Chemokine signaling and HIV-1 fusion mediated by macrophage CXCR4: implications for target cell tropism

To better understand CXCR4 function on macrophages and the relationship bet ween coreceptor use and macrophage tropism among diverse HIV-1 isolates, we analyzed macrophage pathways involved in Env-mediated fusion, productive H IV-1 infection, and chemokine-elicited signaling. We found that both CXCR4 and CCR5 transduced intracellular signals in monocyte-derived macrophages, activating K+ and Cl- ion channels and elevating intracellular calcium in r esponse to their chemokine ligands stromal cell-derived factor-1 alpha and macrophage inflammatory protein-1 beta, respectively. The prototype T-tropi c X4 strain IIIB infected macrophages poorly, and this,vas associated with failure of the IIIB Env to fuse efficiently with target macrophages despite functional CXCR4. In contrast, several primary X4 isolates mediated effici ent CXCR4-dependent fusion and productive macrophage infection. Several R5X 4 strains could fuse with and infect macrophages through both CCR5 and CXCR 4. Thus, macrophages express functional CXCR4 and CCR5 but primary and prot otype X4 isolates differ in their ability to utilize macrophage CXCR4. Isol ates classified as X4 based on coreceptor use may be phenotypically either T-tropic or dual-tropic and, conversely, phenotypically dual-tropic isolate s may be either R5X4 or X4 based on coreceptor use.