HIV Envelope-CXCR4 Signaling Activates Cofilin to Overcome Cortical Actin Restriction in Resting CD4 T Cells

Yoder, Alyson; Yu, Dongyang; Li, Dong; Iyer, Subashini R.; Xu, Xuehua; Kelly, Jeremy; Liu, Juan; Wang, Weifeng; Vorster, Paul J.; Agulto, Liane; Stephany, David; Cooper, James N.; Marsh, Jeanne C.; Wu, Yuntao

doi:10.1016/j.cell.2008.06.036

Cited by 262 publications

(594 citation statements)

References 45 publications

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“…One of the earliest events in HIV-1 NL4-3 infection is CXCR4-mediated activation of LIMK1 and cofilin phosphorylation; these events increase cortical actin dynamics in resting CD4 + T cells (27,32), a process that might require CXCR4 dimerization (53). Our data confirm these observations, because we detected rapid gp120 IIIB -mediated actin polymerization following transient LIMK1 activation and cofilin inactivation.…”

Section: Discussionsupporting

confidence: 81%

“…gp120-triggered actin polymerization involves transient LIMK1 activation, which phosphorylates and, thus, inactivates the actin depolymerization factor cofilin (27,32). Cofilin phosphorylation by LIMK1 is also critical for CXCL12-induced actin reorganization and chemotactic responses in T lymphocytes (29).…”

Section: Ccr5 Expression In Cd4/cxcr4 Cells Blocks Gp120 Iiib -Inducementioning

confidence: 99%

“…Shortly after binding to its receptors on resting CD4 + T cells, gp120 promotes rapid, transient polymerization of cortical actin (27,28), a process that mimics the chemotactic response initiated by CXCL12 binding to CXCR4 (27)(28)(29). We tested the effect of gp120 IIIB on actin in 293T cells expressing CD4/CXCR4 or CD4/CXCR4/CCR5.…”

Section: Ccr5 Expression Alters Cxcr4/cxcr4 Homodimeric and Cd4/cxcr4mentioning

confidence: 99%

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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: 81%

Section: Ccr5 Expression In Cd4/cxcr4 Cells Blocks Gp120 Iiib -Inducementioning

confidence: 99%

Section: Ccr5 Expression Alters Cxcr4/cxcr4 Homodimeric and Cd4/cxcr4mentioning

confidence: 99%

See 1 more Smart Citation

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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“…More recently, Env was found to trigger actin rearrangement through G␣ i -mediated CXCR4 signaling or G␣ q -mediated CCR5 signaling. These events were shown to be critical at both entry and postentry stages of HIV-1 replication, particularly in resting T cells (20)(21)(22)(23). We have obtained evidence that CCR5 exists in multiple cell surface conformations that differ in their antigenicity, i.e., their reactivity with specific monoclonal antibodies (MAbs) (24).…”

mentioning

confidence: 90%

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Berro

Yasmeen

Abrol

et al. 2013

J Virol

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Small-molecule CCR5 inhibitors such as vicriviroc (VVC) and maraviroc (MVC) are allosteric modulators that impair HIV-1 entry by stabilizing a CCR5 conformation that the virus recognizes inefficiently. Viruses resistant to these compounds are able to bind the inhibitor-CCR5 complex while also interacting with the free coreceptor. CCR5 also interacts intracellularly with G proteins, as part of its signal transduction functions, and this process alters its conformation. Here we investigated whether the action of VVC against inhibitor-sensitive and -resistant viruses is affected by whether or not CCR5 is coupled to G proteins such as G␣ i . Treating CD4 ؉ T cells with pertussis toxin to uncouple the G␣ i subunit from CCR5 increased the potency of VVC against the sensitive viruses and revealed that VVC-resistant viruses use the inhibitor-bound form of G␣ i -coupled CCR5 more efficiently than they use uncoupled CCR5. Supportive evidence was obtained by expressing a signaling-deficient CCR5 mutant with an impaired ability to bind to G proteins, as well as two constitutively active mutants that activate G proteins in the absence of external stimuli. The implication of these various studies is that the association of intracellular domains of CCR5 with the signaling machinery affects the conformation of the external and transmembrane domains and how they interact with small-molecule inhibitors of HIV-1 entry.

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“…The mammalian cofilin-1 is the most ubiquitous and involved in viral infection. HIV-1 inactivates cofilin to optimize immune evasion, replication, release, and cell-cell transmission [19,20,21]. We have previously reported that cofilin-1 play a crucial role in mediating biphasic F-actin dynamics to facilitate HSV-1 infection and replication [22,23].…”

Section: Introductionmentioning

confidence: 99%

Cofilin-1 is involved in regulation of actin reorganization during influenza A virus assembly and budding

Liu

Xiang

Guo

et al. 2014

Biochemical and Biophysical Research Communications

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Influenza A virus (IAV) assembly and budding on host cell surface plasma membrane requires actin cytoskeleton reorganization. The underlying molecular mechanism involving actin reorganization remains unclarified. In this study, we found that the natural antiviral compound petagalloyl glucose (PGG) inhibits F-actin reorganization in the host cell membrane during the late stage of IAV infection, which are associated with the suppression of total cofilin-1 level and its phosphorylation. Knock-down of cofilin-1 reduces viral yields. These findings provide the first evidence that cofilin-1 plays an important role in regulating actin reorganization during IAV assembly and budding.

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HIV Envelope-CXCR4 Signaling Activates Cofilin to Overcome Cortical Actin Restriction in Resting CD4 T Cells

Cited by 262 publications

References 45 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

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Cofilin-1 is involved in regulation of actin reorganization during influenza A virus assembly and budding

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HIV Envelope-CXCR4 Signaling Activates Cofilin to Overcome Cortical Actin Restriction in Resting CD4 T Cells

Cited by 262 publications

References 45 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

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Cofilin-1 is involved in regulation of actin reorganization during influenza A virus assembly and budding

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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