Constitutive association of cell surface CCR5 and CXCR4 in the presence of CD4

Wang, Jinhai; Alvarez, Raymond; Roderiquez, Gregory; Guan, Ennan; Norcross, Michael A.

doi:10.1002/jcb.20161

Cited by 27 publications

(25 citation statements)

References 37 publications

(30 reference statements)

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“…We determined viral infection by using the entire population of CCR5-transfected CD4 + primary T or Jurkat CD4 + cells (40% transfection efficiency), whose expression of CCR5 resembled that of activated primary T cells and Th1 cells (54,55), whereas our analysis of the mechanism involving actin polymerization was restricted to CCR5 + cells. Our data concur with a report that, in NIH 3T3 cells coexpressing CD4, CXCR4, and CCR5, the T-tropic HIV-1 isolate HCF was less infective than in CCR5-negative cells (56); another study showed lower infectivity of primary X4 viruses (ELI 1 and K4) in HeLa-CD4 cells when CCR5 was coexpressed (57). HIV-1 NL4-3 replication is also higher in peripheral blood mononuclear cells from CCR5-Δ32 heterozygous donors than from controls (58).…”

Section: Discussionsupporting

confidence: 93%

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

Martínez-Muñoz

Barroso

Dyrhaug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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 gp120 IIIB 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.chemokine receptors | oligomer formation | FRET/BRET F or HIV-1 to enter a target cell, the viral envelope glycoprotein gp120 must interact with a set of cell surface molecules that include the primary receptor, CD4 (1), and a chemokine receptor (CCR5 or CXCR4) that acts as a coreceptor (2, 3). These molecules form CD4/chemokine receptor complexes, as deduced from coprecipitation data for CXCR4 or CCR5 with CD4 (4-8).Most HIV-1 variants isolated from newly infected individuals use CCR5 and CD4 to enter host cells; these M-tropic R5 strains are predominant in acute and asymptomatic phases of HIV infection. CD4 + T helper type 1 (Th1) cells, which express high CCR5 levels (9, 10), are implicated in maintaining asymptomatic status (11, 12). The "viral shift" from R5 to T-tropic X4 HIV-1 strains correlates with AIDS progression (13,14). X4 strains infect mainly CD4 + Th2 cells, which express little CCR5 and whose CXCR4 levels resemble those of Th1 cells (15,16), which suggests that cell susceptibility to HIV-1 infection depends on the CD4/coreceptor ratio and on receptor levels during cell activation and/or differentiation (17). CXCR4 and CCR5 are present as homodimers and heterodimers at the plasma membrane (18)(19)(20). In addition, gp120-mediated CD4/CXCR4 and CD4/CCR5 association and clustering is reported (21-23). Nonetheless, little is known of how CCR5 expression influences the CD4/CXCR4 interaction, or of the molecular basis that underlies the differences in X4 strains infection relative to CCR5 levels at the cell surface.Here, we identify CD4/CXCR4/CCR5 oligomers at the cell membrane, even in the absence of ligands. CCR5 expression in these complexes modifies the heterodimeric CD4/CXCR4 conformation and blocks gp120 IIIB binding, without altering binding of the CXCR4 ligand CXCL12 and its subsequent signaling. gp120 IIIB -triggered LIMK1 activation, cofilin dephosphorylation, and the actin cytoskeleton rearrangement necessary for cell-cell fusion were impeded in CD4/CXCR4/CCR5-expressing c...

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Section: Discussionsupporting

confidence: 93%

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

Martínez-Muñoz

Barroso

Dyrhaug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The constitutive association between CD4 and CXCR4 (Lapham et al, 1999;Wang et al, 2004) is augmented after gp120-CD4 engagement. Remarkably, functional FL-moesin strongly enhanced the HIV-1 gp120-induced CD4-CXCR4 interaction and co-clustering at one pole of the lymphocyte, whereas dominant-negative N-moesin or moesin knockdown impaired this association.…”

Section: Discussionmentioning

confidence: 99%

“…The constitutive CD4-CXCR4 association (Lapham et al, 1999;Wang et al, 2004) was enhanced after gp120/CD4 engagement in CEM T cells ( Fig. 6A; supplementary material Fig.…”

Section: Hiv-1 Env-mediated Moesin Activation Promotes Cd4-cxcr4 Clusmentioning

confidence: 99%

Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes

Barrero-Villar

Cabrero

Gordon-Alonso

et al. 2009

Journal of Cell Science

115

210

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The human immunodeficiency virus 1 (HIV-1) envelope regulates the initial attachment of viral particles to target cells through its association with CD4 and either CXCR4 or CCR5. Although F-actin is required for CD4 and CXCR4 redistribution, little is known about the molecular mechanisms underlying this fundamental process in HIV infection. Using CD4+ CXCR4+ permissive human leukemic CEM T cells and primary lymphocytes, we have investigated whether HIV-1 Env might promote viral entry and infection by activating ERM (ezrin-radixin-moesin) proteins to regulate F-actin reorganization and CD4/CXCR4 co-clustering. The interaction of the X4-tropic protein HIV-1 gp120 with CD4 augments ezrin and moesin phosphorylation in human permissive T cells, thereby regulating ezrin-moesin activation. Moreover, the association and clustering of CD4-CXCR4 induced by HIV-1 gp120 requires moesin-mediated anchoring of actin in the plasma membrane. Suppression of moesin expression with dominant-negative N-moesin or specific moesin silencing impedes reorganization of F-actin and HIV-1 entry and infection mediated by the HIV-1 envelope protein complex. Therefore, we propose that activated moesin promotes F-actin redistribution and CD4-CXCR4 clustering and is also required for efficient X4-tropic HIV-1 infection in permissive lymphocytes.

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“…Surface expression levels of CXCR4 have been shown to be regulated by several different mechanisms, including ubiquitination, 48 cytokine stimulation, 49,50 and by the formation of heterodimers. 48 Notably, both CCR2 and CCR5, which were downregulated in the absence of Mef2c, have been demonstrated to form dimers with CXCR4, leading to increased cell surface expression and/or increased activity, 51,52 suggesting a mechanism by which surface levels of CXCR4 may be differentially regulated in cells expressing Mef2c.…”

Section: How May Mef2c Regulate Homing and Invasiveness?mentioning

confidence: 99%

Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C

Schwieger

Schüler

Förster

et al. 2009

Blood

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Constitutive association of cell surface CCR5 and CXCR4 in the presence of CD4

Cited by 27 publications

References 37 publications

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes

Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C

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Constitutive association of cell surface CCR5 and CXCR4 in the presence of CD4

Cited by 27 publications

References 37 publications

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIBbinding to the cell surface

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIBbinding to the cell surface

Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes

Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C

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CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface