Soluble complexes of regulated upon activation, normal T cells expressed and secreted (RANTES) and glycosaminoglycans suppress HIV-1 infection but do not induce Ca(2+) signaling.
Chemokines comprise a family of low-molecular-weight proteins that elicit a variety of biological responses including chemotaxis, intracellular Ca(2+) mobilization, and activation of tyrosine kinase signaling cascades. A subset of chemokines, including regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta, also suppress infection by HIV-1. All of these activities are contingent on interactions between chemokines and cognate seven-transmembrane 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 could reconstitute the biological activities of RANTES on glycanase-treated cells. Complexes formed between RANTES and a number of soluble GAG failed to induce intracellular Ca(2+) mobilization on either glycanase-treated or untreated peripheral blood mononuclear cells and were unable to stimulate chemotaxis. In contrast, the same complexes demonstrated suppressive activity against macrophage tropic HIV-1. Complexes composed of (125)I-labeled RANTES demonstrated saturable binding to glycanase-treated peripheral blood mononuclear cells, and such binding could be reversed partially by an anti-CCR5 antibody. These results suggest that soluble chemokine-GAG complexes represent seven-transmembrane ligands that do not activate receptors yet suppress HIV infection. Such complexes may be considered as therapeutic formulations for the treatment of HIV-1 infection.
Burns
J M
JM
Division of Basic Science, Institute of Human Virology, University of Maryland, Baltimore, MD 21201, USA.
Lewis
G K
GK
DeVico
A L
AL
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019713:Receptors, CCR5 / Q000502:physiology; D015728:Receptors, HIV / Q000187:drug effects; D013601:T-Lymphocytes / Q000502:physiology*
D018946:Chemokine CCL5; D006025:Glycosaminoglycans; D019713:Receptors, CCR5; D015728:Receptors, HIV