C-C chemokine ligand 5 (CCL5), also known as RANTES, is a target gene of NF-kappaB, and is expressed by T lymphocytes, macrophages, platelets, synovial fibroblasts, tubular epithelium, and certain types of tumour cells [, ]. CCL5 plays a role in recruiting a variety of leukocytes into inflammatory sites including T cells, macrophages, eosinophils, and basophils. CCL5 activity is mediated through its binding to CCR1, CCR3, and mainly CCR5 [, ].CCR5 is a G-protein-coupled receptor for CCL3, CCL4 and CCL5. CCR5 is also the major coreceptor for HIV-1 entry into target cells and is thought to be a suitable therapeutic target for HIV-1 blockade []. However, the affinity between CCR5 and natural CCL5 is low and has limited viral entry inhibiting activity. Therefore, several CCL5 derivatives with high anti-HIV-1 potency have been produced to act as entry inhibitors and CCR5 antagonists [, ].
CC chemokine receptor 5 (CCR5) is found on the surface of white blood cells, such as macrophages [], T cells []and dendritic cells [, ], and expressed in lymphoid organs []. Transfected cells expressing CCR5 receptor bind CCL5 (RANTES), CCL4 (MIP-1beta) and CCL3 (MIP-1alpha), and generate inositol phosphates in response to these chemokines. The same combination of chemokines has been shown to potently inhibit human immunodeficiency virus replication in human peripheral blood leukocytes []. CCR5 is the major coreceptor for HIV-1 entry into target cells and is thought to be a suitable therapeutic target for HIV-1 blockade [].Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.
Human herpesvirus 6A (HHV-6A) and HHV-6B are classified as roseoloviruses and are highly prevalent in the human population. Roseolovirus reactivation in an immunocompromised host can cause severe pathologies []. HHV6 A/B encode two putative chemokine receptors and a chemokine-like protein. The HHV6 U83 gene encodes a CC chemokine, which functions as a highly selective and efficacious agonist for the human CCR2 receptor, both in respect of signal transduction and the ability to induce chemotaxis. Homologues of the U83 gene products are found in Human cytomegalovirus encoded chemokines vCXC1 and vCXC2.HHV-6 U83, also known as vCCL4, contains a region with the CC/CX3C chemokine motif and a glycosaminoglycan (GAG)-binding epitope, BBXB (B being a basic residue), found right before the third Cys residue, which very likely forms a disulfide bridge back to the first Cys of the protein []. This gene is the only HHV-6A/B divergent gene that is specific for these viruses. The U83 chemokine gene is distinct between HHV-6A and HHV-6B strains, encoding up to 13 amino acid differences. The HHV-6A (U83A) and HHV-6B (U83B) chemokines have distinct specificities which determine chemoattraction or diversion of different leukocyte subsets for infection or immune evasion, thus an early component of cellular tropism as well as mediator of innate immunity. U83 also has a varied gene structure, with N-terminal length variation determining production of the encoded mature secreted chemokine, coupled with control by cell-directed splicing which truncates the chemokine gene early in replication to encode an antagonist. The 'long' active form of U83A has a unique broad specificity for receptors CCR1, CCR4, CCR5, CCR6 and CCR8 present on plasmacytoid and myeloid dendritic and monocyte/macrophage antigen presenting cells, as well as both TH1 and TH2 skin homing lymphocytes and NK cells; it is also amongst the highest affinity ligands for CCR5 and inhibits HIV-1 binding at this coreceptor. U83A can both block and divert human chemokine action while occupying the human chemokine receptors [].
