 15 out of 25 amino acids comprising this region. Subsequently, we evaluate the ability of the bnMAb 2F5 to recognize 31 varying sequences of the gp41 MPER at a molecular level. In 19 cases, resulting crystal structures show the various MPER peptides bound to the 2F5 Fab'. A variety of amino acid substitutions outside the 664DKW666 core epitope are tolerated. However, changes at the 664DKW666 motif itself are restricted to those residues that preserve the aspartate's negative charge, the hydrophobic alkyl-{pi} stacking arrangement between the β-turn lysine and tryptophan, and the positive charge of the former. We also characterize a possible molecular mechanism of 2F5 escape by sequence variability at position 667, which is often observed in HIV-1 clade C isolates. Based on our results, we propose a somewhat more flexible molecular model of epitope recognition by bnMAb 2F5, which could guide future attempts at designing small-molecule MPER-like vaccines capable of eliciting 2F5-like antibodies.

* Corresponding author: Mailing address: Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Phone: (416) 978-7015. Fax: (416) 978-8548. E-mail: pai{at}hera.med.utoronto.ca

{triangledown} Published ahead of print on 9 September 2009.

{dagger} S.B. and J.-P.J. contributed equally to the manuscript.

Journal of Virology, November 2009, p. 11862-11875, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01604-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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