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Journal of Virology, December 2007, p. 12946-12953, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01260-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Monoclonal Fab Derived from a Human Nonimmune Phage Library Reveals a New Epitope on gp41 and Neutralizes Diverse Human Immunodeficiency Virus Type 1 Strains{triangledown}

Elena Gustchina,1 John M. Louis,1 Son N. Lam,2 Carole A. Bewley,2* and G. Marius Clore1*

Laboratories of Chemical Physics,1 Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-05202

Received 9 June 2007/ Accepted 18 September 2007

A monoclonal Fab (Fab 3674) selected from a human nonimmune phage library by panning against the chimeric construct NCCG-gp41 (which comprises an exposed coiled-coil trimer of gp41 N helices fused in the helical phase onto the minimal thermostable ectodomain of gp41) is described. Fab 3674 is shown to neutralize diverse laboratory-adapted B strains of human immunodeficiency virus type 1 (HIV-1) and primary isolates of subtypes A, B, and C in an Env-pseudotyped-virus neutralization assay, albeit with reduced potency (approximately 25-fold) compared to that of 2F5 and 4E10. Alanine scanning mutagenesis maps a novel epitope to a shallow groove on the N helices of gp41 that is exposed between two C helices in the fusogenic six-helix bundle conformation of gp41. Bivalent Fab 3674 and the C34 peptide (a potent fusion inhibitor derived from the C helix of gp41) are shown to act at similar stages of the fusion reaction and to neutralize HIV-1 synergistically, providing additional evidence that the epitope of Fab 3674 is new and distinct from the binding site of C34.

* Corresponding author. Mailing address for G. Marius Clore: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0820. Phone: (301) 496 0782. Fax: (301) 496 0825. E-mail: mariusc{at}mail.nih.gov. Mailing address for Carole A. Bewley: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0820. Phone: (301) 594 5187. Fax: (301) 402 0008. E-mail: caroleb{at}mail.nih.gov

{triangledown} Published ahead of print on 26 September 2007.

Journal of Virology, December 2007, p. 12946-12953, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01260-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gustchina, E., Bewley, C. A, Clore, G. M. (2008). Sequestering of the Prehairpin Intermediate of gp41 by Peptide N36Mut(e,g) Potentiates the Human Immunodeficiency Virus Type 1 Neutralizing Activity of Monoclonal Antibodies Directed against the N-Terminal Helical Repeat of gp41. J. Virol. 82: 10032-10041 [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]  


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