CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIB binding to the cell surface

Proc Natl Acad Sci U S A. 2014 May 13;111(19):E1960-9. doi: 10.1073/pnas.1322887111. Epub 2014 Apr 28.


CCR5 and CXCR4, the respective cell surface coreceptors of R5 and X4 HIV-1 strains, both form heterodimers with CD4, the principal HIV-1 receptor. Using several resonance energy transfer techniques, we determined that CD4, CXCR4, and CCR5 formed heterotrimers, and that CCR5 coexpression altered the conformation of both CXCR4/CXCR4 homodimers and CD4/CXCR4 heterodimers. As a result, binding of the HIV-1 envelope protein gp120IIIB to the CD4/CXCR4/CCR5 heterooligomer was negligible, and the gp120-induced cytoskeletal rearrangements necessary for HIV-1 entry were prevented. CCR5 reduced HIV-1 envelope-induced CD4/CXCR4-mediated cell-cell fusion. In nucleofected Jurkat CD4 cells and primary human CD4(+) T cells, CCR5 expression led to a reduction in X4 HIV-1 infectivity. These findings can help to understand why X4 HIV-1 strains infection affect T-cell types differently during AIDS development and indicate that receptor oligomerization might be a target for previously unidentified therapeutic approaches for AIDS intervention.

Keywords: FRET/BRET; chemokine receptors; oligomer formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors / metabolism
  • CD4 Antigens / chemistry
  • CD4 Antigens / metabolism*
  • Cell Fusion
  • Dimerization
  • Flow Cytometry
  • Fluorescence Resonance Energy Transfer
  • HEK293 Cells
  • HIV Envelope Protein gp120 / metabolism*
  • HIV Infections / metabolism*
  • HIV-1 / metabolism*
  • Humans
  • Jurkat Cells
  • Lim Kinases / metabolism
  • Protein Binding / physiology
  • Protein Structure, Quaternary
  • Receptors, CCR5 / chemistry
  • Receptors, CCR5 / metabolism*
  • Receptors, CXCR4 / chemistry
  • Receptors, CXCR4 / metabolism*
  • Th1 Cells / metabolism
  • Th1 Cells / virology
  • Th2 Cells / metabolism
  • Th2 Cells / virology


  • Actin Depolymerizing Factors
  • CCR5 protein, human
  • CD4 Antigens
  • CXCR4 protein, human
  • HIV Envelope Protein gp120
  • Receptors, CCR5
  • Receptors, CXCR4
  • LIMK1 protein, human
  • Lim Kinases