CCCKR5;  CC-CKR-5;  CCR-5;  CD195;  CKR5;  CKR-5;  CMKBR5;  IDDM22

The CC chemokine receptor 5 (CCR5) belongs to the G protein-coupled receptor (GPCR) family. Chemokines and their receptors were initially discovered in the context of cell trafficking and effector functions in cells of the immune system. Before CCR5 was described as receptor, one of its inhibitory ligands (RANTES, regulated on activation, normal T cell expressed and secreted) was found in the late 1980s as a molecule derived from T-cells (Schall et al. 1988). However, this detection of the ligand did not facilitate the detection of the corresponding receptor. This first description of CCR5 was part of the search for the entry mechanism of the human immunodeficiency virus type 1 (HIV-1) in the mid-1990s. At this time, it was well described that the T-cell receptor CD4 is mandatory for transmission of HIV-1 but the virus requires an additional unknown coreceptor for invasion. CCR5 was found to be the major coreceptor for HIV-1 infection. Since the inhibitory RANTES ligand was described to reduce the susceptibility against HIV-1 infection, CCR5 became a potential HIV-1 treatment target (Cocchi et al. 1995). Furthermore, the observation that some people are obviously resistant against HIV-1 transmission led to the detection of the CCR5-delta32 deletion in 1996 (Liu et al. 1996). This mutation is present in Caucasians in 10–15% indicating a selective advantage for carrier of this mutation against an up-to-date unknown threat. Homozygosity for this deletion leads to a complete loss of CCR5 function and consecutively to a natural protection against HIV-1 and mimicking this finding by gene therapy approaches is one of the great challenges in gene therapy in the last decade.

The CCR5 gene is located on the short arm of chromosome 3 at position 21 within a cluster of other chemokine receptors. The gene is composed of three exons, two introns, and two promotor sides. Consistent to other chemokine coreceptors, CCR5 has a common 7-transmembrane structure – similar to rhodopsin – forming three extracellular loops with the N-terminal domain and four intracellular loops with the C-terminal domain. CCR5 consists of 352 amino acids which shares 71% sequences identity with CCR2 and a molecular weight of 40.6 kDa. As an evolutionary conserved structure in the GPCR family, there is a disulfide bridge formed between two cysteine residues on the second and third extracellular loop. Posttranslational modifications of CCR5 have been described on tyrosine kinase sides at the N-terminal domain or O-linked glycosylation on serine residues like Ser-6 (Oppermann 2004).

CCR5 is present on the surface of immune effector cells (memmory T-cells, T helper type 1 effector cells, activated T-cells), antigen presenting cells (monocytes, macrophages, dendritic cells, micro glia), and basophils. It is also present on epithelium, endothelium, vascular smooth muscles, and fibroblast. An enhanced CCR5 expression is observed in chronically inflamed tissues and the expression correlates with severity of inflammation (Rottman et al. 1997). Several ligands for CCR5 have been described, which are secreted by macrophages and T-cells including MIP-1α (CCL3), MIP-1β (CCL4), RANTES (CCL5), MCP-2 (CCL8), Eotaxin (CCL11), HCC-1 (CCL14α), and HCC-4 (CCL16) (consensus names in bracelets).

For the CCR5 gene, two substantially different promoter regions have been identified: the downstream promotor region P1 and P2 as the upstream region. In these promotor regions, binding sites for interferon regulatory factors, nuclear factors, and cAMP response elements (e.g., CREB-1) have been identified. Mutations in the promotor region can alter the expression of CCR5 in both directions as shown with the 59,353 T/T and the 59,402 A/A genotype (Clegg et al. 2000). Epigenetic regulation mechanisms have also been described. The CCR5 gene has an evolutionary conserved CpG region at position −41. Downstream of this CpG side in the cis-region the methylation differs depending on the differentiation state of the cells, whereas methylation status of CCR5-intron 2 is closely related to the CCR5 surface expression on memory T-cells (Gornalusse et al. 2015)

Despite regulation mechanism on the genomic or epigenomic level, CCR5 is a dynamic receptor and its surface density and activity are related to the effects of signaling, trafficking, and internalization due to extra- or intracellular stimuli. Binding to its ligands can lead to internalization and thereby reduce the surface density of the receptor. After endocytosis, CCR5 accumulates in perinuclear endosomes and recycles back to the plasma membrane in a dephosphorylated form.

Less is known on heterologous receptor regulation of CCR5 and corresponding or downstream partners. Coexpression of the chemokine receptor CXCR1 or other immune response related genes like LRG1, CXCR2, CCRL2, CD6, CD7, and CD30L together with CCR5 have been described (Hütter et al. 2011).