CCR5

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.

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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, 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). ^[1]

Further information: HIV Tropism and Entry inhibitors

CCR5-Δ32

CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is a genetic variant of CCR5.^{[2] [3]}

It 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 European descent. It has been hypothesized that this allele was favored by natural selection during the Black Death, or during smallpox outbreaks, which is unlikely, given that the frequency of CCR5-Δ32 in Bronze Age samples is similar to that seen today.^[4] The allele 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 largely dispensable. However, CCR5 plays a role in mediating resistance to West Nile virus infection in humans, as CCR5-Δ32 individuals are enriched in cohorts of West Nile virus symptomatic patients ^[5], indicating that all of the functions of CCR5 may not 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.^[6] This allele is found in 5-14% of Europeans but is rare in Africans and Asians.^[7] 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.

Further information: Long-term nonprogressors

References

Further reading