Multiple nonfunctional alleles of CCR5 are frequent in various human populations

Blanpain, Cédric; Lee, Benhur; Tackoen, Marie; Puffer, Bridget A.; Boom, Alain; Libert, Frédérick; Sharron, Mathew; Wittamer, Valérie; Vassart, Gilbert; Doms, Robert W.; Parmentier, Marc

doi:10.1182/blood.v96.5.1638

Cited by 94 publications

(30 citation statements)

References 56 publications

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“…Indeed, we found that both MIP-1b and 125 I-MIP-1b bound CCR1 with a higher or similar anity than did a number of more recognized CCR1 ligands such as MCP-3, MIP-1d or HCC-1. That being said, the anity MIP-1b for CCR1 was 5 ± 10 fold lower than what is reported for CCR5 (1 ± 2 nM; (Raport et al, 1996;Blanpain et al, 2000)). In [ 35 S]GTPgS exchange assays in HL-60(Rx) membranes, MIP-1b was a very weak agonist and was essentially inactive in stimulating calcium signalling or chemotaxis in whole cells.…”

Section: Discussionmentioning

confidence: 54%

“…These concentrations of MIP-1b are quite high relative to the eective concentrations of MIP-1a and MPIF-1 required to activate CCR1 and it is not known if these levels of MIP-1b are physiologically relevant. Nevertheless, these concentrations of MIP-1b are in the range required to ux (Blanpain et al, 2000), tyrosine kinase activation (Ganju et al, 1998) and stimulation of GTPgS exchange ( Figure 6).…”

Section: Discussionmentioning

confidence: 98%

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Pharmacological characterization of the chemokine receptor, hCCR1 in a stable transfectant and differentiated HL‐60 cells: antagonism of hCCR1 activation by MIP‐1β

Chou¹,

Fine²,

Pugliese-Sivo³

et al. 2002

British J Pharmacology

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1 C-C chemokine receptor-1 (CCR1) has been implicated in mediating a variety of in¯ammatory conditions including multiple sclerosis and organ rejection. Although originally referred to as the MIP-1a/RANTES receptor, CCR1 is quite promiscuous and can be activated by numerous chemokines. 2 We used radioligand binding and [ 35 S]-GTPgS exchange assays in membranes from a cell line transfected to express CCR1 (Ba/F3-hCCR1) to characterize a panel of chemokines (HCC-1, MIP1a, MIP-1b, MIP-1d, MPIF-1, MCP-2, MCP-3, and RANTES) as CCR1 ligands. In this recombinant model, these chemokines displaced 125 I-MIP-1a with a wide range of potencies and, with the exception of MCP-2, acted as full agonists in stimulating [ 35 S]-GTPgS exchange. 3 We then assessed the utility of HL-60 cells cultured with known di erentiating agents (PMA, DMSO, dibutyryl-cAMP or retinoic acid) for investigating CCR1 pharmacology. In [ 35 S]-GTPgS exchange assays, membranes from cells cultured with retinoic acid (4 ± 6 days) were the most responsive to activation by MIP-1a and MPIF-1. FACS analysis and comparative pharmacology con®rmed that these activities were mediated by CCR1. HCC-1, haemo®ltrate CC chemokine 1; IP-10, interferon-inducible protein of 10 kDa; I-TAC, interferoninducible T cell a chemoattractant; IL-8, interleukin-8; MIP-1a, macrophage in¯ammatory protein-1a; MIP-1b, macrophage in¯ammatory protein-1b; MIP-1d, macrophage in¯ammatory protein-1d; MCP-1, MCP-2, MCP-3, monocyte chemotactic protein-1, -2 and -3; Met-RANTES, methionylated RANTES; Mig, monokine-induced by human interferon g; MPIF-1, myeloid progenitor inhibitor factor-1; NAP-2, neutrophil activating peptide-2; RANTES, regulated upon activation, normal T cell expressed and secreted; WGA-SPA, wheat germ agglutinin bead-scintillation proximity assay

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 98%

Pharmacological characterization of the chemokine receptor, hCCR1 in a stable transfectant and differentiated HL‐60 cells: antagonism of hCCR1 activation by MIP‐1β

Chou¹,

Fine²,

Pugliese-Sivo³

et al. 2002

British J Pharmacology

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“…The latter group have much more diverse eects (MCP-2 is an agonist whereas MCP-3 is an antagonist in some tests) and this must indicate a fundamental dierence in the manner in which they interact with CCR5. Further support for the division of the chemokines in to dierent functional groups with dierent interactions with CCR5 comes from studies of naturally occurring mutants of CCR5 (Blanpain et al, 2000). The A29S mutant of CCR5 was severely impaired with respect of responses to MIP-1a, MIP-1b and RANTES, whereas eects of MCP-2 were comparable to those of the native receptor.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterization of the chemokine receptor, CCR5

Müeller

Mahmoud

Goedecke

et al. 2002

British J Pharmacology

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1 We investigated the e ects of a number of naturally occurring chemokines (MIP-1a, MIP-1b, RANTES, MCP-2, MCP-3, MCP-4) on di erent processes linked to the chemokine receptor CCR5 in recombinant CHO cells expressing the receptor at di erent levels. 2 Internalization of CCR5 following chemokine treatment was studied and MIP-1a, MIP-1b and RANTES (50 nM) were able to induce internalization (*50%) of the receptor. Internalization due to MCP-2, MCP-3 and MCP-4 was less (*20%). 3 Phosphorylation of CCR5 following chemokine treatment was studied and MIP-1a, MIP-1b and RANTES (50 nM) were able to induce phosphorylation of CCR5 whereas the other chemokines did not induce CCR5 phosphorylation. 4 MIP-1a, MIP-1b, RANTES and MCP-2 were able to stimulate [ 35 S]-GTPgS binding, an index of receptor/G protein activation, whereas MCP-3 and MCP-4 had no e ect in this assay. MCP-2 was a partial agonist (*80%) compared to MIP-1a, MIP-1b and RANTES, which gave similar maximal stimulations in this assay. 5 MIP-1a, MIP-1b, RANTES, MCP-2 and MCP-4 were able to stimulate increases in intracellular calcium ions via activation of CCR5 whereas MCP-3 was without e ect. 6 It is concluded that di erent chemokines interacting with CCR5 mediate di erent patterns of cellular responses.

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“…In addition to Delta32 mutations, only C101X is totally unable to mediate entry of HIV-1. The fact that nonfunctional CCR5 alleles are relatively frequent in various human populations reinforces the hypothesis of a selective pressure favoring these alleles (Blanpain et al, 2000). Polymorphisms of the chemokine receptor CCR5 genes have been implicated in HIV disease progression, resistance, or nonprogressive infection.…”

Section: E Env Interactions With Cxcr4 and Ccr5mentioning

confidence: 92%

“…Studies with CCR5 show that 10 variants out of 16 natural CCR5 mutations, described in various human populations, responding to chemokines, are able to act as coreceptors, are efficiently expressed at the cell surface, and bind [(125)I]-MIP-1beta with affinities similar to wtCCR5 (Blanpain et al, 2000). In addition to Delta32 mutations, only C101X is totally unable to mediate entry of HIV-1.…”

Section: E Env Interactions With Cxcr4 and Ccr5mentioning

confidence: 99%

Structure and Function of the HIV Envelope Glycoprotein as Entry Mediator, Vaccine Immunogen, and Target for Inhibitors

Prabakaran¹,

Dimitrov

Fouts

et al. 2007

Advances in Pharmacology

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The HIV envelope glycoprotein (Env) binds to cell surface-associated receptor (CD4) and coreceptor (CCR5 or CXCR4) by one of its two noncovalently associated subunits, gp120. The induced conformational changes activate the other subunit (gp41), which causes fusion of the viral with the plasma cell membranes resulting in delivery of the viral genome into the cell Prabakaran et al. Liganded gp120 CD4 BS CD4 BS mAbs X5, 17b (CD4i) Unliganded gp120 mAbs X5, 17b (CD4i) B A CD4 FIGURE 4 Molecular surface diagrams of unliganded (A) and liganded (B) gp120 cores are rendered as viewed from the perspective of CD4 receptorbinding. The residues in direct contact with CD4 are in blue; residues contacting the CD4i antibodies, namely, 17b and X5 are in red. The contact residues were selected by limiting interatomic distance of 3.8 Å between gp120 core to the CD4 and CD4i antibodies. 42Prabakaran et al.

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Multiple nonfunctional alleles of CCR5 are frequent in various human populations

Cited by 94 publications

References 56 publications

Pharmacological characterization of the chemokine receptor, hCCR1 in a stable transfectant and differentiated HL‐60 cells: antagonism of hCCR1 activation by MIP‐1β

Pharmacological characterization of the chemokine receptor, hCCR1 in a stable transfectant and differentiated HL‐60 cells: antagonism of hCCR1 activation by MIP‐1β

Pharmacological characterization of the chemokine receptor, CCR5

Structure and Function of the HIV Envelope Glycoprotein as Entry Mediator, Vaccine Immunogen, and Target for Inhibitors

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