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Updated: Jun 5, 2026
Conformational Evaluation of HIV-1 Trimeric Envelope Glycoproteins Using a Cell-based ELISA Assay
Published on: September 14, 2014
CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity
Jasminka Sterjovski1, Melissa J Churchill, Michael Roche
1Center for Virology, Burnet Institute, Melbourne, Victoria, Australia.
Abstract:
CD4-binding site (CD4bs) alterations in gp120 contribute to different pathophysiological phenotypes of CCR5-using (R5) HIV-1 strains, but the potential structural basis is unknown. Here, we characterized functionally diverse R5 envelope (Env) clones (n=16) to elucidate potential structural alterations within the gp120 CD4bs that influence Env function. Initially, we showed that the magnitude of gp120-CD4-binding correlates with increased fusogenicity and reduced CD4 dependence. Analysis of three-dimensional gp120 structural models revealed two CD4bs variants, D279 and N362, that were associated with reduced CD4 dependence. Further structural analysis showed that a wider aperture of the predicted CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop, was associated with amino acid alterations within V5 and correlated with increased gp120-CD4 binding and increased fusogenicity. Our results provide evidence that the gp120 V5 loop may alter CD4bs conformation and contribute to increased gp120-CD4 interactions and Env fusogenicity.
Insights
Alterations in the HIV gp120 CD4-binding site influence viral function. The V5 loop may change the CD4-binding site conformation, enhancing gp120-CD4 interactions and viral fusion.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Alterations in the CD4-binding site (CD4bs) of gp120 are linked to distinct pathophysiological phenotypes in CCR5-using (R5) HIV-1 strains.
- The structural basis for these CD4bs alterations and their functional consequences remains largely unexplored.
Purpose of the Study:
- To investigate potential structural alterations within the gp120 CD4bs of R5 HIV-1 strains.
- To elucidate how these structural changes influence envelope (Env) protein function, including CD4 binding and viral fusion.
Main Methods:
- Characterization of 16 functionally diverse R5 HIV-1 Env clones.
- Analysis of three-dimensional gp120 structural models.
- Correlation of structural features with gp120-CD4 binding, CD4 dependence, and Env fusogenicity.
Main Results:
- Increased gp120-CD4 binding correlated with enhanced fusogenicity and reduced CD4 dependence.
- Specific CD4bs variants (D279 and N362) were associated with reduced CD4 dependence.
- A wider CD4bs cavity, influenced by the V5 loop and V1V2 stem, correlated with increased gp120-CD4 binding and fusogenicity.
Conclusions:
- The gp120 V5 loop plays a role in modulating CD4bs conformation.
- Alterations in the V5 loop can enhance gp120-CD4 interactions and Env fusogenicity, contributing to R5 HIV-1 pathogenesis.
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