Alternative titles; symbols
HGNC Approved Gene Symbol: CCL5
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:35,871,491-35,880,360 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | {HIV-1 disease, delayed progression of} | 609423 | 3 | |
| {HIV-1 disease, rapid progression of} | 609423 | 3 |
Using a human cDNA library that was enriched by subtractive hybridization for sequences expressed by T lymphocytes but not B lymphocytes, Schall et al. (1988) isolated a gene, which they designated RANTES, that encodes a novel T cell-specific molecule. (RANTES is an acronym for 'Regulated upon Activation, Normally T-Expressed, and presumably Secreted.') The gene product was predicted to be a 10-kD protein which, after cleavage of the signal peptide, could be expected to be approximately 8 kD. Of the 68 residues, 4 are cysteines, and there are no sites for N-linked glycosylation. Significant homology (30 to 70%) was found between the RANTES sequence and several other T-cell genes, suggesting that they constitute a family of small, secreted T-cell molecules.
Schall et al. (1988) found that RANTES, also designated p228 (TCP228), was expressed in 10 functional T-cell lines, but not in 8 hematopoietic tumor lines or in 6 T-cell tumor lines. Its expression was increased more than 10-fold in peripheral blood lymphocytes 3 to 5 days following mitogenic or antigenic stimulation.
CD8-positive T lymphocytes are involved in the control of human immunodeficiency virus (HIV) infection in vivo (see 609423). Cocchi et al. (1995) demonstrated that the chemokines RANTES, MIP-1-alpha (182283), and MIP-1-beta (182284) are the major HIV-suppressive factors produced by CD8-positive T cells. HIV-suppressive factor activity produced by either immortalized or primary CD8-positive T cells was completely blocked by a combination of neutralizing antibodies against these 3 cytokines. On the other hand, recombinant forms of the 3 human cytokines induced a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Cocchi et al. (1995) speculated that chemokine-mediated control of HIV may occur either directly, through their inherent anti-lentiretroviral activity, or indirectly, through their ability to chemoattract T cells and monocytes to the proximity of the infection foci. However, this latter mechanism may also have the opposite effect of providing new, uninfected targets for HIV infection. The authors noted that the findings may be relevant for the prevention and therapy of AIDS.
Arenzana-Seisdedos et al. (1996) investigated a derivative of RANTES as a possible therapeutic agent for inhibition of HIV infection. The derivative, called RANTES(9-68), lacks the first 8 N-terminal amino acids and has no chemotactic or leukocyte-activating properties. RANTES(9-68) was a potent receptor antagonist and inhibited infection of macrophage-tropic HIV. The anti-HIV activity was somewhat lower than that of RANTES itself, which correlated with its lower affinity for CC chemokine receptors. Arenzana-Seisdedos et al. (1996) found that the anti-HIV activity of RANTES and RANTES(9-68) showed some variability depending on the donor cells. The authors concluded that structural modification of a chemokine can yield variants lacking activation properties but retaining both high-affinity for chemokine receptors and the ability to block HIV infection.
Using astrocytes obtained from 5- to 10-week-old fetal forebrains and in situ hybridization and immunohistochemical analyses, Bakhiet et al. (2001) showed that expression of RANTES mRNA and protein, but not of other chemokines, increases with age. Responses to RANTES in cultured astrocytes differed with age. Stimulation of 5-week-old astrocytes enhanced their proliferation but not their survival, whereas stimulation of 10-week-old cells prolonged their survival but diminished their ability to proliferate. The RANTES receptors, CCR1 (601159), CCR3 (601268), and CCR5, were all found to be expressed on astrocytes in vivo. Immunohistochemical and in situ hybridization analysis showed that cells expressing CCR5 do not express RANTES mRNA, while cells lacking CCR5 do express RANTES mRNA, suggesting a paracrine mode of action. Using astrocytes from wildtype and Ccr5 -/- mice at embryonic day 7, which are equivalent to 10-week-old human cells, Bakhiet et al. (2001) demonstrated that RANTES inhibited proliferation and prolonged survival of wildtype cells but had no effect on the Ccr5 -/- cells. In response to RANTES stimulation, 5- and 10-week-old human astrocytes enhanced their production of gamma-interferon (IFNG; 147570), but only the older cells expressed IFNG receptor (IFNGR; see 107470). Blockade of IFNGR reversed RANTES inhibition of proliferation and promotion of survival. Immunoblot analysis showed that RANTES stimulation of 5-week-old cells rapidly increased tyrosine kinase activity and protein phosphorylation. Immunofluorescence microscopy revealed that RANTES stimulation of 5- or 10-week-old astrocytes induced the translocation of STAT1 (600555) from the cytoplasm to the nucleus. Bakhiet et al. (2001) concluded that RANTES regulates the growth and survival of first-trimester forebrain astrocytes. Furthermore, they suggested that chemokines are not only mediators of inflammation, but are also significant regulators of differentiation in development.
Pritts et al. (2002) investigated the effect of PPAR-gamma ligands upon transcription and translation of RANTES in human endometrial stromal cells. Three putative PPAR response elements (PPREs) were found in the human RANTES promoter. In cells transfected both with RANTES promoter vectors containing 958 bp and 3 PPREs, the addition of 2 PPAR-gamma ligands inhibited promoter activity by 60% (P less than 0.01) and 48% (P less than 0.02), respectively. Truncation of the gene promoter to delete all putative PPREs abrogated the ligand-induced inhibition. Stromal cells showed a 40% decrease in RANTES protein secretion when treated with a PPAR-gamma ligand (P less than 0.01). The authors concluded that use of PPAR-gamma ligands to reduce chemokine production and inflammation may be a productive strategy for future therapy of endometrial disorders, such as endometriosis.
Apolinario et al. (2002) found that CCL5 expression was low in normal liver, but it was significantly enhanced after hepatitis C virus (HCV; see 609532) infection, particularly in areas with greatest lymphocytic infiltration.
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 (601373) and the downstream ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and AKT (164730) signaling pathways.
Schistosoma species (see 181460) are helminth parasites that are adept at manipulating the host immune system to allow tolerance of chronic worm infections without overt morbidity. This modulation of immunity by schistosomes prevents a range of immune-mediated diseases, including allergies and autoimmunity. Smith et al. (2005) identified a molecule produced by Schistosoma eggs, termed S. mansoni chemokine-binding protein (smCKBP), that bound several chemokines, including CCL5. SmCKBP blocked interaction of these chemokines with their receptors and thereby inhibited induction of inflammation. Smith et al. (2005) proposed that since smCKBP is unrelated to host proteins, it may have potential as an antiinflammatory agent.
Karnoub et al. (2007) demonstrated that bone marrow-derived mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumor xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion, and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signaling through the chemokine receptor CCR5. Karnoub et al. (2007) concluded that the tumor microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.
Using RT-PCR and flow cytometry, Hartmann et al. (2008) showed that CCL5 induced ERK1/ERK2 phosphorylation and expression of both isoforms of CRAM (CCRL2; 608379), but not other CCL5-binding molecules, in a pre-B cell line. CCL5 did not induce calcium mobilization or migratory responses in the cell lines. Hartmann et al. (2008) suggested that CRAM may be involved in immunomodulatory functions together with CCL5.
By analysis of somatic cell hybrids and by in situ hybridization using the cDNA probe, Donlon et al. (1990) assigned the RANTES locus (D17S136E) to 17q11.2-q12. A secondary hybridization peak was noted in the region 5q31-q34, which may represent the location of other members of the gene family. The region on chromosome 5 overlaps with the location of an extended linked cluster of growth factor and receptor genes, some of which may be coregulated with members of the RANTES gene family.
RANTES is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showing that peripheral blood mononuclear cells or CD4+ lymphocytes obtained from different individuals have wide variations in their ability to secrete RANTES prompted Liu et al. (1999) to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. They found 2 polymorphic positions, 1 of which was associated with reduced CD4+ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This -28G mutation of the RANTES gene (187011.0001) occurred at an allele frequency of approximately 17% in the non-HIV-1-infected Japanese population and exerted no influence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the -28G mutation increases transcription of the RANTES gene. Taken together, these data suggested that the -28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease.
An et al. (2002) tested the influence of 4 RANTES SNPs and their haplotypes on HIV-1 infection and AIDS progression in 5 AIDS cohorts. Three SNPs in the RANTES gene region on chromosome 17 (403A in the promoter, In1.1C in the first intron, and 3-prime 222C in the 3-prime UTR) were associated with increased frequency of HIV-1 infection. The In1.1C SNP allele is nested within an intronic regulatory sequence element (168923T/C; 187011.0002) that exhibits differential allele binding to nuclear proteins and a downregulation of gene transcription. The In1.1C allele, or haplotypes that include In1.1C, display a strong dominant association with rapid progression to AIDS among HIV-1-infected individuals in African American, European American, and combined cohorts. The principal RANTES SNP genetic influence on AIDS progression derives from the downregulating RANTES In1.1C allele, although linkage disequilibrium with adjoining RANTES SNPs, including a weaker upregulating RANTES promoter allele (-28G; 187011.0001), can modify the observed epidemiologic patterns. The In1.1C-bearing genotypes accounted for 37% of the attributable risk for rapid progression among African Americans and may also be an important influence on AIDS progression in Africa. The diminished transcription of RANTES afforded by the In1.1C regulatory allele is consistent with increased HIV-1 spread in vivo, leading to accelerated progression to AIDS.
Associations Pending Confirmation
Nakajima et al. (2003) analyzed 2 RANTES polymorphisms in 616 Japanese patients with type 2 diabetes (see 125853) and found a significant association between the -28G allele and diabetic nephropathy (see 603933).
Konta et al. (2008) analyzed 4 CCL5 polymorphisms in 2,749 Japanese nondiabetic individuals (rs2107538 in the promoter, rs2280789 in intron 1, rs3817655 in intron 2, and rs9909416 3-prime to CCL5) and identified a 4-SNP haplotype (GTTG, designated 'haplotype 1') that was significantly associated with an elevated urine albumin/creatinine ratio (p = 0.001). The authors suggested that genetic variation of CCL5 might be a common factor for the development of albuminuria.
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 a 32-bp deletion in CCR5 (601373.0001), which results in a nonfunctional receptor. 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 large Japanese cohort of HIV-1-infected and non-HIV-1-infected individuals, Liu et al. (1999) identified a C-to-G transversion at position -28 in the promoter of the SCYA5 gene, also referred to as the RANTES gene. The -28G allele had a frequency of approximately 17% in the Japanese population and appeared to have no influence on the incidence of HIV-1 infection. However, functional analyses indicated that the -28G mutation increased transcription of the RANTES gene. Liu et al. (1999) suggested that the -28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease (see 609423). They showed that the -28G mutation is associated with reduced rates of depletion of CD4+ lymphocytes in HIV-1-infected individuals, thus confirming that this polymorphism delays HIV-1 disease progression.
Association Pending Confirmation
Nakajima et al. (2003) analyzed 2 polymorphisms in the CCL5 gene in 616 Japanese patients with type 2 diabetes with or without nephropathy (see 603933) and found a significant association between the -28G allele and nephropathy (defined by the presence of macroalbuminuria; p = 0.0268). Discriminant analysis showed that the CCL5 -28G allele and the 59029A allele in the CCR5 gene (601373.0006) were both independently and interactively associated with nephropathy: 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.
Among 7 SNPs within the RANTES gene investigated by An et al. (2002), one was the intronic RANTES regulatory element, In1.1T/C (168923T/C). They found that In1.1C-bearing genotypes accounted for 37% of the attributable risk for rapid progression to AIDS (see 609423) among African Americans. Because 36% of African Americans carry the In1.1C allele, it is likely that In1.1C may have a significant impact on the AIDS epidemic in sub-Saharan Africa.
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Bakhiet, M., Tjernlund, A., Mousa, A., Gad, A., Stromblad, S., Kuziel, W. A., Seiger, A., Andersson, J. RANTES promotes growth and survival of human first-trimester forebrain astrocytes. Nature Cell Biol. 3: 150-157, 2001. [PubMed: 11175747] [Full Text: https://doi.org/10.1038/35055057]
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Donlon, T. A., Krensky, A. M., Wallace, M. R., Collins, F. S., Lovett, M., Clayberger, C. Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12. Genomics 5: 548-553, 1990.
Hartmann, T. N., Leick, M., Ewers, S., Diefenbacher, A., Schraufstatter, I., Honczarenko, M., Burger, M. Human B cells express the orphan chemokine receptor CRAM-A/B in a maturation-stage-dependent and CCL5-modulated manner. Immunology 125: 252-262, 2008. [PubMed: 18397265] [Full Text: https://doi.org/10.1111/j.1365-2567.2008.02836.x]
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Pritts, E. A., Zhao, D., Ricke, E., Waite, L., Taylor, R. N. PPAR-gamma decreases endometrial stromal cell transcription and translation of RANTES in vitro. J. Clin. Endocr. Metab. 87: 1841-1844, 2002. [PubMed: 11932328] [Full Text: https://doi.org/10.1210/jcem.87.4.8409]
Schall, T. J., Jongstra, J., Dyer, B. J., Jorgensen, J., Clayberger, C., Davis, M. M., Krensky, A. M. A human T cell-specific molecule is a member of a new gene family. J. Immun. 141: 1018-1025, 1988. [PubMed: 2456327]
Smith, P., Fallon, R. E., Mangan, N. E., Walsh, C. M., Saraiva, M., Sayers, J. R., McKenzie, A. N. J., Alcami, A., Fallon, P. G. Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. J. Exp. Med. 202: 1319-1325, 2005. [PubMed: 16301741] [Full Text: https://doi.org/10.1084/jem.20050955]
Thio, C. L., Astemborski, J., Thomas, R., Mosbruger, T., Witt, M. D., Goedert, J. J., Hoots, K., Winkler, C., Thomas, D. L., Carrington, M. Interaction between RANTES promoter variant and CCR5-delta-32 favors recovery from hepatitis B. J. Immun. 181: 7944-7947, 2008. [PubMed: 19017985] [Full Text: https://doi.org/10.4049/jimmunol.181.11.7944]
Tyner, J. W., Uchida, O., Kajiwara, N., Kim, E. Y., Patel, A. C., O'Sullivan, M. P., Walter, M. J., Schwendener, R. A., Cook, D. N., Danoff, T. M., Holtzman, M. J. CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nature Med. 11: 1180-1187, 2005. [PubMed: 16208318] [Full Text: https://doi.org/10.1038/nm1303]