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Journal of Virology, May 2004, p. 5270-5278, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5270-5278.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Immunogenicity of Constrained Monoclonal Antibody A32-Human Immunodeficiency Virus (HIV) Env gp120 Complexes Compared to That of Recombinant HIV Type 1 gp120 Envelope Glycoproteins

Duke Human Vaccine Institute and Department of Medicine,¹ Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710,⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,² Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana 70112³

Received 29 September 2003/ Accepted 16 January 2004

One strategy for the generation of broadly reactive neutralizing antibodies (NA) against human immunodeficiency virus type 1 (HIV-1) primary isolates is to use immunogens that have constrained HIV-1 envelope gp120 conformations reflective of triggered envelope on the surface of virions. A major change in gp120 following binding to CD4 is the enhanced exposure of the CCR5 binding site. One inducer of CCR5 binding site epitopes on gp120 is the human anti-gp120 monoclonal antibody, A32. We have made cross-linked A32-rgp120_89.6 and A32-rgp120_BaL complexes and have compared their immunogenicities to those of uncomplexed recombinant gp120_BaL (rgp120_BaL) and rgp120_89.6. A32-rgp120_89.6 and A32-rgp120_BaL complexes had stable induced CCR5 binding site expression compared to that of uncomplexed rgp120s. However, the A32-rgp120 complexes had similar capacities in guinea pigs for induction of NA against HIV-1 primary isolates versus that of rgp120 alone. A32-rgp120_89.6 induced antibodies that neutralized 6 out of 11 HIV-1 isolates, while rgp120_89.6 alone induced antibodies that neutralized 4 out of 11 HIV-1 isolates. A32-rgp120_BaL complexes induced antibodies that neutralized 4 out of 14 HIV-1 isolates while, surprisingly, non-cross-linked rgp120_BaL induced antibodies that neutralized 9 out of 14 (64%) HIV-1 isolates. Thus, stable enhanced expression of the coreceptor binding site on constrained gp120 is not sufficient for inducing broadly neutralizing anti-HIV-1 NA. Moreover, the ability of HIV-1 rgp120_BaL to induce antibodies that neutralized 60% of subtype B HIV-1 isolates warrants consideration of using HIV-1 BaL as a starting point for immunogen design for subtype B HIV-1 experimental immunogens.

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