CCR5

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a

CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1α and 1β, respectively), and CCL3L1.^[14][15] CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).^[14][16][17]

CCR5 is predominantly

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.^[23] These regulatory mechanisms include: genetic deletions that abrogate cell surface expression of CCR5,^[24] downregulation of CCR5 on the surface of CD4+ T cells, in particular on memory cells,^[25] and delayed onset of CCR5 expression on the CD4+ T cells during development.^[26][27]

HIV

HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells.^[28] 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.^[29] The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell.^[29] 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.^[29] 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.^[29] The Gp120 envelope protein is a chemokine mimic.^[28] Though it lacks the unique structure of a chemokine, it is still capable of binding to the CCR5 and CXCR4 chemokine receptors.^[28] 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.^[28] 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.^[28] 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.^[30] 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.^[30] 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,^[31] 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.^[30]

CCR5 is essential for the spread of the R5-strain of the HIV-1 virus.

Expression of CCR5 is induced in breast and prostate epithelial cells upon transformation.[18]^[19] The induction of CCR5 expression promotes cellular invasion, migration, and metastasis.^[5][18][21] The induction of metastasis involves homing to the metastatic site. CCR5 inhibitors including maraviroc and leronlimab have been shown to block lung metastasis of human breast cancer cell lines.^[18][36] In preclinical studies of immune competent mice CCR5 inhibitors blocked metastasis to the bones and brain.^[19] CCR5 inhibitors also reduce the infiltration of tumor associated macrophages.^[37] A Phase 1 clinical study of a CCR5 inhibitor in heavily pretreated patients with metastatic colon cancer demonstrated an objective clinical response and reduction in metastatic tumor burden.^[38]

Brain

Increased levels of CCR5 are part of the inflammatory response to stroke and death. Blocking CCR5 with Maraviroc (a drug approved for HIV) may enhance recovery after stroke.^[39][40]

In the developing brain, chemokine receptors such as CCR5 influence neuronal migration and connection. After stroke, they seem to decrease the number of connection sites on neurons near the damage.^[39]

CCR5-Δ32

CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is an allele of CCR5.^[41][42]

CCR5 Δ32 is a 32-base-pair deletion that introduces a premature

Recent research indicates that CCR5 Δ32 enhances cognition and memory. In 2016, researchers showed that removing the CCR5 gene from mice significantly improved their memory.[50] CCR5 is a powerful suppressor for neuronal plasticity, learning, and memory; CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits.^[51]

Evolutionary history and age of the allele

The CCR5 Δ32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution,^[52] which together suggest that (a) it arose from a single mutation, and (b) it was historically subject to positive selection.

Two studies have used linkage analysis to estimate the age of the CCR5 Δ32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 Δ32 deletion would be proportional to the age of the deletion.^[42][53] Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-Δ32 deletion occurred 700 years ago (275-1875, 95% confidence interval). Another group, Libert et al. (1998), used microsatellite mutations to estimate the age of the CCR5 Δ32 mutation to be 2100 years (700-4800, 95% confidence interval). On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years (900-4700, 95% confidence interval).^[53] A third hypothesis relies on the north-to-south gradient of allele frequency in Europe, which shows that the highest allele frequency occurred in the Nordic countries and lowest allele frequency in southern Europe. Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe due to the Viking dispersal in the 8th to 10th centuries.^[54] Vikings were later replaced by the Varangians in Russia, which may have contributed to the observed east-to-west cline of allele frequency.^[52][54]

HIV-1 was initially transmitted from chimpanzees (Pan troglodytes) to humans in the early 1900s in Southeast Cameroon, Africa,

Evidence for a single mutation

Several lines of evidence suggest that the CCR5 Δ32 allele evolved only once.^[52] First, CCR5 Δ32 has a relatively high frequency in several different European populations but is comparatively absent in Asian, Middle Eastern and American Indian populations,^[42] suggesting that a single mutation occurred after divergence of Europeans from their African ancestor.^[42][43][61] Second, genetic linkage analysis indicates that the mutation occurs on a homogeneous genetic background, implying that inheritance of the mutation occurred from a common ancestor.^[53] This was demonstrated by showing that the CCR5 Δ32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 Δ32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele. By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele.^[53] This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 Δ32 alleles arose from a single mutational event. Finally, the CCR5 Δ32 allele has a unique geographical distribution indicating a single Northern origin followed by migration. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%).^[53]

Positive selection

In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%.^[42] Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.

It is estimated that HIV-1 entered the human population in Africa in the early 1900s,^[55] but symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 Δ32 from zero to 10% in 2000 years.

Protection from bubonic plague. Stephens, et al. (1998), suggest that bubonic plague (Yersinia pestis) had exerted positive selective pressure on CCR5 Δ32.^[42] This hypothesis was based on the timing and severity of the Black Death pandemic, which killed 30% of the European population of all ages between 1346 and 1352.^[62] After the Black Death, there were less severe, intermittent epidemics. Individual cities experienced high mortality, but overall mortality in Europe was only a few percent.^[62][63][64] In 1655-1656 a second pandemic called the "Great Plague" killed 15-20% of London's population.^{[65][66][dubious – discuss]} Importantly, the plague epidemics were intermittent. Bubonic plague is a zoonotic disease, primarily infecting rodents, spread by fleas, and only occasionally infecting humans.^[67] Human-to-human infection of bubonic plague does not occur, though it can occur in pneumonic plague, which infects the lungs.^[68] Only when the density of rodents is low are infected fleas forced to feed on alternative hosts such as humans, and under these circumstances a human epidemic may occur.^[67] Based on population genetic models, Galvani and Slatkin (2003) argue that the intermittent nature of plague epidemics did not generate a sufficiently strong selective force to drive the allele frequency of CCR5 Δ32 to 10% in Europe.^[41] To test this hypothesis, Galvani and Slatkin (2003) modeled the historical selection pressures produced by plague and smallpox.^[41]

Protection from smallpox. Plague was modeled according to historical accounts,^[69][70] while age-specific smallpox mortality was gleaned from the age distribution of smallpox burials in York (England) between 1770 and 1812.^[63] Smallpox preferentially infects young, pre-reproductive members of the population since they are the only individuals who are not immunized or dead from past infection. Because smallpox preferentially kills pre-reproductive members of a population, it generates stronger selective pressure than plague.^[41] Unlike plague, smallpox does not have an animal reservoir and is only transmitted from human to human.^[71][72] The authors calculated that if plague were selecting for CCR5 Δ32, the frequency of the allele would still be less than 1%, while smallpox has exerted a selective force sufficient to reach 10%.

The hypothesis that smallpox exerted positive selection for CCR5 Δ32 is also biologically plausible, since poxviruses, like HIV, enter white blood cells using chemokine receptors.^[73] By contrast, Yersinia pestis is a bacterium with a very different biology.

Although Europeans are the only group to have subpopulations with a high frequency of CCR5 Δ32, they are not the only population that has been subject to selection by smallpox, which had a worldwide distribution before it was declared eradicated in 1980. The earliest unmistakable descriptions of smallpox appear in the 5th century A.D. in China, the 7th century A.D. in India and the Mediterranean, and the 10th century A.D. in southwestern Asia.^[72] By contrast, the CCR5 Δ32 mutation is found only in European, West Asian, and North African populations.^[74] The anomalously high frequency of CCR5 Δ32 in these populations appears to require both a unique origin in Northern Europe and subsequent selection by smallpox.

Potential costs

CCR5 Δ32 can be beneficial to the host in some infections (e.g., HIV-1, possibly smallpox), but detrimental in others (e.g., tick-borne encephalitis, West Nile virus). Whether CCR5 function is helpful or harmful in the context of a given infection depends on a complex interplay between the immune system and the pathogen.^[75]

In general, research suggests that the CCR5 Δ32 mutation may play a deleterious role in post-infection inflammatory processes, which can injure tissue and create further pathology.^[76] The best evidence for this proposed antagonistic pleiotropy is found in flavivirus infections. In general many viral infections are asymptomatic or produce only mild symptoms in the vast majority of the population. However, certain unlucky individuals experience a particularly destructive clinical course, which is otherwise unexplained but appears to be genetically mediated. Patients homozygous for CCR5 Δ32 were found to be at higher risk for a neuroinvasive form of tick-borne encephalitis (caused by a flavivirus).^[77] In addition, functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus, another flavivirus; CCR5 Δ32 was associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus.^[78]

This finding in humans confirmed a previously observed experiment in an animal model of CCR5 Δ32 homozygosity. After infection with West Nile virus, CCR5 Δ32 mice had markedly increased viral titers in the central nervous system and had increased mortality^[79] compared with that of wild-type mice, thus suggesting that CCR5 expression was necessary to mount a strong host defense against West Nile virus.

Medical applications

A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for

This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia, and was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with 2 copies of CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.^[7][81] 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.^[7] However, this outcome 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 HIVX4.^[82] After over six years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.^[8]

Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified with a

See also

• Discovery and development of CCR5 receptor antagonists
• Entry inhibitor
• HIV tropism
• Stephen Crohn
• HIV immunity

References