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

Jasminka Sterjovski, Melissa J. Churchill, Michael Roche, Anne Ellett, William Farrugia, Steven L. Wesselingh, Anthony L Cunningham, Paul A. Ramsland, Paul R. Gorry

Research output: Contribution to journalArticleResearchpeer-review

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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