CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIB binding to the cell surface.
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.
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain;
Laura
L
Martínez-Muñoz
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain;
Rubén
R
Barroso
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain;
Sunniva Y
SY
Dyrhaug
Department of Biochemistry and Molecular Biology, Universidad de Barcelona, E-08028, Barcelona, Spain;
Gemma
G
Navarro
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain;
Pilar
P
Lucas
Department of Immunology, Hospital General Universitario Gregorio Marañón, E-28007, Madrid, Spain; andCellomics Unit, Centro Nacional de Investigaciones Cardiovasculares, E-28029, Madrid, Spain.
Silvia F
SF
Soriano
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain;
Beatriz
B
Vega
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain;
Coloma
C
Costas
Department of Immunology, Hospital General Universitario Gregorio Marañón, E-28007, Madrid, Spain; and.
M Ángeles
MÁ
Muñoz-Fernández
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain;
César
C
Santiago
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain;
José Miguel
JM
Rodríguez Frade
Department of Biochemistry and Molecular Biology, Universidad de Barcelona, E-08028, Barcelona, Spain;
Rafael
R
Franco
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, E-28049, Madrid, Spain; mmellado@cnb.csic.es.
Mario
M
Mellado
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D002459:Cell Fusion; D019281:Dimerization; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D054461:Lim Kinases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D020836:Protein Structure, Quaternary; D019713:Receptors, CCR5 / Q000737:chemistry / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism / Q000821:virology; D018418:Th2 Cells / Q000378:metabolism / Q000821:virology
D051339:Actin Depolymerizing Factors; C584933:CCR5 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C515892:LIMK1 protein, human; D054461:Lim Kinases
FRET/BRET; chemokine receptors; oligomer formation