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Interaction of Chemokine Receptor CCR5 with its Ligands: Multiple Domains for HIV-1 gp120 Binding and a Single Domain for Chemokine Binding
| Content Provider | Scilit |
|---|---|
| Author | Wu, Lijun LaRosa, Greg Kassam, Nasim Gordon, Cynthia J. Heath, Heidi Ruffing, Nancy Chen, Howard Humblias, Jason Samson, Michel Parmentier, Marc Moore, John P. Mackay, Charles |
| Copyright Year | 1997 |
| Description | 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)-1α, and MIP-1β, 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-1α, or MIP-1β. This mAb inhibited most of the RANTES and MIP-1α 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. |
| Related Links | http://jem.rupress.org/content/186/8/1373.full.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199098/pdf http://jem.rupress.org/content/jem/186/8/1373.full.pdf |
| Ending Page | 1381 |
| Page Count | 9 |
| Starting Page | 1373 |
| DOI | 10.1084/jem.186.8.1373 |
| Journal | The Journal of experimental medicine |
| Issue Number | 8 |
| Volume Number | 186 |
| Language | English |
| Publisher | Rockefeller University Press |
| Publisher Date | 1997-10-20 |
| Access Restriction | Open |
| Subject Keyword | Immunology Hiv Chemokine Ccr5 Binding Sites Mip Rantes Strains Mabs That Inhibit Binding Site Mapped Journal: The Journal of experimental medicine (Vol- 186, Issue- 8) |
| Content Type | Text |
