THE AMINO-TERMINAL DOMAIN OF THE CCR2 CHEMOKINE RECEPTOR ACTS AS CORECEPTOR FOR HIV-1 INFECTION

The chemokines are a homologous serum protein family characterized by their ability to induce activation of integrin adhesion molecules and leukocyte migration. Chemokines interact with their receptors, which a re composed of a single-chain, seven-helix, membrane-spanning protein coupled to G proteins. Two CC chemokine receptors, CCR3 and CCR5, as w ell as the CXCR4 chemokine receptor, have been shown necessary for inf ection by several HIV-1 virus isolates. We studied the effect of the c hemokine monocyte chemoattractant protein 1 (MCP-1) and of a panel of MCP-1 receptor (CCR2)-specific monoclonal antibodies (mAb) on the supp ression of HIV-1 replication in peripheral blood mononuclear cells. We have compelling evidence that MCP-1 has potent HIV-1 suppressive acti vity when HIV-1-infected peripheral blood lymphocytes are used as targ et cells. Furthermore, mAb specific for the MCP-1R CCR2 which recogniz e the third extracellular CCR2 domain inhibit all MCP-1 activity and a lso block MCP-1 suppressive activity. Finally, a set of mAb specific f or the CCR2 amino-terminal domain, one of which mimics MCP-1 activity, has a potent suppressive effect on HIV-1 replication in M- and T-trop ic HIV-1 viral isolates. We conjecture a role for CCR2 as a coreceptor for HIV-1 infection and map the HIV-1 binding site to the amino-termi nal part of this receptor. This concurs with results showing that the CCR5 amino terminus is relevant in HIV-1 infection, although chimeric fusion of various extracellular domains shows that other domains are a lso implicated, We discuss the importance of CCR2 structure relative t o its coreceptor role and the role of anti-CCR2 receptor antibodies in the prevention of HIV-1 infection.