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Journal of Virology, October 2003, p. 10557-10565, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10557-10565.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Access of Antibody Molecules to the Conserved Coreceptor Binding Site on Glycoprotein gp120 Is Sterically Restricted on Primary Human Immunodeficiency Virus Type 1

Aran F. Labrijn,1,{dagger} Pascal Poignard,1 Aarti Raja,2 Michael B. Zwick,1 Karla Delgado,1 Michael Franti,1 James Binley,1 Veronique Vivona,1 Christoph Grundner,2 Chih-Chin Huang,3 Miro Venturi,3 Christos J. Petropoulos,4 Terri Wrin,4 Dimiter S. Dimitrov,5 James Robinson,6 Peter D. Kwong,3 Richard T. Wyatt,2,3 Joseph Sodroski,2,7,8 and Dennis R. Burton1,9*

Department of Immunology,1 Department of Molecular Biology, The Scripps Research Institute, La Jolla,9 ViroLogic, Inc., South San Francisco, California,4 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,2 Department of Pathology, Division of AIDS, Harvard Medical School,7 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts,8 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,3 Laboratory of Experimental and Computational Biology, National Cancer Institute-Frederick, National Institute of Health, Frederick, Maryland,5 Department of Pediatrics, Tulane University Medical Center, New Orleans, Louisiana6

Received 14 April 2003/ Accepted 9 July 2003

Anti-human immunodeficiency virus type 1 (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated the abilities of different forms (immunoglobulin G [IgG], Fab, and single-chain Fv) of X5 and other CD4i monoclonal antibodies to neutralize a range of primary HIV-1 isolates. Our results show that, for a number of isolates, the size of the neutralizing agent is inversely correlated with its ability to neutralize. Thus, the poor ability of CD4i-specific antibodies to neutralize primary isolates is due, at least in part, to steric factors that limit antibody access to the gp120 epitopes. Studies of temperature-regulated neutralization or fusion-arrested intermediates suggest that the steric effects are important in limiting the binding of IgG to the viral envelope glycoproteins after HIV-1 has engaged CD4 on the target cell membrane. The results identify hurdles in using CD4i epitopes as targets for antibody-mediated neutralization in vaccine design but also indicate that the CD4i regions could be efficiently targeted by small molecule entry inhibitors.

* Corresponding author. Mailing address: Scripps Research Institute, Department of Immunology (IMM2), 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9298. Fax: (858) 784-8360. E-mail: burton{at}scripps.edu.

{dagger} Present address: Genmab BV, 3584CK Utrecht, The Netherlands.

Journal of Virology, October 2003, p. 10557-10565, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10557-10565.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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