CCR5

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.

In humans, the ''CCR5'' gene that encodes the CCR5 protein is located on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the ''Delta 32'' mutation, resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to infection by macrophage-tropic (M-tropic) strains of HIV-1.

Tissue distribution

CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils, microglia and a subpopulation of either breast or prostate cancer cells. The expression of CCR5 is selectively induced during the cancer transformation process and is not expressed in normal breast or prostate epithelial cells. Approximately 50% of human breast cancer expressed CCR5, primarily in triple negative breast cancer.

Structure

CCR5, or CC chemokine receptor 5, is a member of the class A G protein-coupled receptor (GPCR) family characterized by a canonical structure comprising seven transmembrane (7TM) α-helices (labeled I–VII), which are interconnected by three extracellular loops (ECL1–3) and three intracellular loops (ICL1–3). The largest extracellular loop, ECL2, adopts a β-hairpin conformation stabilized by disulfide bonds: one links Cys101 in helix III with Cys178 in ECL2, and another connects Cys20 at the N-terminus to Cys269 in helix VII, constraining the receptor’s extracellular architecture. The N-terminal region and extracellular loops are critical for ligand (chemokine) recognition and binding, with the N-terminus forming specific interactions with chemokines such as MIP-1α and RANTES. The transmembrane helices form a deep ligand-binding pocket, accommodating both endogenous chemokines and small molecule inhibitors like maraviroc, with key residues such as Glu283 and Tyr251 mediating ligand interactions through hydrogen bonds and salt bridges. On the intracellular side, helix VI undergoes conformational changes upon activation to facilitate G protein coupling, while helix VIII forms a short α-helix unique to CCR5 compared to related receptors like CXCR4. The overall architecture, including the arrangement of helices and loops, underpins CCR5’s roles in immune signaling and as a co-receptor for HIV-1 entry.

Function

The CCR5 protein belongs to the beta chemokine receptors family of integral membrane proteins. It is a G protein–coupled receptor which functions as a chemokine receptor in the CC chemokine group.

CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1''α'' and 1''β'', respectively), and CCL3L1. CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).

Clinical significance

It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, the functional response of the receptor, and HIV co-receptor activity.

Modulation of CCR5 activity contributes to a non-pathogenic course of infection with simian immunodeficiency virus (SIV) in several African non-human primate species that are long-term natural hosts of SIV and avoid immunodeficiency upon the infection. These regulatory mechanisms include: genetic deletions that abrogate cell surface expression of CCR5, downregulation of CCR5 on the surface of CD4+ T cells, in particular on memory cells, and delayed onset of CCR5 expression on the CD4+ T cells during development.

HIV

HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells. These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell. The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell. The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 ''env'' gene: the Gp120 external subunit and the Gp41 transmembrane subunit. This envelope glycoprotein structure is arranged into a spike-like structure located on the surface of the virion and consists of a trimer of Gp120-Gp41 hetero-dimers. The Gp120 envelope protein is a chemokine mimic. Though it lacks the unique structure of a chemokine, it is still capable of binding to the CCR5 and CXCR4 chemokine receptors. During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell, forming a heterotrimeric complex. The formation of this complex stimulates the release of a fusogenic peptide, causing the viral membrane to fuse with the membrane of the target host cell. Because binding to CD4 alone can sometimes result in gp120 shedding, gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine-sulfated amino terminus of this co-receptor is the "essential determinant" of binding to the gp120 glycoprotein. The co-receptor also recognizes the V1-V2 region of gp120 and the bridging sheet (an antiparallel, 4-stranded β sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity. The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection ''in vitro''. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection, suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.

CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, released from its metastable conformation and inserted into the membrane of the host cell. Although it has not been confirmed, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine-sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains.

CCR5 is essential for the spread of the R5-strain of the HIV-1 virus. Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function. A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with binding between the Gp120 envelope protein and the HIV co-receptor CCR5. These experimental drugs include PRO140 ( CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) ( Schering Plough), Aplaviroc (GW-873140) ( GlaxoSmithKline) and Maraviroc (UK-427857) ( Pfizer). Maraviroc was approved for use by the FDA in August 2007. It is the only one thus far approved by the FDA for clinical use, thus becoming the first CCR5 inhibitor. A problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist

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