Alternative titles; symbols
HGNC Approved Gene Symbol: CCR5
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:46,370,142-46,376,206 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | {Diabetes mellitus, insulin-dependent, 22} | 612522 | 3 | |
| {Hepatitis C virus, resistance to} | 609532 | 3 | ||
| {HIV infection, susceptibility/resistance to} | 609423 | 3 | ||
| {West nile virus, susceptibility to} | 610379 | 3 |
Samson et al. (1996) cloned a human C-C chemokine receptor gene from a human genomic DNA library based on its similarity to a murine C-C chemokine receptor clone (MOP020). The human gene, which they designated ChemR13, encodes a 352-amino acid protein (designated CCCKR5 by them) with a calculated molecular mass of 40,600 Da and a potential N-linked glycosylation site. With a set of overlapping lambda clones, they showed that the gene is 17.5 kb from the CMKBR2 gene (CCR2; 601267). The 2 coding regions share 75% DNA and amino acid sequence identity.
Mummidi et al. (1997) analyzed the genomic structure of CCR5, which contains 4 exons, spanning approximately 6 kb, and only 2 introns. There is no intron between exons 2 and 3. Exon 4 contains the open reading frame, the complete 3-prime UTR, and 11 nucleotides of the 5-prime UTR. Transcripts are initiated from 2 distinct promoters, both of which are AT-rich and lack canonical TATA or CAAT motifs; one is upstream of exon 1 and the other downstream, including the 'intronic' region between exons 1 and 3. Complex alternative splicing patterns in the 5-prime UTR and in the 4 exons give rise to multiple CCR5 transcripts. The regulatory sequences and noncoding exons are polymorphic, whereas the protein sequence is not.
By radiation hybrid mapping, Liu et al. (1996) localized the CCR5 gene (designated CKR5 by them) to chromosome 3p21.
Using Northern blot analysis, Bonecchi et al. (1998) showed that polarized Th1 cells preferentially express CXCR3 (300574) and CCR5. In contrast, Th2 cells preferentially express CCR4 (604836) and, at least in a subpopulation of Th2 cells, CCR3 (601268).
Samson et al. (1996) functionally expressed the CCR5 gene in a stably transfected CHO-K1 cell line. In transfected cells, macrophage inflammatory protein (MIP)-1-alpha (182283) appeared to be the most potent agonist for CCCKR5, with MIP-1-beta (CCL4; 182284) and RANTES (CCL5; 187011) also active at physiologic concentrations. Samson et al. (1996) detected transcript from the gene in a promyeloblastic cell line, which suggested a potential role for the chemokine receptor in granulocyte lineage proliferation and differentiation.
The C-C chemokine receptor CMKBR5 was identified as a coreceptor for the human immunodeficiency virus-1 (HIV-1) by Deng et al. (1996) and Dragic et al. (1996). CMKBR5 and fusin (CXCR4; 162643) facilitate the fusion of HIV-1 with the plasma membrane of CD4+ cells (CD4; 186940). Deng et al. (1996) found that CMKBR5, and not fusin, promotes entry of the macrophage-tropic viruses believed to be the key pathogenic strains in vivo.
Dragic et al. (1996) showed that MIP-1-alpha, MIP-1-beta, and RANTES each inhibit infection of CD4+ cells by primary, nonsyncytium-inducing (NSI) HIV-1 strains at the virus entry stage and also block env-mediated cell-cell fusion. Both groups showed that expression of the CCCKR5 protein renders nonpermissive CD4+ cells susceptible to infection by HIV-1 strains (see 609423). Alkhatib et al. (1996) reported similar observations and detected mRNA for the receptor only in cell types susceptible to macrophage-tropic isolates of HIV-1. See also Choe et al. (1996), who implicated both CCR5 and CCR3 in the ability of HIV-1 to infect cells expressing those receptors.
Using a panel of monoclonal antibodies specific for human CCR5, Rottman et al. (1997) showed by immunohistochemistry and flow cytometry that CCR5 is expressed by bone marrow-derived cells known to be targets for HIV-1 infection, including a subpopulation of lymphocytes and monocytes/macrophages in blood, primary and secondary lymphoid organs, and noninflamed tissues. In the central nervous system, CCR5 was expressed on neurons, astrocytes, and microglia. In other tissues, CCR5 was expressed on epithelium, endothelium, vascular smooth muscle, and fibroblasts. Chronically inflamed tissues contained an increased number of CCR5-positive mononuclear cells, and the number of immunoreactive cells was directly associated with a histopathologic correlate of inflammatory severity. The results suggested that CCR5-positive cells are recruited to inflammatory sites and, as such, may facilitate transmission of macrophage-tropic strains of HIV-1.
Zagury et al. (1998) found that there were factors other than CCR5 polymorphisms accounting for the fact that exposure to HIV-1 does not usually lead to infection. Although this fact could be because of insufficient virus titer, there is abundant evidence that some individuals resist infection even when directly exposed to a high titer of HIV. This protection is related to homozygous mutations in CCR5, the receptor for the beta-chemokines, and earlier studies had shown that the same chemokines markedly suppressed the nonsyncytial inducing variants of HIV-1, the chief virus type transmitted from person to person. However, CCR5 mutations are not likely to be the unique mechanism of protection because HIV-1 variants can use other chemokine receptors as their coreceptor and, indeed, infection has been demonstrated within the presence of such mutations. Zagury et al. (1998) found transient natural resistance over time of most of 128 hemophiliacs who were inoculated repeatedly with HIV-1-contaminated factor VIII (300841) concentrate from plasma during 1980 to 1985, before the development of the HIV blood test. Furthermore, and remarkably, 14 subjects remained unaffected to the time of the report, and in these subjects homozygous CCR5 mutations were found in none, but in most of them there was overproduction of beta-chemokines. In vitro experiments confirmed the potent anti-HIV suppressive effect of these chemokines. The chemokines studied were generically referred to as MMR, an abbreviation for MIP-1-alpha, MIP-1-beta, and RANTES.
Farzan et al. (1999) showed that the chemokine receptor CCR5, a principal HIV-1 coreceptor, is posttranslationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines. Sulfated tyrosines contributed to the binding of CCR5 to MIP-1-alpha, MIP-1-beta, and HIV-1 gp120/CD4 complexes, and to the ability of HIV-1 to enter cells expressing CCR5 and CD4. Farzan et al. (1999) concluded that tyrosine sulfation may contribute to the natural function of many 7-transmembrane-segment receptors and may be a modification common to primate immunodeficiency virus coreceptors.
The HIV-1 envelope glycoprotein gp120 interacts consecutively with CD4 and the CCR5 coreceptor to mediate the entry of certain HIV-1 strains into target cells. Cormier et al. (2000) presented results indicating that amino acids 2-18 of the CCR5 amino-terminal domain compose a gp120-binding site that determines specificity of the interaction between CCR5 and gp120s from 2 HIV-1 isolates. Posttranslational sulfation of the tyrosine residues in the CCR5 N terminus is required for gp120 binding and may modulate critically the susceptibility of target cells to HIV-1 infection in vivo.
Using immunofluorescence microscopy, Yeaman et al. (2004) examined expression of the HIV receptors CD4 and galactosylceramide (see GALC; 606890) and the HIV coreceptors CXCR4 and CCR5 in ectocervical specimens from hysterectomy patients with benign diseases. CD4 expression was detected on epithelial cells at early and midproliferative stages of the menstrual cycle, whereas galactosylceramide expression was uniform in all stages of the menstrual cycle. CXCR4 was not detected on ectocervical epithelial cells, whereas CCR5 was expressed on ectocervical epithelial cells at all stages of the menstrual cycle. CD4-positive leukocytes were present in the basal and precornified layers of squamous epithelium during early and midproliferative phases of the menstrual cycle, but were absent in later proliferative phases and the secretory phase; the presence of CD4-positive leukocytes was not related to inflammation. Yeaman et al. (2004) concluded that HIV infection of the ectocervix most likely occurs through galactosylceramide and CCR5.
Using bronchoalveolar lavage and flow cytometry, Campbell et al. (2001) determined that T lymphocytes homing to the lung in both normal and asthmatic subjects express CCR5 and CXCR3 but not CCR9 (604738), which is found on T cells homing to intestinal mucosal sites, or CLA (see SELPLG; 600738), which is found on skin-homing T cells.
Using mouse splenic dendritic cells (DCs) and DCs from Ccr5 -/- mice and Myd88 (602170) -/- mice, Aliberti et al. (2003) found that Toxoplasma gondii stimulated Il12 (161560) production not only through a Toll-like receptor/Myd88-dependent mechanism, but also through the release of an 18-kD protein, cyclophilin-18 (C18), that interacted directly with Ccr5 on DCs. Cyclosporin A, a major ligand of cyclophilin, or anti-C-18 inhibited Il12 production in DCs. Aliberti et al. (2003) concluded that C18 is a molecular mimic of a CCR5 chemokine ligand.
Once virus-infected cells are eliminated by cytotoxic lymphocytes, removal of these dead cells requires macrophage clearance without the macrophages being killed by virus. Tyner et al. (2005) showed that Ccl5-deficient mice had delayed viral clearance, excessive airway inflammation, and respiratory death after infection with either murine parainfluenza or human influenza viruses. CCL5 was required to hold apoptosis and mitochondrial dysfunction in check in virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo, and the protective effect of CCL5 required activation of CCR5 and the downstream ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and AKT (164730) signaling pathways.
IL16 (603035) binds to CD4 and induces a migratory response in CD4-positive T cells. Lynch et al. (2003) observed a preferential migratory response in mouse Th1 cells, which express Ccr5, compared with Th2 cells, which express little Ccr5. T cells from Ccr5-deficient mice were unable to migrate in response to Il16. In transfected human osteosarcoma cells, the presence of CCR5 significantly increased IL16 binding compared with CD4 alone; however, IL16 could not bind CCR5 alone. Lynch et al. (2003) concluded that augmentation of IL16 stimulation by CCR5 plays a role in regulation of Th1 cell recruitment and activation at sites of inflammation.
Castellino et al. (2006) reported that naive mouse CD8 (see 186910)-positive T cells upregulated expression of Ccr5 after immunization and before antigen recognition, allowing them to be attracted to sites of antigen-specific dendritic cell-CD4-positive T-cell interaction where Ccl3 and Ccl4 are produced. Blockage of Ccl3/Ccl5-Ccr5 binding reduced CD8-positive T-cell accumulation and the ability of CD4-positive T cells to promote generation of memory CD8-positive T cells. Castellino et al. (2006) concluded that early, nonrandom cell clustering around limiting numbers of antigen-loaded dendritic cells, promoted by this cascade of chemokine-mediated events, leads to optimum T-cell activation.
Floto et al. (2006) found that mycobacterial heat-shock protein 70 (HSP70; see 140550), in addition to enhancing antigen delivery to human dendritic cells, signals through the CCR5 chemokine receptor, promoting dendritic cell aggregation, immune synapse formation between dendritic cells and T cells, and the generation of effector immune responses. They demonstrated that a mycobacterial lysate, as well as purified mycobacterial HSP70, stimulated a CCR5-dependent calcium response, indicating further connection between the innate and adaptive immune responses during mycobacterial infection. Floto et al. (2006) concluded that CCR5 acts as a pattern-recognition receptor for mycobacterial Hsp70, which has implications for both the pathophysiology of tuberculosis and the use of mycobacterial heat-shock proteins in tumor-directed immunotherapy.
Gulati et al. (2006) investigated the expression of chemokine receptor CCR5 in the conjunctival epithelium in 45 patients with dry eye syndromes and 15 control individuals. They found a significant up-regulation in cell surface expression of CCR5 in patients with either aqueous tear-deficient (e.g., Sjogren syndrome; 270150) or evaporative forms of dry eye syndrome. The majority of the cells expressing CCR5 were non-bone marrow-derived resident epithelial cells of the conjunctiva, suggesting a role of ocular surface epithelial cells in modulating immunoinflammatory responses in dry eye syndromes. Gulati et al. (2006) suggested that chemokine receptor CCR5 or its ligands might serve as useful targets for modulation of these responses.
Using flow cytometry and ELISA, Sato et al. (2007) found that CCR2-positive, but not CCR2-negative, CD4-positive T cells produced IL17. Within the CCR2-positive population, CCR5-positive cells produced IFNG (147570) and CCR5-negative cells produced IL17 (603149). Sato et al. (2007) concluded that human Th17 cells are CCR2-positive/CCR5-negative.
By phylogenetic analysis, Toda et al. (2009) found that the C-terminal region of CCR5 has high homology to that of CCR2, which interacts with FROUNT (NUP85; 170285). Yeast 2-hybrid and coimmunoprecipitation analyses demonstrated that the CCR2-binding domain of FROUNT bound to the C termini of CCR2 and CCR5, but not to those of CCR1 (601159), CCR3, or CXCR4. CCL4, a CCR5 ligand, induced chemotaxis in cells expressing CCR5 and intact FROUNT. Toda et al. (2009) concluded that FROUNT is a common regulator of CCR2 and CCR5.
KLF2 (602016) is a transcription factor that promotes T-cell quiescence and regulates T-cell migration. Richardson et al. (2012) found that CD4-positive T cells stimulated with phytohemagglutinin plus IL2 (147680) had increased expression of KLF2 and CCR5 and increased susceptibility to infection with HIV-1 compared with T cells stimulated with immobilized anti-CD3 (see 186740) and anti-CD28 (186760). Enhanced expression of KLF2 did not regulate expression of chemokine receptor ligands (e.g., CCL3) that downregulate CCR5 expression. Knockdown of KLF2 in CD4-positive T cells via small interfering RNA resulted in reduced CCR5 expression. Chromatin immunoprecipitation analysis showed that KLF2 bound to the CCR5 promoter in resting, but not CD3/CD28-activated, CD4-positive T cells. Transduction of KLF2 induced CCR5 in some, but not all, transformed T-cell lines. CCR5 upregulation after KLF2 transduction restored susceptibility to CCR5-tropic HIV-1 in the Jurkat T-cell line, which expresses little to no KLF2. Richardson et al. (2012) concluded that KLF2 is a host factor that modulates CCR5 expression in CD4-positive T cells and influences susceptibility to CCR5-tropic viruses.
Alonzo et al. (2013) identified the human immunodeficiency virus coreceptor CCR5 as a cellular determinant required for cytotoxic targeting of subsets of myeloid cells and T lymphocytes by the Staphylococcus aureus leukotoxin ED (LukED). Alonzo et al. (2013) further demonstrated that LukED-dependent cell killing is blocked by CCR5 receptor antagonists, including the HIV drug maraviroc. Remarkably, Ccr5-deficient mice are largely resistant to lethal S. aureus infection, highlighting the importance of CCR5 targeting in S. aureus pathogenesis.
Belew et al. (2014) described a programmed -1 ribosomal frameshift (-1 PRF) signal in the human mRNA encoding CCR5, the HIV-1 coreceptor. CCR5 mRNA-mediated -1 PRF is directed by an mRNA pseudoknot, and is stimulated by at least 2 microRNAs, MIR1224 (611620) and MIR141 (612093). Mapping the mRNA-miRNA interaction suggested that formation of a triplex RNA structure stimulates -1 PRF. A -1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay pathway. At least 1 additional mRNA decay pathway is also involved. Belew et al. (2014) reported that functional -1 PRF signals regulated by miRNAs are also demonstrated in mRNAs encoding 6 other cytokine receptors, suggesting a novel mode through which immune responses may be fine-tuned in mammalian cells.
Marques et al. (2015) observed reduced replication of dengue virus (DENV; see 614371) in mouse and human monocytes treated with an antagonist of CCR5 expression. DENV induced expression of CCR5 ligands, and CCR activation was required for permissiveness to DENV replication. CCR5 did not act as a DENV receptor, but it colocalized with DENV at the macrophage membrane. Based on these findings and studies in mice (see ANIMAL MODEL), Marques et al. (2015) concluded that CCR5 contributes to DENV replication in vitro and to disease development in vivo.
Implications for HIV-1 Treatment
To test the possibility that strategies aiming to prevent or limit expression of CCR5 might be beneficial in the treatment of HIV-1 disease, Steinberger et al. (2000) developed a CCR5-specific single-chain antibody that was expressed intracellularly and retained in the endoplasmic reticulum. This CCR5 intrabody efficiently blocked surface expression of human and rhesus CCR5 and thus prevented cellular interactions with CCR5-dependent HIV-1 and simian immunodeficiency virus (SIV) envelope glycoprotein. Intrabody-expressing cells were shown to be highly refractory to challenge with R5 HIV-1 viruses or infected cells. These results suggested that gene therapy approaches that deliver this intracellular antibody could be of benefit to infected individuals. Because the antibody reacts with a conserved primate epitope on CCR5, the authors pointed out that this strategy could be tested in nonhuman lentivirus models of HIV-1 disease.
Strizki et al. (2001) described a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. It had no effect on infection of CXCR4 (162643)-expressing cells. The molecule, called SCH-C, has an oral bioavailability in rodents and primates of 50 to 60% and a serum half-life of 5 to 6 hours. Thus, it was a promising new candidate for therapeutic intervention for HIV infection.
Double-stranded RNAs approximately 21 nucleotides long, called small interfering RNAs (siRNAs), are powerful reagents to reduce the expression of specific genes. Effective methods for introducing siRNAs into cells are required to use them as reagents to protect cells against viral infection. Qin et al. (2003) successfully constructed a lentivirus-based vector to introduce siRNAs against the HIV-1 coreceptor CCR5 into human peripheral blood T lymphocytes. Specific inhibition of CCR5 expression on the cell surface was observed. Blocking of CCR5 expression by siRNAs provided a substantial protection for the lymphocyte population from CCR5-tropic HIV-1 virus infection.
Crystal Structure
Huang et al. (2007) applied nuclear magnetic resonance and crystallographic techniques to analyze the structure of the CCR5 N terminus and that of the tyrosine-sulfated antibody 412d in complex with HIV-1 gp120 and CD4. The conformations of tyrosine-sulfated regions of CCR5 (alpha-helix) and 412d (extended-loop) are surprisingly different. Nonetheless, a critical sulfotyrosine on CCR5 and on 412d induces similar structural rearrangements in gp120. Huang et al. (2007) concluded that their results provided a framework for understanding HIV-1 interactions with the CCR5 N terminus during viral entry and defined a conserved site on gp120, whose recognition of sulfotyrosine engenders posttranslational mimicry by the immune system.
Tan et al. (2013) reported the 2.7-angstrom-resolution crystal structure of human CCR5 bound to the HIV drug maraviroc. The structure revealed a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 (162643) crystal structures, along with models of coreceptor-gp120-V3 complexes, suggested that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 coreceptor selectivity.
Some individuals remain uninfected by HIV-1 despite repeated exposure to the virus. Both Liu et al. (1996) and Samson et al. (1996) identified a molecular basis for such HIV-1 resistance. Samson et al. (1996) postulated that variants of the CMKBR5 gene may be responsible for relative or absolute resistance to HIV-1 infection. In an HIV-1-infected patient with slow disease progression, Samson et al. (1996) identified a heterozygous 32-bp deletion in the CMKBR5 gene (601373.0001) that results in a frameshift and premature termination of translation of the transcript. Liu et al. (1996) identified the same homozygous 32-bp deletion with CMKBR5 in 2 individuals who, though multiply exposed to HIV-1 infection, remained uninfected. Liu et al. (1996) found that the deletion comprises nucleotides 794 to 825 of the cDNA sequence and results in a reading frameshift after amino acid 174, inclusion of 7 novel amino acids, and truncation at codon 182. They showed that the severely truncated protein could not be detected at the surface of cells that normally express the protein. Samson et al. (1996) stated that the mutant protein lacks the last 3 of 7 putative transmembrane regions of the receptor as well as regions involved in G protein coupling and signal transduction. Through in vitro fusion assays, both Liu et al. (1996) and Samson et al. (1996) determined that the truncated receptor did not allow fusion of CD4+ cells with cells expressing env protein from either macrophage-tropic or dual-tropic viruses. Samson et al. (1996) found that coexpression of the deletion mutant with wildtype CCR5 reduced the fusion efficiency of 2 different viral envelope proteins in 3 independent experiments.
Dean et al. (1996) reported results of their CKR5 studies in 1,955 individuals included in 6 well-characterized AIDS cohort studies. They identified 17 individuals who were homozygous for the CKR5 32-bp deletion allele (601373.0001). Deletion homozygotes occurred exclusively among the 612 members of the HIV-1-exposed, antibody-negative group and not at all in 1,343 HIV-1 infected individuals. The frequency of the CKR5 deletion heterozygotes was significantly elevated in groups of individuals who had survived HIV-1 infection for more than 10 years. In some risk groups the frequency of CKR5 deletion heterozygotes was twice as frequent as in groups with rapid progressors to AIDS. Survival analysis clearly showed that the disease progression was slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 allele. Dean et al. (1996) postulated that the CKR5 32-bp deletion may act as 'a recessive restriction gene against HIV-1 infection' and may exert a dominant phenotype of delayed progression to AIDS among infected individuals. Dean et al. (1996) reported that in addition to the CKR5 32-bp deletion allele, they found unique single-strand conformation polymorphisms (SSCPs) in other patients, some of whom were long-term nonprogressors. They speculated that at least some of these alleles disrupt CKR5 function and inhibit the spread of HIV-1 or the progression to AIDS. Dean et al. (1996) recommended that the entire coding region of CKR5 be screened in nonprogressors and in rapid progressors to identify other CKR5 variants.
To determine the role of the 32-bp deletion in CKR5 in HIV-1 transmission and disease progression, Huang et al. (1996) analyzed the CKR5 genotype of 1,252 homosexual men enrolled in the Chicago component of the Multicenter AIDS Cohort Study. No infected participant was found to be homozygous for the 32-bp deletion allele, whereas 3.6% of at-risk but uninfected Caucasian participants were homozygous, showing the highly protective role of this genotype against sexual acquisition of HIV-1. No evidence was found that suggested heterozygotes were protected against HIV-1 infection, but a limited protective role against disease progression was noted.
Zimmerman et al. (1997) reported results of a large study that analyzed the frequency of the 32-bp deletion allele of CMKBR5 in populations from North America, Asia, and Africa (see 601373.0001). Ansari-Lari et al. (1997) also published data on the population frequencies of various mutations in CCR5. The study indicated that the mutations are relatively specific to different ethnicities; apart from the 32-bp deletion allele in the American Caucasian population, and 2 alleles in Chinese and Japanese populations (see 601373.0002), the CCR5 locus did not show a high degree of genetic variation. The authors stated that, while additional population screening at this locus might identify other sequence variants, their frequencies are likely to be less than 0.01. The frequency of the 32-bp deletion allele in American Caucasians was approximately 0.16, a value somewhat higher than that previously reported for this group.
Smith et al. (1997) analyzed 2-locus genotypes and found that the 32-bp deletion at the CCR5 locus and the 64I allele at the CCR2 locus (601267.0001) are in strong, perhaps complete, linkage disequilibrium with each other. This means that CCR5-del32 invariably occurs on a chromosome with allele CCR2-64V, whereas CCR2-64I occurs on a chromosome that has the wildtype (undeleted) allele at the CCR5 locus. Thus, they could estimate the independent effects of the CCR2 and CCR5 polymorphisms. An estimated 38 to 45% of AIDS patients who had rapid progression of less than 3 years from HIV-1 exposure to onset of AIDS symptoms could be attributed to their wildtype status at one or the other of these loci, whereas the survival of 28 to 29% of long-term survivors, who avoided AIDS for 16 years or more, could be explained by a mutant genotype for CCR2 or CCR5.
Biti et al. (1997) reported an HIV-infected, asymptomatic individual of European descent who was found to be homozygous for the 32-bp deletion. The presence of homozygosity was supported by genotyping his sole surviving parent (a heterozygote) and his sibs (a CCR5-del32 homozygous brother, a heterozygous brother, and a CCR5 wildtype homozygous sister). The patient presented in 1992 with a seroconversion-like illness of 1-month duration, at which time he was diagnosed HIV-1 seropositive by Western blot. At the time of their report, his CD4+ T-cell count was 460, and a plasma RNA viral load test showed 19,000 copies per milliliter. Biti et al. (1997) noted that the tropism of the infecting HIV-1 strain was still under investigation.
Cohen et al. (1997) studied a cohort of 33 HIV-1 nonprogressors and compared 21 patients who were homozygous wildtype at the CCR5 locus with 12 who were heterozygous for the 32-bp deletion mutation in CCR5. There were no differences in CD4+ or CD8+ T-cell counts, or in plasma or lymph node viral loads. The authors concluded that CCR5 is not the sole determinant of long-term nonprogression in some HIV-1 infected individuals. Although no differences were detected at an average of 11 years postinfection, the authors suggest that CCR5 may still play a role in nonprogression by limiting viral replication during acute infection.
Martin et al. (1998) showed by genetic association analysis of 5 cohorts of people with AIDS that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of the genotypes bearing CCR5P1, CCR5-delta-32, CCR2-64I (see 601267), and SDF1-3-prime A (see 600835) affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17% of patients who developed AIDS within 3.5 years of HIV-1 infection did so because they were homozygous for CCR5P1/P1, and 7 to 13% of all people carry this susceptible genotype. The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors limiting AIDS disease progression.
CCR5 and CCR2 are tightly linked on 3p22-p21, separated by 20 kb. Common allelic variants in both genes are associated with slower progression to AIDS after infection. The protective influences of CCR5-delta-32 and CCR2-64I are independent in AIDS cohorts, and the 2 mutations have never been found on the same chromosome haplotype. The physical proximity of CCR2 and CCR5, the equivalent functional efficiency of alternative CCR2 allelic products as chemokine or HIV-1 coreceptors, and the rarity of HIV-1 strains that use the CCR2 receptor led to the speculation that CCR2-64I may be hitchhiking (or tracking by linkage disequilibrium) with an undiscovered CCR5 variant, perhaps in the cis-regulatory region, that is directly responsible for the CCR2-64I protective effect. Martin et al. (1998) found that among 2,603 individuals enrolled in 5 AIDS cohorts, CCR2-64I was always found on a CCR5P1-bearing haplotype and that CCR5-delta-32 was consistently found on a CCR5P1 haplotype as well. All 43 CCR2-64I/64I homozygotes were always CCR5P1/P1 homozygotes. Similarly, all 18 CCR5-delta-32/delta-32 homozygotes were CCR5P1/P1 homozygotes. Finally, none of 657 individuals who lacked the CCR5P1 allele had either the CCR5-delta-32 or the CCR2-64I allele. Thus the entire CCR2-CCR5 complex can be considered as a 6-allele genotype system, based on the composite CCR2 and CCR5 haplotype.
In a denaturing high-pressure liquid chromatography (DHPLC) screen of AIDS patients, Martin et al. (1998) detected 4 common allelic variants (CCR5P1-P4); 6 rare alleles (CCR5P5-P10) were discovered as heterozygotes upon subsequent single-strand conformation polymorphism (SSCP) screening of 5 AIDS cohorts. Sequence analysis of the CCR5 promoter region of individuals homozygous for the CCR5P1-P4 variants and heterozygotes of the 6 rare variants revealed 10 polymorphic nucleotide positions that described 10 CCR5 promoter haplotype alleles, referred to as promoter alleles. McDermott et al. (1998) reported a G/T variant, corresponding to position 303 of the promoter region, that showed an epidemiologic association with rapid progression to AIDS.
Martin et al. (1998) observed no significant differences in CCR5P allele or genotype frequencies in Caucasians or African Americans.
Carrington et al. (1999) reviewed the growing number of genetic variants within the coding and 5-prime regulatory region of CCR5 that had been identified, several of which have functional consequences for HIV-1 pathogenesis. The findings provided logic for the development of therapeutic strategies that target the interaction of HIV-1 envelope and CCR5 in HIV-1 associated disease.
Blanpain et al. (2000) investigated the functional consequences of 16 natural CCR5 mutations (in addition to the 32-bp deletion) described in various human populations. They found that 10 of these variants behaved normally; 6 were characterized by major alterations in their functional response to chemokines, as a consequence of intracellular trapping and poor expression at the cell surface, general or specific alteration of ligand-binding affinities, or relative inability to mediate receptor activation. In addition to the 32-bp deletion, only the C101X (601373.0005) mutation was totally unable to mediate entry of HIV-1. The fact that nonfunctional CCR5 alleles are relatively frequent in various human populations reinforces the hypothesis of a selective pressure favoring these alleles.
Gonzalez et al. (1999) presented findings indicating that the CCR5 haplotypes associated with altered rates of HIV-1 disease progression in Caucasians were different from those in African Americans. The heterogeneous distribution of CCR5 haplotypes in the ethnic groups may influence the results of genotype-phenotype association studies. The findings also highlighted the importance of understanding the evolutionary context in which disease-associated haplotypes are found and underscored the potential impact of allele-allele interactions, especially between alleles with different evolutionary histories. Gonzalez et al. (1999) commented as follows: 'Given that defining the phenotypic effects of variation in the human genome is one of the next major challenges in genetic medicine, our studies illustrate the complexity of the relationships that are certain to be encountered.'
The studies of Gonzalez et al. (1999) started from the fact that human populations have varied evolutionary histories and have coevolved with different combinations of microbes. Hence, the repertoire of alleles that afford resistance or susceptibility to pathogens may vary in different populations, as indicated for malaria by Hill (1998) (see 611162).
As more single-nucleotide polymorphism (SNP) marker data become available, researchers have used haplotypes of markers, rather than individual polymorphisms, for association analysis of candidate genes. Clark et al. (2001) characterized haplotypes comprising alleles at 7 biallelic loci in the CCR2 (601267)-CCR5 chemokine receptor gene region, a span of 20 kb on chromosome 3p21. The 40 3-generation CEPH families were genotyped. Both pedigree analysis and the Expectation-Maximization (EM) algorithm yielded the same small number of haplotypes for which linkage disequilibrium was nearly maximal. For genetic epidemiology studies, CCR2-CCR5 allele and haplotype frequencies were determined in 30 African-American, 24 Hispanic, and 34 European-American populations.
HIV-1 susceptibility and time to progression to AIDS have been associated with polymorphisms in CCR5. Many of these polymorphisms are located in the 5-prime cis regulatory region of CCR5, suggesting that it may have been a target of natural selection. Bamshad et al. (2002) characterized CCR5 sequence variation in this region in 400 chromosomes from worldwide populations and compared this variation to a genomewide analysis of 100 Alu polymorphisms typed in the same populations. Variation was substantially higher than expected and characterized by an excess of intermediate frequency alleles. A genealogy of CCR5 haplotypes had deep branch lengths despite markedly little differentiation among populations. This finding suggested a deviation from neutrality not accounted for by population structure, which was confirmed by tests for natural selection. The results of the study by Bamshad et al. (2002) provided strong evidence that balancing selection has shaped the pattern of variation in CCR5 and suggested that HIV-1 resistance afforded by CCR 5-prime cis-regulatory region haplotypes may be the consequence of adaptive changes to older pathogens.
The most common mode of acquiring HIV infection is by sexual transmission across genital epithelial tissue. Studies in rhesus macaques exposed intravaginally to SIV suggested that Langerhans cells (LCs), the resident DCs of stratified squamous epithelia, are the first cells to encounter virus. Kawamura et al. (2003) found that HIV infection of LCs ex vivo and LC-mediated transmission of virus to CD4+ T cells were both dependent on CCR5. By contrast, transfer of infection from monocyte-derived DCs to CD4+ T cells was mediated by CCR5-dependent as well as DC-specific ICAM3-grabbing nonintegrin (604672)-dependent pathways. Furthermore, in 62 healthy individuals, HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for a 32-bp deletion in the open reading frame of the CCR5 gene (601373.0001) revealed that LCs isolated from individuals heterozygous for the deletion were significantly less susceptible to HIV when compared with LCs isolated from homozygous wildtype individuals (P = 0.016). Strikingly, further genetic analyses of the -2459A/G (601373.0009) CCR5 promoter polymorphism in individuals heterozygous for the 32-bp deletion revealed that individuals heterozygous at both loci were markedly less susceptible to HIV than were LCs from -2459A/A individuals who were heterozygous for the 32-bp deletion (P = 0.012). These genetic susceptibility data in LCs paralleled those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. This led Kawamura et al. (2003) to suggest that CCR5-mediated infection of the LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection.
Nakajima et al. (2003) found association between the 59029A allele (601373.0006) and diabetic nephropathy (see 603933) in Japanese patients.
AIDS restriction genes (ARGs) are genes with polymorphic variants in loci that regulate HIV-1 cell entry, acquired and innate immunity, and cytokine defenses to HIV-1. O'Brien and Nelson (2004) stated that the CCR5 794del32 mutation (601373.0001), which blocks HIV-1 infection, was the first identified ARG variant, and reviewed genetic association studies that had demonstrated 13 additional ARGs.
Glass et al. (2006) analyzed the distribution of CCR5 delta-32 in independent cohorts of West Nile virus (see 610379)-seropositive individuals. They observed a strong deviation from Hardy-Weinberg equilibrium due to an increased frequency of delta-32 homozygotes. The delta-32 homozygotes also had increased risk of fatal WNV infection. Glass et al. (2006) concluded that CCR5 delta-32 is a risk factor for symptomatic WNV infection. In a review, Lim et al. (2006) noted that CCR5 is a target for drug development in HIV/AIDS, but the benefits of blocking CCR5 may carry an increased risk of WNV disease.
Ahuja et al. (2008) found that variations in CCL3L1 (601395) copy number and CCR5 genotype, but not HLA alleles, influenced immune reconstitution after highly active antiretroviral therapy (HAART) in HIV-infected individuals, particularly when HAART was initiated at less than 350 CD4-positive T cells/mm3. CCL3L1-CCR5 genotypes favoring CD4-positive T-cell recovery were similar to those that reduced CD4-positive T-cell depletion in the pre-HAART era, suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes. Ahuja et al. (2008) proposed that CCL3L1-CCR5 variations may be useful in identifying patients requiring earlier initiation of HAART.
Although CD4 was identified initially as the cellular receptor for HIV, several lines of evidence indicated that expression of CD4 alone was insufficient to confer susceptibility to infection by the virus. Specifically, HIV did not infect mouse cells transfected with a human CD4 expression vector or mice transgenic for the expression of human CD4. Furthermore, although HIV binding and internalization can be mediated by CD4 acting together with one of several members of the chemokine receptor superfamily, CCR5 appears to be the critical coreceptor used by HIV in the initial stages of infection. However, because mouse CCR5 differs significantly from human CCR5, it cannot function as a coreceptor for HIV, and thus, expression of human CD4 alone is insufficient to permit entry of HIV into mouse cells. Browning et al. (1997) found that mice transgenic for both CD4 and CCR5 are susceptible to HIV infection.
To determine whether ablation of CCR5 would inhibit the development of corneal neovascularization, Ambati et al. (2003) created mice with targeted homozygous disruption of the CCR5 gene. These CCR5-deficient mice showed a persistent 34 to 35% inhibition of corneal neovascularization for up to 4 weeks. This inhibition correlated with reduced expression of vascular endothelial growth factor (VEGF; 192240). These data implicated CCR5 as 1 essential component in the development of corneal neovascularization.
CCR5 is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, Belnoue et al. (2003) investigated whether CCR5 plays a role in the pathogenesis of experimental cerebral malaria. They found that whereas 70 to 85% of wildtype and Ccr5 +/- mice infected with Plasmodium berghei ANKA developed cerebral malaria, whereas only about 20% of Plasmodium-infected Ccr5-deficient mice exhibited the characteristic neurologic signs of cerebral malaria. Other observations supported the conclusion that CCR5 is an important factor in the development of experimental cerebral malaria.
To test whether the CCR5-delta-32 mutation would lead to protection from Yersinia pestis infection, Mecsas et al. (2004) infected CCR5-deficient and CCR5-expressing mice by orogastric lavage with Y. pseudotuberculosis or intravenously with Y. pestis. There was no significant difference in the bacterial load in the caecum or in Peyer patches at 2 or 4 days postinfection between C57BL/6 CCR5-deficient and CCR5-expressing mice following oral infection. Macrophages from CCR5-deficient animals showed little to no difference in bacterial growth of Y. pseudotuberculosis or Y. pestis compared with those from CCR5-expressing mice. Mecsas et al. (2004) concluded that their results argue against CCR5 being essential for infection by Y. pestis or Y. pseudotuberculosis, and noted that a modeling study by Galvani and Slatkin (2003) suggested that smallpox, rather than plague, is the disease that selected for the CCR5-delta-32 allele.
To test the effect of Ccr5 on survival after Y. pestis infection, Elvin et al. (2004) challenged groups of specific pathogen-free Ccr5 +/+ and Ccr5 -/- mice with lethal inocula of Y. pestis GB, a highly virulent strain isolated from a fatal human case of plague. Additionally, they performed phagocytosis experiments with macrophages from Ccr5-deficient and wildtype mice. Although like Mecsas et al. (2004) the authors did not see any difference in the survival of the 2 groups of mice, they did observe significantly reduced uptake of Y. pestis by Ccr5-deficient macrophages in vitro.
To elucidate the relative contributions of CCR2 and CCR5 in collagen-induced arthritis and collagen antibody-induced arthritis, Quinones et al. (2004) genetically inactivated the 2 receptors in an arthritis-prone murine strain. Contrary to expectations, they found that Ccr2-null mice had markedly enhanced susceptibility to both collagen-induced and collagen antibody-induced arthritis, whereas the Ccr5-null mice had an arthritis phenotype similar to that of wildtype mice. Quinones et al. (2004) concluded that CCR2 serves a protective role in rheumatoid arthritis and that there are likely alternative receptors responsible for monocyte/macrophage accumulation in inflamed joints.
Algood and Flynn (2004) found that Ccr5-deficient mice controlled tuberculosis infection, formed granulomas, and induced a Th1 response comparable to that seen in wildtype mice. Ccr5-deficient mice recruited greater numbers of lymphocytes and higher levels of inflammatory cytokines to the lung compared with wildtype mice, with no apparent detrimental effects.
To determine whether patterns of genetic variation at the 5-prime cis-regulatory region of the CCR5 gene in chimpanzees are similar to those in humans, Wooding et al. (2005) analyzed patterns of DNA sequence variation in 37 wild-born chimpanzees, along with published 5-prime CCR5 data from 112 humans and 50 noncoding regions in the human and the chimpanzee genomes. These analyses showed that patterns of variation in 5-prime CCR5 differ dramatically between chimpanzees and humans. In chimpanzees, 5-prime CCR5 was less diverse than 80% of noncoding regions and was characterized by an excess of rare variants. In humans, 5-prime CCR5 was more diverse than 90% of noncoding regions and had an excess of common variants. Under a wide range of demographic histories, these patterns suggested that, whereas human 5-prime CCR5 had been subject to balancing selection, chimpanzee 5-prime CCR5 had been influenced by a selective sweep. This result suggested that chimpanzee 5-prime CCR5 might harbor or be linked to functional variants that influence chimpanzee resistance to disease caused by both simian immunodeficiency virus (SIVcpz) and HIV-1.
Using RNase protection and RT-PCR analyses, Glass et al. (2005) identified a number of factors associated with a Th1-type immune response in mouse brain following West Nile virus (WNV) infection. ELISA analysis showed greatest induction of Ccl5, although other cytokines, chemokines, and their receptors were also upregulated. Histologic analysis indicated a significant role for Ccr5 in the migration of lymphocytes and macrophages into brains of WNV-infected mice. WNV-infected Ccr5 -/- mice had impaired leukocyte trafficking to the central nervous system compared with wildtype mice, but expression of chemokine ligands was not altered. Surviving WNV-infected wildtype mice started to clear WNV 12 days after infection. In contrast, the few surviving WNV-infected Ccr5 -/- mice showed a 32-fold increase in viral load on day 12 compared with controls. Adoptive transfer of splenocytes from WNV-infected Ccr5 +/+ mice to WNV-infected Ccr5 -/- recipients reduced mortality to the level observed for wildtype mice. Glass et al. (2005) concluded that CCR5 is a critical protective factor for recruiting and maintaining leukocytes necessary for clearing WNV in fatal encephalitis in mice.
Turner et al. (2008) found that Ccr5 -/- mice exposed to nephrotoxic sheep serum exhibited augmented renal T-cell and monocyte recruitment and increased lethality due to uremia, accompanied by greater renal expression of Ccl5 and Ccl3, but not Ccl4, compared with wildtype nephritic mice. Ccr5 -/- mice showed an increased renal Th1 response, but systemic humoral and cellular immune responses were unchanged. Blockade of Ccr1 (601159), an additional receptor for Ccl3 and Ccl5, resulted in significantly reduced renal chemokine expression, T-cell infiltration, and glomerular crescent formation, indicating that increased renal leukocyte recruitment and consecutive tissue damage in nephritic Ccr5 -/- mice depends on functional Ccr1. Turner et al. (2008) concluded that CCR5 deficiency aggravates glomerulonephritis via enhanced CCL3/CCL5-CCR1-driven renal T-cell recruitment.
Marques et al. (2015) demonstrated that antagonism of Ccr5 in mouse macrophages prevented replication of DENV. Macrophages lacking Ccr5 also showed reduced DENV replication. Ccr5 -/- mice were protected against lethal challenge from at least 2 strains of DENV, and this protection was associated with reduced viral load, lower cytokine production, and lower inflammatory responses. Mice pretreated with Ccr5 antagonists were protected from DENV infection. Marques et al. (2015) concluded that CCR5 contributes to DENV replication in vitro and to disease development in vivo.
In an HIV-1-exposed patient with slow disease progression (see 609423), Samson et al. (1996) identified a homozygous 32-bp deletion in the CMKBR5 gene that results in a frameshift and premature termination. Samson et al. (1996) found that the mutation had an allelic frequency of 0.092 in Caucasian populations but was absent in populations from western and central Africa and from Japan. Among HIV-1-infected Caucasian subjects, no homozygous individuals were found, and the frequency of heterozygotes was 35% lower in infected individuals than in the general population. Samson et al. (1996) speculated that a 10-bp direct repeat that flanks the deleted region promoted a recombination event leading to the 32-bp deletion.
Independently and simultaneously, Liu et al. (1996) identified the same homozygous 32-bp deletion in the CMKBR5 gene in 2 individuals who, though multiply exposed to HIV-1, remained uninfected. The deletion comprises nucleotides 794 to 825 of their cDNA sequence (codons 175 to 185) and results in a reading frameshift after amino acid 174, inclusion of 31 novel amino acids, and truncation at codon 206. The severely truncated protein could not be detected at the surface of cells that normally express the protein. They stated that the defect had no other obvious phenotype. Liu et al. (1996) stated that the frequency of CKR5-deleted homozygotes is about 1% in persons of western European heritage. The investigators also stated that heterozygous individuals were common (approximately 20%) in unrelated individuals of western European heritage but were present at a much lower frequency in a panel of individuals from Venezuela.
Ansari-Lari et al. (1997) stated that this mutation results in a frameshift at codon 185, causing a deletion of 168 amino acids and the gain of 31 new residues in the C terminus of the putative translation product.
Martinson et al. (1997) followed up on the observation that, although a gene frequency of approximately 10% was found for the 32-bp deletion in the CCR5 gene in populations of European descent, no mutant alleles were reported in indigenous non-European populations. They devised a rapid PCR assay for the deletion and used it to screen 3,342 individuals from a globally distributed range of populations. They found that the deletion in the CCR5 gene is not confined to persons of European descent but is found at frequencies of 2 to 5% throughout Europe, the Middle East, and the Indian subcontinent. Isolated occurrences were seen elsewhere throughout the world, but these most likely represented recent European gene flow into the indigenous populations. Martinson et al. (1997) suggested that the interpopulation differences in the frequency of the CCR5 deletion may influence the pattern of HIV transmission, and if so, the differences will need to be incorporated into future predictions of HIV levels.
In a study of genomic DNA from random blood donors from North America, Asia, and Africa, Zimmerman et al. (1997) found the inactive CCR5 allele, designated by them CCR5-2, as the only mutant allele. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in 111 highly exposed-seronegative (4.5%) and 614 HIV-1-seropositive (0%) Caucasians relative to 387 Caucasian random blood donors (0.8%). This difference was highly significant (p less than 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same 3 groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of 2 cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1-positive Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconverters had a 52.6% lower risk of developing AIDS than homozygous wildtype seroconverters. Zimmerman et al. (1997) suggested that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. They suggested that since the majority (approximately 96%) of highly exposed-seronegative individuals tested were not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of normal antiretroviral therapy. See, however, Biti et al. (1997).
Libert et al. (1998) investigated the frequency of the delta-CCR5 polymorphism in 18 European populations. A north-south gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%) and the lowest in Sardinia (4%). Highly polymorphic microsatellite markers flanking the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the variant. More than 95% of the delta-CCR5 chromosomes carried an allele that was found in only 2% of the chromosomes carrying a wildtype CCR5 gene. From these data, it was inferred that most, if not all, delta-CCR5 alleles originated from a single mutation event, and that this mutation event probably took place a few thousand years ago in northeastern Europe. The high frequency of the delta-CCR5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with the homozygous or heterozygous carriers of the mutant allele.
Husain et al. (1998) described a family with heterozygosity for the 32-bp deletion in CCR5. They stated that this was the first such finding in an Indian without European admixture, and they estimated that the frequency of the deleted allele in India is likely to be very low (less than 1%).
Alvarez et al. (1998) analyzed DNA from 150 HIV-1 positive intravenous drug users and 250 healthy controls from northern Spain for the presence of the delta-CCR5 mutation. The deletion was rare among seropositive intravenous drug users, and the authors found that patients carrying the deletion allele tended to show a fuller progression of HIV-1-related disease.
Using a mathematical model, Sullivan et al. (2001) characterized epidemic HIV within 3 dynamic subpopulations: homozygous wildtype, heterozygous CCR5-del32, and homozygous CCR5-del32. The results indicated that the prevalence of HIV/AIDS is greater in populations lacking the CCR5-del32 alleles (homozygous wildtypes only) as compared with populations that include persons heterozygous or homozygous for the mutation. Also, they showed that HIV can provide selective pressure for CCR5-del32, increasing the frequency of this allele.
Hall et al. (1999) reported that individuals carrying the 32-bp deletion in the CCR5 gene are at reduced risk of developing asthma. They suggested that this is a possible explanation for the high prevalence of this mutation in the general population.
Szalai et al. (2000) determined the CCR5del32 allelic frequencies in 121 nonasthmatic, atopic children aged 1 to 14 years and in 295 age-matched controls in Hungary. They found no significant differences between allergic and control children, and suggested that the CCR5del32 mutation, even in homozygous form, has no protective effect on the development of allergic inflammation.
Although functional evidence might suggest that CCR5 is a good candidate gene for atopic asthma, a study by Mitchell et al. (2000) of 2 panels of nuclear families containing 1,284 individuals found no genetic evidence that the CCR5del32 polymorphism is related to atopy or asthma/wheeze.
Barcellos et al. (2000) found that patients with multiple sclerosis (MS; 126200) carrying the CCR5-delta-32 deletion showed an age at onset approximately 3 years later than did patients without the deletion. Studying 256 Israeli patients with MS, Kantor et al. (2003) presented evidence suggesting that the CCR5-delta-32 deletion may contribute to a slower rate of disease progression in MS.
Fischereder et al. (2001) demonstrated another benefit of homozygosity for the CCR5del32 mutation: longer survival of renal transplants, suggesting a pathophysiologic role for CCR5 in transplant loss. This receptor may be a useful target for the prevention of transplant loss.
Strieter and Belperio (2001) reviewed evidence on the implication of various chemokine receptors and their respective ligands in promoting allograft rejection. They commented on the expanding critical role of chemokine biology in transplantation immunology, which should pave the way for the development of pharmaceutical agents that will target pathogenetic steps in chemokine biology and provide new treatments for enhancing long-term allograft survival.
In a genotype survey of 4,166 individuals, Stephens et al. (1998) identified a cline of CCR5-del32 allele frequencies of 0 to 14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and 2 microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, Stephens et al. (1998) estimated the origin of the CCR5-del32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275 to 1,875 years. The geographic cline of mutation frequencies and its recent emergence are consistent with a historic strong selective event (i.e., an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.
Majumder and Dey (2001) studied 1,438 unrelated individuals belonging to 40 ethnic groups from India. The CCR5del32 allele was absent in most ethnic populations, but was present in some populations of the northern and western regions. The authors suggested that the allele might have been introduced by Caucasian gene flow, consistent with the historical fact that Caucasoid migrants from central Asia and western Eurasia had entered India about 8,000 to 10,000 earlier.
Using a population genetic model based on the demography of Europe, Duncan et al. (2005) suggested that annual widespread epidemics of plague, a viral hemorrhagic fever, from 1347 until 1670 forced up the frequency of the delta-32 mutation.
Novembre et al. (2005) evaluated the selection hypothesis for the origin and maintenance of the delta-32 mutation in Europe. Assuming uniform selection across Europe and western Asia, they found support for northern European origin of delta-32 and Viking-mediated dispersal, which was originally proposed by Lucotte and Mercier (1998). On the other hand, if gradients in selection intensity were assumed, Novembre et al. (2005) estimated the origin to be outside of northern Europe and selection intensities to be strongest in the northwestern part of the continent.
Using denser genetic maps and more extensive control data than previous studies, Sabeti et al. (2005) determined that genetic variation at delta-32 is not exceptional relative to other loci across the genome. They estimated that the delta-32 allele arose more than 5,000 years ago, considerably earlier than the origin proposed by Stephens et al. (1998). While not ruling out selection, especially given the biology of the gene, Sabeti et al. (2005) concluded that the results imply that the pattern of genetic variation at delta-32 is consistent with neutral evolution.
Glass et al. (2006) analyzed the distribution of CCR5 delta-32 in independent cohorts of West Nile virus (see 610379)-seropositive individuals. They observed a strong deviation from Hardy-Weinberg equilibrium due to an increased frequency of delta-32 homozygotes. The delta-32 homozygotes also had increased risk of fatal WNV infection. Glass et al. (2006) concluded that CCR5 delta-32 is a risk factor for symptomatic WNV infection.
Goulding et al. (2005) genotyped 283 Irish women exposed to hepatitis C virus (HCV; see 609532) genotype-1b from a single donor for CCR5, CCR2 (601267), and CCL5 (187011) polymorphisms. They found that CCR5 delta-32 heterozygotes showed significantly higher spontaneous clearance of HCV compared with wildtype CCR5 homozygotes. In addition, the authors observed a trend toward lower hepatic inflammation scores in CCR5 delta-32 heterozygotes compared with wildtype CCR5 homozygotes. No significant relationships were found with CCR2 or CCL5.
Thio et al. (2008) stated that 95% of adults recover from acute hepatitis B virus (HBV; see 610424) infection and that the likelihood of recovery is enhanced in those carrying the 32-bp deletion in CCR5. By comparing 181 individuals with persistent HBV infection with 316 who had recovered, Thio et al. (2008) showed that the combination of the 32-bp deletion in CCR5 with the minor allele of a functional promoter polymorphism in CCL5, -403G-A, was significantly associated with recovery (odds ratio = 0.36; P = 0.02). CCL5 -403A without the 32-bp deletion in CCR5 was not associated with HBV recovery, and the 32-bp deletion in CCR5 without CCL5 -403A showed only weak, nonsignificant protection. Thio et al. (2008) noted that -403A is associated with higher levels of CCL5 in cell lines. They proposed that excess CCL5 due to -403A combined with the nonfunctional CCR5 receptor due to the 32-bp deletion favors recovery from HBV infection. However, Thio et al. (2008) stated that they could not totally eliminate the possibility that interaction with the 32-bp deletion in CCR5 is due to another CCL5 SNP, 524T-C, rather than -403A, because 524C is in tight linkage disequilibrium with -403A.
In a study involving 8,064 patients with type 1 diabetes and 9,339 controls, Smyth et al. (2008) found significant association between the 32-bp insertion/deletion in the CCR5 gene on chromosome 3p21 and a decreased risk for type 1 diabetes (odds ratio, 0.54; p = 1.88 x 10(-6)); see 612522. The association was validated in 2,828 families providing 3,064 parent-child trios (relative risk, 0.53; p = 1.81 x 10(-8)). The mutation encodes a nonfunctional receptor (Liu et al., 1996; Samson et al., 1996).
In Japanese and Chinese populations, Ansari-Lari et al. (1997) identified 2 variant alleles of the CMKBR5 gene, each with an approximate frequency of 0.04. One of these alleles was a 1-bp deletion, causing premature termination of translation, with the predicted 54-amino acid deletion located at the C-terminal intracellular domain of the protein. Several putative phosphorylation sites in this domain have potential importance for signal transduction. The other allele in Chinese and Japanese populations caused an arg-to-gln conversion in the putative third intracellular loop of the protein (601373.0003). One person homozygous for this allele was identified in the Hispanic population. This may reflect admixture of the Hispanic population.
See 601373.0002 and Ansari-Lari et al. (1997).
In a study of the CMKBR5 gene in an African-American population sample, Ansari-Lari et al. (1997) found 1 allele with valine instead of alanine at amino acid position 335, with a frequency of approximately 0.03.
In 1 of 18 men who had frequent unprotected sexual intercourse with a seropositive partner who was unaffected by HIV, Quillent et al. (1998) found a variant of CCR5 that showed total resistance to in vitro infection by CCR5-dependent viruses (see 609423). The patient was a compound heterozygote for the CCR5 delta-32 allele (601373.0001) and a single point mutation, 303T-A, resulting in a cys101-to-ter substitution. The polymorphism was found also in the father and sister of the proband and in 209 healthy blood donors who were not exposed to HIV-1, 3 of whom were heterozygous for the mutant allele.
McDermott et al. (1998) identified an A/G polymorphism at basepair 59029 in the CCR5 promoter. In a cohort of HIV-1 seroconverters (see 609423) lacking both CCR5 delta-32 (601373.0001) and CCR2-64I (601267.0001), 59029-G/G individuals progressed to AIDS on average 3.8 years more slowly than 59029-A/A individuals (p = 0.004). CCR5 59029-G/G appeared to be protective relative to the A/A homozygote, about twice as protective as CCR5 delta-32 or the 64I polymorphism of CCR2. The effect was thought to be the result of reduced CCR5 mRNA production. These results identified the first site in the CCR5 promoter that may be a useful target for treatment of HIV-1 infection (see 609423).
Association Pending Confirmation
In a study of 616 Japanese patients with type 2 diabetes (125853), Nakajima et al. (2003) found that 2 SNPs in the CCL5 and CCR5 genes, -28G (187011.0001) and 59029G, respectively, were both independently and interactively associated with nephropathy (see 603933): the percentage of macroalbuminuria was 2-fold higher in patients carrying -28G or 59029A, and 3-fold higher in patients carrying both, compared to patients without either variant.
Kostrikis et al. (1999) reported a C-to-T polymorphism at basepair 59356 in the CCR5 promoter. Homozygosity for CCR5 59356T was found to be associated with an increased rate (5.9 relative risk) of HIV-1 perinatal transmission (see 609423). The CCR5 59356T polymorphism was found at significantly higher frequency in African-Americans (21%) than in Hispanic (6%) or Caucasian (3%) populations. Mutations associated with a reduced rate of perinatal transmission (CCR5 delta-32 (601373.0001) and CCR5 59402G) were found to be less common among African-Americans.
Carrington et al. (1997) described a CCR5 allele that carries a single amino acid substitution, arg60 to ser (R60S), in the first intracellular domain of the protein, present in heterozygous state in one HIV-exposed, uninfected individual (see 609423). Tamasauskas et al. (2001) pointed out that a homologous mutation in the Duffy blood group antigen gene (DARC; 613665), like the R60S allele of CCR5, results in reduced expression of the gene product and appears to protect against infectious disease: malarial infection by Plasmodium vivax in the case of the Duffy gene; AIDS in the case of the CCR5 gene.
Using in vitro studies, McDermott et al. (1998) showed that alleles containing an A at the -2459 position of the CCR5 gene displayed higher CCR5 promoter activity than alleles with a G at this position. The in vivo relevance of these observations was supported by the finding that HIV-infected individuals homozygous for the A allele (-2459A/A) progressed more rapidly to AIDS (see 609423) than those who were homozygous for the G allele (-2459G/G). A 32-bp deletion in the open reading frame of the CCR5 gene (601373.0001), which confers protection against HIV infection, is tightly linked to the promoter -2459A allele.
Kawamura et al. (2003) found that, in vitro, Langerhans cells from individuals heterozygous for both the -2459A/G polymorphism and the 32-bp deletion in the CCR5 gene were markedly less susceptible to HIV than were Langerhans cells from individuals homozygous for the A allele at -2459 and heterozygous for the 32-bp deletion (P = 0.012). These genetic susceptibility data in Langerhans cells paralleled those of susceptibility studies performed in cohorts of HIV-infected individuals. This suggested that CCR5-mediated infection of Langerhans cells is the biologic basis for host genetic susceptibility to initial HIV infection. Kawamura et al. (2003) stated that the resistant diplotype occurs in approximately 10% of whites, whereas the more susceptible diplotype occurs in approximately 6% of whites.
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