Interaction of Chemokine Receptor CCR5 with its Ligands: Multiple Domains for HIV-1 gp120 Binding and a Single Domain for Chemokine Binding
| Autor: | Charles R. Mackay, Nancy Ruffing, Greg LaRosa, Howard H. Chen, Nasim Kassam, Heidi Heath, Michel Samson, Lijun Wu, Marc Parmentier, John P. Moore, Jason Humblias, Cynthia J. Gordon |
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| Rok vydání: | 1997 |
| Předmět: |
Receptors
CCR5 Chemokine receptor CCR5 viruses Immunology HIV Envelope Protein gp120 Ligands Lymphoma T-Cell Binding Competitive Article Mice 03 medical and health sciences Chemokine receptor 0302 clinical medicine Antibody Specificity Tumor Cells Cultured Animals Humans Immunology and Allergy CCL15 Antibodies Blocking Chemokine CCL4 CCL13 Chemokine CCL5 Chemokine CCL3 030304 developmental biology 0303 health sciences biology Antibodies Monoclonal virus diseases Articles Macrophage Inflammatory Proteins Molecular biology Protein Structure Tertiary 3. Good health Mice Inbred C57BL CXCL2 Chemokine binding Chemokines CC 030220 oncology & carcinogenesis HIV-1 biology.protein XCL2 Protein Binding CCL21 |
| Zdroj: | ResearcherID The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.186.8.1373 |
| Popis: | CCR5 is a chemokine receptor expressed by T cells and macrophages, which also functions as the principal coreceptor for macrophage (M)-tropic strains of HIV-1. To understand the molecular basis of the binding of chemokines and HIV-1 to CCR5, we developed a number of mAbs that inhibit the various interactions of CCR5, and mapped the binding sites of these mAbs using a panel of CCR5/CCR2b chimeras. One mAb termed 2D7 completely blocked the binding and chemotaxis of the three natural chemokine ligands of CCR5, RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta, to CCR5 transfectants. This mAb was a genuine antagonist of CCR5, since it failed to stimulate an increase in intracellular calcium concentration in the CCR5 transfectants, but blocked calcium responses elicited by RANTES, MIP-1alpha, or MIP-1beta. This mAb inhibited most of the RANTES and MIP-1alpha chemotactic responses of activated T cells, but not of monocytes, suggesting differential usage of chemokine receptors by these two cell types. The 2D7 binding site mapped to the second extracellular loop of CCR5, whereas a group of mAbs that failed to block chemokine binding all mapped to the NH2-terminal region of CCR5. Efficient inhibition of an M-tropic HIV-1-derived envelope glycoprotein gp120 binding to CCR5 could be achieved with mAbs recognizing either the second extracellular loop or the NH2-terminal region, although the former showed superior inhibition. Additionally, 2D7 efficiently blocked the infectivity of several M-tropic and dual-tropic HIV-1 strains in vitro. These results suggest a complicated pattern of HIV-1 gp120 binding to different regions of CCR5, but a relatively simple pattern for chemokine binding. We conclude that the second extracellular loop of CCR5 is an ideal target site for the development of inhibitors of either chemokine or HIV-1 binding to CCR5. |
| Databáze: | OpenAIRE |
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