cAMP up-regulates cell surface expression of lymphocyte CXCR4: Implications for chemotaxis and HIV-1 infection

The chemokine receptor CXCR4 mediates lymphocyte chemotaxis in response to stromal cell-derived factor-1 (SDF-1) and functions as a coreceptor for T c ell-tropic strains of HIV-1. We examined the role of the cAMP-protein kinas e A (PKA) signaling pathway in regulating expression of CXCR4. In response to exogenous dibutyryl cAMP or cAMP-inducing ligands, cell surface expressi on of CXCR4 was increased by up to 10-fold on CD3/CD28-stimulated PBMC and by up to sixfold on unstimulated PBMC. cAMP did not alter receptor mRNA lev els or affect the size of the total CXCR4 pool, However, cAMP did significa ntly reduce CXCR4 internalization rates and thereby increased the fraction of the total CXCR4 pool expressed on the cell, surface. cAMP-induced increa ses in CXCR4 expression counteracted SDF-1-induced receptor internalization and enhanced both chemotactic response to SDF-1 and cellular vulnerability to HIV-1 infection. Thus, altered chemokine receptor expression may provid e one mechanism by which cAMP-inducing ligands influence lymphocyte localiz ation and HIV pathogenesis.