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CCR5, short for chemokine (C-C motif) receptor 5, is a chemokine receptor. The natural chemokines that bind to this receptor are RANTES, MIP-1α and MIP-1β. CCR5 is also the name of the gene that codes for the CCR5 receptor. It is located on chromosome 3 on the short (p) arm at position 21. 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 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-1βand 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.
A number of new HIV drugs have been designed to interfere with the interaction between CCR5 and HIV, including PRO140 (Progenics), Vicriviroc (Schering Plough) and UK-427,857 (Pfizer). A potential problem of this approach is that CCR5 is the major, but not the only co-receptor by which HIV infects cells. It is possible that under selective pressure HIV will evolve to use another coreceptor. 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.
Recently, CCR5 has been shown to mediate resistance to West Nile Virus infection in humans, as CCR5Δ32 individuals are enriched in cohorts of West Nile Virus symptomatic patients, indicating that all of the functions of CCR5 may not be compensated by other receptors.
CCR5-Δ32
CCR5-Δ32 (or CCR5-D32) is a genetic defect affecting the human immune system that has both harmful and beneficial effects. It is a deletion mutation of a gene specifically impacting the function of T cells. CCR5-D32 is widely dispersed throughout Northern Europe and in those of European descent. The gene has a negative effect upon T cell function, but appears to protect against smallpox, plague and HIV. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is dispensable.
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 gene provide strong protection against HIV infection, although the protection is not absolute. This gene is found in up to 20% of Europeans but is rare in Africans and Asians. Multiple studies of HIV-infected persons have shown that presence of one copy of this gene delays progression to the condition of AIDS by about 2 years. And it is possible that a person with the CCR5-Δ32 receptor gene will not be infected with HIV R5 strains.
External links
- Entrez Gene entry for CCR5
- CDC fact sheet: CCR5 receptor gene and HIV infection - 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
- Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele
- Dating the Origin of the CCR5-D32 AIDS-Resistance Allele by the Coalescence of Haplotypes
"CCR5"