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Stable exposure of the coreceptor-binding site in a CD4-independent HIV-1 envelope protein
Journal article   Open access   Peer reviewed

Stable exposure of the coreceptor-binding site in a CD4-independent HIV-1 envelope protein

Trevor L. Hoffman, Celia C. LaBranche, Wentao Zhang, Gabriella Canziani, James Robinson, Irwin Chaiken, James A. Hoxie and Robert W. Doms
Proceedings of the National Academy of Sciences - PNAS, v 96(11), pp 6359-6364
25 May 1999
DOI: https://doi.org/10.1073/pnas.96.11.6359
PMID: 10339592
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1073/pnas.96.11.6359View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Biological Sciences
We recently derived a CD4-independent virus from HIV-1/IIIB, termed IIIBx, which interacts directly with the chemokine receptor CXCR4 to infect cells. To address the underlying mechanism, a cloned Env from the IIIBx swarm (8x) was used to produce soluble gp120. 8x gp120 bound directly to cells expressing only CXCR4, whereas binding of IIIB gp120 required soluble CD4. Using an optical biosensor, we found that CD4-induced (CD4i) epitopes recognized by mAbs 17b and 48d were more exposed on 8x than on IIIB gp120. The ability of 8x gp120 to bind directly to CXCR4 and to react with mAbs 17b and 48d in the absence of CD4 indicated that this gp120 exists in a partially triggered but stable state in which the conserved coreceptor-binding site in gp120, which overlaps with the 17b epitope, is exposed. Substitution of the 8x V3 loop with that from the R5 virus strain BaL resulted in an Env (8x-V3BaL) that mediated CD4-independent CCR5-dependent virus infection and a gp120 that bound to CCR5 in the absence of CD4. Thus, in a partially triggered Env protein, the V3 loop can change the specificity of coreceptor use but does not alter CD4 independence, indicating that these properties are dissociable. Finally, IIIBx was more sensitive to neutralization by HIV-positive human sera, a variety of anti-IIIB gp120 rabbit sera, and CD4i mAbs than was IIIB. The sensitivity of this virus to neutralization and the stable exposure of a highly conserved region of gp120 suggest new strategies for the development of antibodies and small molecule inhibitors to this functionally important domain.

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Collaboration types
Domestic collaboration
Web of Science research areas
Virology
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