HIV Coreceptor Downregulation as Antiviral Principle: SDF-1α–dependent Internalization of the Chemokine Receptor CXCR4 Contributes to Inhibition of HIV Replication

Amara, Ali; Gall, Sylvie Le; Salamero, Jean; Montes, Monica; Loetscher, Pius; Baggiolini, Marco; Virelizier, Jean-Louis; Arenzana-Seisdedos, Fernando

doi:10.1084/jem.186.1.139

Cited by 522 publications

(489 citation statements)

References 31 publications

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“…Ligand-induced receptor internalization of CXCR4 has been studied in detail on lymphocytes [13]. After binding of SDF, CXCR4 is sequestered into early endosomes enabling a rapid recycling of the chemokine receptor after removal of the ligand.…”

Section: Discussionmentioning

confidence: 99%

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Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Brühl¹,

Cohen²,

Linder³

et al. 2003

Eur J Immunol

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We have investigated the regulation and function of the chemokine receptor CXCR4 on neutrophils. CXCR4 is hardly detectable on neutrophils in the peripheral blood. However, overnight culture strongly up-regulates CXCR4 expression on the cell surface. The functional activity of CXCR4 on cultured neutrophils was confirmed by stromal cell-derived factor (SDF)-induced migration and up-regulation of the integrins CD11b and CD11c. CXCR4 surface expression on neutrophils but not on lymphocytes and monocytes is rapidly downregulated after stimulation with TNF- § and IFN-+ , resulting in significantly decreased SDFinduced functional responses of neutrophils. In contrast to surface expression, CXCR4 mRNA expression was several-fold increased in cytokine-stimulated neutrophils, suggesting a post-translational regulation. By confocal microscopy we demonstrate that CXCR4 is internalized after stimulation with TNF- § and IFN-+ . b he down-modulation of CXCR4 surface expression in response to TNF- § and IFN-+ was fully reversible after cytokine removal. Further, CXCR4 down-modulation could be completely blocked by hypertonic sucrose and significantly reduced by chlorpromazine indicating the involvement of clathrin-coated pits. Internalization of CXCR4 by cytokines in a cell type-specific manner is a novel and functionally important mechanism of chemokine receptor regulation.

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Section: Discussionmentioning

confidence: 99%

“…Depending on the intracellular pathway, internalization leads to either degradation or recycling and functional reconstitution of the receptor. Chemokineinduced internalization of CXCR4 has been studied in detail on lymphocytes [13]. Other stimuli for chemokine receptor internalization include the activation of protein kinases, e.g.…”

Section: Introductionmentioning

confidence: 99%

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Brühl¹,

Cohen²,

Linder³

et al. 2003

Eur J Immunol

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“…As ligand binding is known to cause receptor internalization and transiently decrease cell surface levels of CXCR4 (Amara et al, 1997), we next sought to define receptor levels in our CXCL12 re-expressing cell lines. CXCR4 mRNA levels were similar between three separate CXCL12 re-expressing cells, control eGFP and wild-type MDA-MB-231 cell lines (Figure 8d).…”

Section: Cxcl12 Re-expression Increased Orthotopic Primary Mammary Tumentioning

confidence: 99%

Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

2007

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Expression of the chemokine receptor CXCR4 has been linked with increased metastasis and decreased clinical prognosis in breast cancer. The current paradigm dictates that CXCR4 fosters carcinoma cell metastasis along a chemotactic gradient to organs expressing the ligand CXCL12. The present study asked if alterations in autocrine CXCR4 signaling via dysregulation of CXCL12 in mammary carcinoma cells modulated their metastatic potential. While CXCR4 was consistently detected, expression of CXCL12 characteristic of human mammary epithelium was silenced by promoter hypermethylation in breast cancer cell lines and primary mammary tumors. Stable re-expression of functional CXCL12 in ligand null cells increased orthotopic primary tumor growth in the mammary fat-pad model of tumorigenesis. Those data parallel increased carcinoma cell proliferation measured in vitro with little-to-no-impact on apoptosis. Moreover, re-expression of autocrine CXCL12 markedly reduced metastatic lung invasion assessed using in vivo bioluminescence imaging following tail vein injection. Consistent with those data, decreased metastasis reflected diminished intracellular calcium signaling and chemotactic migration in response to exogenous CXCL12 independent of changes in CXCR4 expression. Together these data suggest that an elevated migratory signaling response to ectopic CXCL12 contributes to the metastatic potential of CXCR4-expressing mammary carcinoma cells, subsequent to epigenetic silencing of autocrine CXCL12.

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“…In vitro, SDF-1 can block X4 HIV-1 entry into CD4-positive cells by binding to and internalizing CXCR4. [13][14][15][16] One single-nucleotide polymorphism (SNP), rs1801157 ( ¼ SDF1-3 0 A), in a conserved area of the 3 0 untranslated region was associated with resistance to infection in heterozygotes in the MACS cohort and with delayed onset of AIDS in HIV-1-infected homozygote seroconvertors; 17 however, subsequent work has reported opposite effects. 18,19,20 In addition, studies that examined the relationship between circulating levels of SDF-1 and HIV-1 disease progression have obtained contrasting results.…”

Section: Introductionmentioning

confidence: 99%

Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study

et al. 2005

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The stromal-derived factor-1 (SDF-1) chemokine gene encodes the only natural ligand for CXCR4, the coreceptor for the pathogenic X4 HIV-1 strains. A single-nucleotide polymorphism (SNP) in the 3 0 untranslated region (SDF1-3 0 A ¼ rs1801157) of SDF-1 was reported to be protective against infection and progression in some, but not other, epidemiological studies. To identify additional alleles that may influence HIV-1 infection and progression to AIDS, nine SNPs (including rs1801157) spanning 20.2 kb in and around the SDF-1 gene were genotyped in over 3000 African American (AA) and European American (EA) participants enrolled in five longitudinal HIV-1/AIDS natural cohort studies. Six or five haplotypes were present at frequencies greater than 5% in AA or EA, respectively. Six of the nine SNPs occur on only one common haplotype (45%), while the remaining three SNPs were found on multiple haplotypes, suggesting a complex history of recombination. Among EA, rs754618 was associated with an increased risk of infection (OR ¼ 1.50, P ¼ 0.03), while rs1801157 ( ¼ SDF1-3 0 A) was associated with protection against infection (OR ¼ 0.63, P ¼ 0.01). In the MACS cohort, rs1801157 was associated with AIDS-87 (RH ¼ 0.31, P ¼ 0.02) and with death (RH ¼ 0.18, P ¼ 0.02). Significant associations to a single disease outcome were found for two SNPs and one haplotype in AA.

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HIV Coreceptor Downregulation as Antiviral Principle: SDF-1α–dependent Internalization of the Chemokine Receptor CXCR4 Contributes to Inhibition of HIV Replication

Cited by 522 publications

References 31 publications

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study

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