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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

Hua-Xin Liao,1* S. Munir Alam,1 John R. Mascola,2 James Robinson,3 Benjiang Ma,1 David C. Montefiori,4 Maria Rhein,1 Laura L. Sutherland,1 Richard Scearce,1 and Barton F. Haynes1

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-rgp12089.6 and A32-rgp120BaL complexes and have compared their immunogenicities to those of uncomplexed recombinant gp120BaL (rgp120BaL) and rgp12089.6. A32-rgp12089.6 and A32-rgp120BaL 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-rgp12089.6 induced antibodies that neutralized 6 out of 11 HIV-1 isolates, while rgp12089.6 alone induced antibodies that neutralized 4 out of 11 HIV-1 isolates. A32-rgp120BaL complexes induced antibodies that neutralized 4 out of 14 HIV-1 isolates while, surprisingly, non-cross-linked rgp120BaL 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 rgp120BaL 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.

* Corresponding author. Mailing address: Box 3258 Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-5858. Fax: (919) 681-8992. E-mail: liao0001{at}mc.duke.edu.

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.



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