INFLUENCE OF THE CCR2-V64I POLYMORPHISM ON HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 CORECEPTOR ACTIVITY AND ON CHEMOKINE RECEPTOR FUNCTION OF CCR2B, CCR3, CCR5, AND CXCR4

The chemokine receptors CCR5 and CXCR4 are used by human immunodeficie ncy virus type 1 (HIV-1) in conjunction with CD4 to infect cells. In a ddition, some virus strains can use alternative chemokine receptors, i ncluding CCR2b and CCR3, for infection. A polymorphism in CCR2 (CCR2-V 64I is associated with a 2- to ii-year delay in the progression to AID S. To investigate the mechanism of this protective effect, we studied the expression of CCR2b and CCR2b-V64I, their chemokine and HIV-1 core ceptor activities, and their effects on the expression and receptor ac tivities of the major HIV-1 coreceptors. CCR2b and CCR2b-V64I were exp ressed at similar levels, and neither molecule affected the expression or coreceptor activity of CCR3, CCR5, or CXCR4 in cotransfected cell lines. Peripheral blood mononuclear cells (PBMCs) from CCR2-V64I heter ozygotes had normal levels of CCR2b and CCR5 but slightly reduced leve ls of CXCR4. CCR2b and CCR2b-V64I functioned equally well as HIV-1 cor eceptors, and CCR2-V64I PBMCs were permissive for HIV-1 infection rega rdless of viral tropism. The MCP-l-induced calcium mobilization mediat ed by CCR2b signaling was unaffected by the polymorphism, but MCP-1 si gnaling mediated by either CCR2b- or CCR2-V64I-encoded receptors resul ted in heterologous desensitization (i.e., limiting the signal respons e of other receptors) of both CCR5 and CXCR4. The heterologous desensi tization of CCR5 and CXCR4 signaling by both CCR2 allele receptor type s provides a mechanistic link that might help explain the in vivo effe cts of CCR2 gene variants on progression to AIDS as well as the report ed antiviral activity of natural CCR2 ligands.