Soluble complexes of regulated upon activation, normal T cells expressed and secreted (RANTES) and glycosaminoglycans suppress HIV-1 infection but donot induce Ca2+ signaling

Chemokines comprise a family of low-molecular-weight proteins that elicit a variety of biological responses including chemotaxis. intracellular Ca2+ m obilization, and activation of tyrosine kinase signaling cascades. A subset of chemokines. including regulated upon activation, normal T cell expresse d and secreted (RANTES). macrophage inflammatory protein-1 alpha (MIP-1 alp ha), and MIP-1 beta, also suppress infection by HIV-1. All of these activit ies are contingent on interactions between chemokines and cognate seven-tra nsmembrane spanning. G protein-coupled receptors. However. these activities are strongly inhibited by glycanase treatment of receptor-expressing cells . indicating an additional dependence on surface glycosaminoglycans (GAG). To further investigate this dependence, we examined whether soluble GAG cou ld reconstitute the biological activities of RANTES on glycanase-treated ce lls. Complexes formed between RANTES and a number of soluble GAG failed to induce intracellular Ca2+ mobilization on either glycanase-treated or untre ated peripheral blood mononuclear cells and were unable to stimulate chemot axis. In contrast, the same complexes demonstrated suppressive activity aga inst macrophage tropic HIV-1. Complexes composed of I-125-labeled RANTES de monstrated saturable binding to glycanase-treated peripheral blood mononucl ear cells, and such binding could be reversed partially by an anti-CCR5 ant ibody. These results suggest that soluble chemokine-GAG complexes represent seven-transmembrane ligands that do not activate receptors yet suppress HI V infection. Such complexes may be considered as therapeutic formulations f or the treatment of HIV-1 infection.