Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

CCR5

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101567

Synonyms

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

Historical Background

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.

Expression, Localization, and Regulation of CCR5

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).

Physiological Function of CCR5

The CCR5 receptor has been found on numerous cells of the immune defense system indicating a role in activation and migration of these effector or antigen presenting cells (Fig. 1). Immature epidermal CCR5+ dendritic cells (Langerhans cells) are attracted by CCR5 binding ligands which secreted by activated macrophages. However, the exact physiological role of CCR5 was unknown for a long time since its involvement in West Nile Virus (WNV) infection was described. The WNV infection can cause severe encephalitis in patients lacking the CCR5 receptor. Interestingly, the lack of CCR5 has only influence on the viral burden in cortical neurons and no influence in lymph nodes, spleen, or cerebellum. In cortical neurons, the CCR5 ligands CCL4 and CCL5 are overexpressed indicating the crucial role of the chemokine receptor in the recruitment of virus inactivating monocytes leading to a faster and more effective viral clearance in the CNS (Durrant et al. 2015). A similar effect of CCR5 in the recruitment of immune defense cells and viral clearance has been observed in the case of cerebral infection with the herpes simplex virus-1 (HSV-1). In opposite to WNV, the overwhelming migration into the brain may also be detrimental for the host (Vilela et al. 2013).
CCR5, Fig. 1

Physiological function of CCR5 during cell trafficking. As response to the side of inflammation cytokines from NK T-cell induce the transcription of CCR5 by a cAMP response element (CREB-1) in the CCR5 promoter region. Chemokines secreted from macrophages attract CCR5+ effector cells to the side of inflammation

Medical Relevance of CCR5

HIV-1 Infection

CCR5 is the major coreceptor together with CD4 for cell entry of the HIV-1. During infection with HIV-1, the viral envelope glycoprotein gp120 binds to CD4 resulting in a conformation change in gp120 causing an opening of a binding side to CCR5. Once the envelope glycoprotein binds to the chemokine receptor, a major conformational change occurs in the envelope uncovering the viral fusion domain gp41 which links the virus to the cell membrane and consecutively facilitates transmission (Lederman et al. 2006). Because of the crucial role in HIV-1 infection, CCR5 became an auspicious target in the development of antiretroviral treatment. Pharmacological attempts to inhibit receptor function by monoclonal antibodies or entry inhibitors (e.g., maraviroc) were rather disappointing. A more compelling approach is the genetically knockdown of the CCR5-gene. This idea was substantially promoted by a successful allogeneic transplantation of an HIV-1 infected patient with leukemia, who received a graft with naturally CCR5 negative stem cells (CCR5-delta32 homozygous). This treatment is commonly aligned as first medical HIV-1 cure. Since then, development of a therapy with artificially CCR5-depleted cells has become a major issue in HIV-1 treatment (Burke et al. 2013).

Infection of human herpes virus-2 (HSV-2) elevates the risk of HIV-1 transmission profoundly (>3-fold). It has been considered that lesions in the mucosa due to HSV-2 may facilitate HIV-1 to break the surface barrier. Recently, it has been reported that a synergetic effect of HSV-2 infection and CCR5 expression may also contribute to this increased risk of transmission. HSV-2 infected cells respond with secretion of TNF-α of monocyte-derived dendritic cells leading to increased readout and expression of CCR5. Additional to the disruption of the protecting epithelial layer, HSV-2 infection paves the way for HIV-1 cell entry (Marsden et al. 2015)

Transplantation Medicine

CCR5 plays a role in solid organ allograft rejection and mediates murine graft versus host disease (GvHD) pathogenesis especially demonstrated in kidney transplantation. Chemokine surface density is upregulated upon allogeneic stimulation, and CCR5 expressing cells are proliferating with cosecretion of T-cell activation markers (tumor necrosis factor-α, interleukin-2, or interferon-γ) leading to activated T-cells (Palmer et al. 2010).

Inhibition of CCR5 during organ and stem cell transplantation to reduce the incidence and severity of graft rejection and GvHD are tested in clinical trials. In a first cohort of 35 patients, ongoing allogeneic stem cell transplantation administration of maraviroc prevented CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro, providing evidence of an antichemotactic activity. The incidence of acute and severe GvHD was lower as compared to the expected rate of GvHD in a comparable control cohort (Reshef et al. 2012).

Summary

CCR5 is a chemokine receptor involved in immune response and cell trafficking in tissues. Complete loss of function in individuals harboring the CCR5-d32/d32 genotype is not associated with noteworthy impairment of health indicating a redundant organization of CCR5 specific function within the chemokine group (Table 1). CCR5 and the manipulation of function or expression gained major interest since the receptor was found as the major coreceptor for HIV-1 cell entry. Current and ongoing research on pharmacological and genetic inhibition of CCR5 expression has shown great potency for this chemokine receptor as a target in modulation of immune response in inflammation and protection against HIV-1 transmission.
CCR5, Table 1

Summary of case-control studies on the impact of the genetic CCR5 variations from 2013 to 2016

Disease

CCR5 variation

Cases/control group

Risk for carrier of CCR5 variation

Diabetes mellitus micro vasculitis

CCR5 promotor

2737/2435

No association

Atherosclerosis

CCR5 exon mutation

60,801/123,504

No association

Behcet’s disease

CCR5-d32

348/477

No association

Cancer

CCR5-d32

3087/3735

Increased risk for breast cancer

Lupus nephritis

CCR5-d32

1092/2229

Increased risk

Sjogren’s syndrome

CCR5-d32

1881/2391

No association

Multiple sclerosis

CCR5-d32

1666/2203

No association

References

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Cellex IncDresdenGermany
  2. 2.Technical UniversityDresdenGermany