RANTES is a potent chemoattractant for a number of different cell types including unstimulated CD4+/CD45RO+ memory T cells and stimulated CD4+ and CD8+ T cells with naive and memory phenotypes, NK cells, basophils, eosinophils, dendritic cells, mast cells, monocytes, and microglia (5-13). In addition to its effects on migration, RANTES can activate a number of cell types including T cells (14-16), monocytes (17), neutrophils (17), NK cells (7), dendritic cells (18), and astrocytes (19). T cell activation generally requires relatively high RANTES concentrations (~ 1 μM) and is dependent upon aggregation of the molecule and association with cell surface glycosaminoglycans (GAGs) (15-17). Whether this activity occurs in vivo remains unclear although in mice, intraperitoneally injected RANTES mutants that are unable to aggregate and/or bind GAG, are not capable of attracting leukocytes when compared to wild-type controls (20). Other in vivo studies show that RANTES knockout mice exhibit deficient recruitment of leukocytes to sites of acute inflammation (21).
RANTES, is known to interact with four identified seven transmembrane G-protein coupled receptors: CCR1, CCR3, CCR4, and CCR5 (22-25). RANTES stimulation can initiate a variety of signaling cascades that are cell context dependent. For instance, in T-cells, RANTES can stimulate elevations of intracellular Ca2+ (26), and activation of focal adhesion kinase (FAK) (27), protein kinase A (28), PI3-kinase (14), Rho GTPase (29), and JAK/STAT signaling pathways (30). The cytomegalovirus protein US28 exhibits significant homology with CC chemokine receptors and is capable of binding RANTES (31). Membrane-spanning US28 can, depending on the context, signal in a constitutive manner (32), bind RANTES and initiate G-protein-mediated signaling cascades (33), or sequester RANTES and potentially alter inflammatory responses (34-36).
The RANTES receptor CCR5 is also the primary co-receptor for R5 (M-tropic) variants of HIV-1 (37, 38). It has been demonstrated that RANTES, as well as the other CCR5 ligands, macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, can competitively inhibit CCR5/HIV-1 interaction and suppress viral infection in vitro (39, 40). These effects apparently do not require fully intact signaling from the CCR5 receptor (41). Consequently, modified forms of RANTES and non-peptide compounds that block the interaction of HIV-1 with CCR5 show promise for future therapies (41-44). In contrast, several reports show that RANTES can enhance in vitro replication of X4 (T-tropic) variants of HIV-1 that use CXCR4 as a co-receptor rather than CCR5 (45, 46). This activity usually requires relatively high RANTES concentrations (~μM) and is dependent upon interaction with cell surface GAGs, oligomerization, and activation of tyrosine kinase and MAP kinase signaling cascades (46, 47).
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