9th Conference on Retroviruses and Opportunistic Infections Seattle, Washington - February 24 -February 28, 2002

Conf Retroviruses Opportunistic Infect 2002 Feb 24-28;9:abstract no. L4
P. Kwong^1,4, S. Majeed^1,4, S.-H. Xiang², R. Gupta², L. Wang², M. Doyle³, D. Casper³, W. Hendrickson¹, J. Sodroski² and R. Wyatt*^2,4
1Columbia Univ., New York, NY; ²Dana-Farber Cancer Inst., Boston, MA; ³GlaxoSmithKline, King of Prussia, PA; and ⁴ NIAID Vaccine Res. Ctr., NIH, Bethesda, MD

BACKGROUND: Our goal was to better understand HIV-1 gp120 receptor interactions and function.

METHODS: We have analyzed the crystal structure of the HXBc2 core gp120 exterior envelope glycoprotein in ternary complex with the primary viral receptor, CD4, and a neutralizing antibody, 17b.

RESULTS: The structural analysis revealed a recessed CD4 binding site that spanned the 2 major domains of the gp120 glycoprotein. The CD4 binding site was characterized by several unusual cavities evident on the gp120 molecular surface. One of the gp120 cavities possessed critical contacts with the CD4 residue Phe 43, which was positioned at the neck of the cavity. This cavity is highly conserved and has virtually an identical relationship to the Phe 43 CD4 residue in the recently solved YU2 core gp120 crystal structure. The primary isolate YU2 core glycoprotein has essentially the same fold as the HXBc2 core, with amino acid and glycosylation variability predominantly localized to the gp120 outer domain. Trimer modeling of the 2 structures indicates that this variable surface is the region of the envelope spike most exposed to the immune system and to potential neutralizing antibodies. Analysis by titration microcalorimetry indicates that CD4 binding to gp120 dramatically decreases gp120 entropy and likely locks gp120 into a distinct conformation. Several structure-based mutants have been designed to lock gp120 into a state that mimics the low entropy, CD4-bound conformation. One such gp120 mutant, S375W, increases CD4 binding yet eliminates recognition by several CD4 binding site antibodies.

CONCLUSIONS: The identification of conformationally-fixed glycoproteins may provide unique molecules useful for the design of gp120-based vaccines and may provide insights for gp120-directed drug development.

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Copyright © 2002 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.