CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity

Jasminka Sterjovski, Melissa Churchill, Michael Roche, Anne Ellett, William Farrugia, Steven Wesselingh, Anthony Cunningham, Paul Ramsland, Paul Gorry

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    23 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)418-428
    Number of pages11
    JournalVirology
    Volume410
    Issue number2
    DOIs
    Publication statusPublished - 20 Feb 2011

    Keywords

    • CD4
    • CD4bs
    • Fusogenicity
    • Gp120
    • HIV-1

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    Sterjovski, J., Churchill, M., Roche, M., Ellett, A., Farrugia, W., Wesselingh, S., Cunningham, A., Ramsland, P., & Gorry, P. (2011). CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity. Virology, 410(2), 418-428. https://doi.org/10.1016/j.virol.2010.12.010