RANTES (Regulated upon Activation, Normal T cell Expressed and presumably Secreted), also
known as CCL5, is a member of the "CC" subfamily of chemokines. It plays a primary role in the
inflammatory immune response via its ability to chemoattract leukocytes and modulate their
function. The cDNA for RANTES was initially discovered by subtractive hybridization as a T cell
specific sequence (1, 2). Human RANTES cDNA encodes a highly basic 91 amino acid (aa) residue
precursor polypeptide with a 23 aa hydrophobic signal peptide that is cleaved to generate the 68 aa
mature protein (1, 2). Human RANTES exhibits approximately 85% homology with mouse RANTES at
the deduced aa level (3, 4).
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
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