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Journal of Virology, October 2005, p. 12148-12163, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12148-12163.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Comparing Antigenicity and Immunogenicity of Engineered gp120

Suganya Selvarajah,1 Bridget Puffer,2 Ralph Pantophlet,1 Mansun Law,1 Robert W. Doms,2 and Dennis R. Burton1*

Departments of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037,1 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 191042

Received 11 May 2005/ Accepted 3 July 2005

We have engineered monomeric gp120 in such a way as to favorably present the conserved epitope for the broadly neutralizing antibody b12 while lowering the exposure of epitopes recognized by some weakly neutralizing and nonneutralizing antibodies. The work presented here describes the immune response in rabbits immunized with two prototype, engineered gp120s to explore the relationship between antigenicity and immunogenicity for these mutants. The GDMR gp120 mutant (residues 473 to 476 on gp120 altered from GDMR to AAAA) has a series of substitutions on the edge of the CD4 binding site (CD4bs), and the mCHO gp120 mutant has seven extra glycans relative to the wild-type protein. Importantly, serum mapping showed that both mutants did not elicit antibodies against a number of epitopes that had been targeted for dampening. The sera from rabbits immunized with the GDMR gp120 mutant neutralized some primary viruses at levels somewhat better than the wild-type gp120 immune sera as a result of an increased elicitation of anti-V3 antibodies. Unlike wild-type gp120 immune sera, GDMR gp120 immune sera failed to neutralize HXBc2, a T-cell line adapted (TCLA) virus. This was associated with loss of CD4bs/CD4-induced antibodies that neutralize TCLA but not primary viruses. The mCHO gp120 immune sera did not neutralize primary viruses to any significant degree, reflecting the masking of epitopes of even weakly neutralizing antibodies without eliciting b12-like antibodies. These results show that antibody responses to multiple epitopes on gp120 can be dampened. More precise focusing to a neutralizing epitope will likely require several iterations comparing antigenicity and immunogenicity of engineered proteins.

* Corresponding author. Mailing address: The Scripps Research Institute, Department of Immunology (IMM-2), 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-9298. Fax: (858) 784-8360. E-mail: burton{at}scripps.edu.

Journal of Virology, October 2005, p. 12148-12163, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12148-12163.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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