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Journal of Virology, June 2007, p. 5579-5593, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02500-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Characterization of Human Immunodeficiency Virus Type 1 Monomeric and Trimeric gp120 Glycoproteins Stabilized in the CD4-Bound State: Antigenicity, Biophysics, and Immunogenicity{triangledown}

Barna Dey,1 Marie Pancera,1 Krisha Svehla,1 Yuuei Shu,1 Shi-Hua Xiang,2 Jeffrey Vainshtein,2 Yuxing Li,1 Joseph Sodroski,2 Peter D. Kwong,1 John R. Mascola,1 and Richard Wyatt1*

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Dana-Farber Cancer Institute, Boston, Massachusetts 021152

Received 13 November 2006/ Accepted 23 February 2007

The human immunodeficiency virus type 1 exterior gp120 envelope glycoprotein is highly flexible, and this flexibility may contribute to the inability of monomeric gp120 immunogens to elicit broadly neutralizing antibodies. We previously showed that an S375W modification of a critical interfacial cavity central to the primary receptor binding site, the Phe43 cavity, stabilizes gp120 into the CD4-bound state. However, the immunological effects of this cavity-altering replacement were never tested. Subsequently, we screened other mutations that, along with the S375W alteration, might further stabilize the CD4-bound state. Here, we define a selected second cavity-altering replacement, T257S, and analyze the double mutations in several gp120 envelope glycoprotein contexts. The gp120 glycoproteins with the T257S-plus-S375W double mutation (T257S+S375W) have a superior antigenic profile compared to the originally identified single S375W replacement in terms of enhanced recognition by the broadly neutralizing CD4 binding-site antibody b12. Isothermal titration calorimetry measuring the entropy of the gp120 interaction with CD4 indicated that the double mutant was also stabilized into the CD4-bound state, with increasing relative fixation between core, full-length monomeric, and full-length trimeric versions of gp120. A significant increase in gp120 affinity for CD4 was also observed for the cavity-filling mutants relative to wild-type gp120. The most conformationally constrained T257S+S375W trimeric gp120 proteins were selected for immunogenicity analysis in rabbits and displayed a trend of improvement relative to their wild-type counterparts in terms of eliciting neutralizing antibodies. Together, the results suggest that conformational stabilization may improve the ability of gp120 to elicit neutralizing antibodies.

* Corresponding author. Mailing address: Vaccine Research Center, National Institutes of Health, 40 Convent Drive, Rm. 4512, Bethesda, MD 20892. Phone: (301) 594-8690. Fax: (301) 480-0274. E-mail: richardwyatt{at}nih.gov

{triangledown} Published ahead of print on 14 March 2007.

Journal of Virology, June 2007, p. 5579-5593, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02500-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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