The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1

Abstract

A PIJfATIVE chemokine receptor that we previously cloned and termed LESTR 1 has recently been shown to function as a coreceptor (termed fusin) for lymphocyte-tropic HIV-1 strains 2 • Cells expressing CD4 became permissive to infection with T -cellline-adapted HIV-1 strains of the syncytium-i.nducing phenotype after transfection with LESTR/fusin complementary DNA. We report here the identification of a human chemokine of the CXC type, stromal cell-derived factor 1 (SDF-1), as the naturaJ ligand for LESTR/fusin, and we propose the term CXCR-4 for this receptor, in keeping with the new cbemokine-receptor nomenclature. SDF-1 activates Chinese hamster ovary (CHO) cells transfected with CXCR-4 eDNA as well as blood leukocytes and lymphocytes. In cell lines expressing CXCR-4 and CD4, and in blood lymphocytes, SDF-1 is a powerful inhibitor of infection by lymphocyte-tropic HIV-1 strains, whereas the CC chemokines RANTES, MIP-1a and MIP-1~, which were shown previously to prevent infection with primary, monocyte-tropic viruses 3 , are inactive. In combination with CC chemokines, which block the infection with monocyte/macrophage-tropic viruses, SDF-1 could help to decrease virus load and prevent the emergence of the syncytium-inducing viruses which are characteristic of the late stages of AIDS 4• LESTR (leukocyte-expressed seven-transmembrane-domain receptor) is an orphan receptor with structural similarity to chemokine receptors. Despite extensive testing of a large number of chemokines, the ligand for LESTR remained elusive 1 • Murine SDF-1 was described as a factor that is produced by bonemarrow stromal cells and shown to induce proliferation of B-cell progenitorsM as well as recruitment of T cells 7 • The human homologue, which was cloned subsequently, is virtually identical to murine SDF-1 (see Methods). SDF-1 is a CXCchemokine with the typical four-cysteine motif and the first two cysteines separated by one amino acid 8 • When human SDF-1 was tested on the CH0-1C2 clone which stably expresses LESTR, a transient rise of cytosolic free Ca 2 + ([Ca 2 +];) was observed (Fig. 1a). This response, which is characteristic of the action of chemokines on blood leukocytes, was not observed with parental CHO cells. Other chemokines, including RANTES (for regulation-upon-activation, normal T expressed and secreted) macrophage inflammatory protein (MIP), MIP-1o: and MIP-1~, were not active. Monocytes, neutrophils and phytohaemagglutinin (PHA)-activated peripheral-blood lymphocytes (PBLs) were also stimulated by SDF-1, as shown by [Ca 2 +]; changes and chemotaxis (Fig. 1b, d). Real-time recordings of Ca 2 + mobilization after sequential stimulation are a reliable way to assess receptor usage by chemokines 8 • Stimulation with a chemokine (at saturating concentrations) causes receptor desensitization, and no response is observed when the cells are restimulated within a short time by a chemokine acting on the same receptor. As shown in Fig. lc, monocytes stimulated with SDF-1 remained fully responsive to subsequent stimulation with ...

The niche of stellate cells within rat liver

“…18,19 The chemokine cysteine-X-cysteine receptor 4 (CXCR4) is a G proteincoupled seven-span transmembrane protein which binds SDF1 exclusively. 20,21 The SDF-1/CXCR4 axis plays an essential role in directing hematopoietic stem cells along a SDF1 gradient to their final niche in the bone marrow during ontogenesis, 22 but also in their mobilization into the peripheral blood. 23 Stem cell niches are further innervated by the sympathetic nervous system, which is involved in regulation of hematopoietic stem cell recruitment.…”

Inhibition of HIV-1 fusion with small interfering RNAs targeting the chemokine coreceptor CXCR4

“…25,26 CXCR4 belongs to the family of seven transmembrane G-proteincoupled receptors. [27][28][29][30][31] These coreceptors transduce signals via heterotrimeric G-proteins. CXCR4 has been clearly identified as one of the major coreceptors for HIV-1 cell entry in vivo.…”

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

“…While some authors were unable to detect expression of CXCR4 [6,7], others have described binding of SDF-1 § , SDF-1 § -induced Ca 2+ flux and migration [8][9][10]. We have detected a clear expression of CXCR4 on neutrophils from the synovial fluid of patients with different inflammatory joint diseases, whereas CXCR4 was hardly detectable in the peripheral blood of patients or normal blood donors, suggesting that CXCR4 on neutrophils could be functionally relevant in the setting of inflammation [11].…”