From Wikipedia, the free encyclopedia

CCR5 is a gene which encodes the CCR5 protein, "Chemokine (C-C motif) receptor 5", a member of the beta chemokine receptors family of integral membrane proteins.^[1][2]

In Humans, the CCR5 gene location is 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 the CCR5 gene. Homozygous carriers of this mutation are resistant to HIV-1 infection ^[3].

The CCR5 protein has also recently been designated CD195: "Cluster of differentiation" 195 (for cell surface molecules present on White blood cells). The CCR5 protein is a seven transmembrane protein ^[1] which functions as a chemokine receptor in the CC chemokine group. The natural chemokine ligands that bind to this receptor are RANTES, MIP-1α and MIP-1β. CCR5 is predominantly expressed on T cells, macrophages, dendritic cells and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear.

HIV

HIV uses CCR5 or another protein, CXCR4, as a co-receptor to enter its target cells. Several chemokine receptors can function as viral coreceptors, but CCR5 is likely the most physiologically important coreceptor during natural infection. 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,^[4] 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.

A number of new experimental HIV drugs, called entry inhibitors, have been designed to interfere with the interaction between CCR5 and HIV, including PRO140 (Progenics), Vicriviroc (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). A potential 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 of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. Development of Aplaviroc has been terminated due to safety concerns (potential liver toxicity).^[5]

CCR5-Δ32

CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is a genetic variant of CCR5.^[6][7]

CCR5-Δ32 is a deletion mutation of a gene that has a specific impact on the function of T cells. CCR5-Δ32 is widely dispersed throughout Northern Europe and in those of Northern European descent. It has been hypothesized that this allele was favored by natural selection during the Black Death. This coalescence date is contradicted by purported evidence of CCR5-Δ32 in Bronze Age samples, at levels comparable to the modern European population.^[8] Research from The University of California at Berkeley published in 2003 indicates that smallpox may be another candidate for the high level of the mutation in the European population.^[6]

The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV. Yersinia pestis was demonstrated in the laboratory not to associate with CCR5. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is largely dispensable. However, CCR5 apparently plays a role in mediating resistance to West Nile virus infection in humans, as CCR5-Δ32 individuals have shown to be disproportionately at higher risk of West Nile virus in studies,^[9] indicating that not all of the functions of CCR5 may be compensated by other receptors.

While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV R5 entry; two copies of this allele provide strong protection against HIV infection.^[10] This allele is found in 5-14% of Europeans but is rare in Africans and Asians.^[11] Multiple studies of HIV-infected persons have shown that presence of one copy of this allele delays progression to the condition of AIDS by about 2 years. CCR5-Δ32 decreases the number of CCR5 proteins on the outside of the CD4 cell, which can have a large effect on the HIV disease progression rates. It is possible that a person with the CCR5-Δ32 receptor allele will not be infected with HIV R5 strains. Several commercial testing companies offer tests for CCR5-Δ32.

In 2008, German doctors announced that an HIV-infected leukemia patient had received a bone marrow transplant from a donor who is homozygous for the CCR5-Δ32 trait. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.^[12][13] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors.^[14] However, this is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.^[15] In 2009, researchers at the University of Pennsylvania began enrolling HIV-positive patients in a clinical trial in which the patients' cells will be genetically modified to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.^[16][17]

Interactions

CCR5 has been shown to interact with CCL5^[18][19][20] and CCL3L1.^[21][19]

See also

• Discovery and development of CCR5 receptor antagonists
• HIV
• Antiviral drugs
• G protein-coupled receptor
• AIDS
• gp41
• Entry inhibitor
• maraviroc
• CD4
• CCL5
• Subtypes of HIV
• HIV tropism

References

Further reading

External links

• Video and text from a PBS documentary about the discovery of CCR5
• "Chemokine Receptors: CCR5". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2228.  
• fact sheet: CCR5 receptor gene and HIV infection at CDC - (note, author is not a CDC employee, and there is no public domain notice on the page, so this cannot be assumed to be public domain)
• http://www.cdc.gov/genomics/hugenet/factsheets/FS_CCR5.htm 2% African American show CCR5 indicating extremely recent origin. Smallpox initiator suspect.
• Schering-Plough Initiates Phase III Studies with CCR5-Vicriviroc in Treatment- Experienced HIV Patients.