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Journal of Virology, March 2004, p. 3155-3161, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.3155-3161.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Long Third Complementarity-Determining Region of the Heavy Chain Is Important in the Activity of the Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5

Michael B. Zwick,1* H. Kiyomi Komori,1 Robyn L. Stanfield,2,3 Sarah Church,1 Meng Wang,1 Paul W. H. I. Parren,4 Renate Kunert,5 Hermann Katinger,5 Ian A. Wilson,2,3 and Dennis R. Burton1*

Departments of Immunology,1 Molecular Biology,2 The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037,3 Genmab, 3584 CK Utrecht, The Netherlands,4 Institute for Applied Microbiology, University of Natural Resources, Vienna, Austria5

Received 9 July 2003/ Accepted 20 November 2003

The human monoclonal antibody 2F5 neutralizes primary human immunodeficiency virus type 1 (HIV-1) with rare breadth and potency. A crystal structure of a complex of 2F5 and a peptide corresponding to its core epitope on gp41, ELDKWAS, revealed that the peptide interacts with residues at the base of the unusually long (22-residue) third complementarity-determining region of the heavy chain (CDR H3) but not the apex. Here, we perform alanine-scanning mutagenesis across CDR H3 and make additional substitutions of selected residues to map the paratope of Fab 2F5. Substitution of residues from the base of the H3 loop or from CDRs H1, H2, and L3, which are proximal to the peptide, significantly diminished the affinity of Fab 2F5 for gp41 and a short peptide containing the 2F5 core motif. However, nonconservative substitutions to a phenylalanine residue at the apex of the H3 loop also markedly decreased 2F5 binding to both gp41 and the peptide, suggesting that recognition of the core epitope is crucially dependent on features at the apex of the H3 loop. Furthermore, substitution at the apex of the H3 loop had an even more pronounced effect on the neutralizing activity of 2F5 against three sensitive HIV-1. These observations present a challenge to vaccine strategies based on peptide mimics of the linear epitope.

* Corresponding author. Mailing address: The Scripps Research Institute, Department of Immunology (IMM-2), 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9298 (Dennis R. Burton) or (858) 784-2833 (Michael B. Zwick). Fax: (858) 784-8360. E-mail: burton{at}scripps.edu or zwick{at}scripps.edu.

Journal of Virology, March 2004, p. 3155-3161, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.3155-3161.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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