Alternative titles; symbols
HGNC Approved Gene Symbol: CCL3L1
Cytogenetic location: 17q11.2 Genomic coordinates (GRCh38) : 17:27,400,001-33,500,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q11.2 | {HIV/AIDS, susceptibility to} | 609423 | 3 |
Chemokines are secreted proteins involved in immunoregulatory and inflammatory processes (Naruse et al., 1996). Blum et al. (1990) and Nakao et al. (1990) obtained evidence for the existence of at least 3 different MIP1A-related genes, which they referred to as LD78-alpha (CCL3; 182283), -beta, and -gamma (a pseudogene). Similarly, Irving et al. (1990) found that the genomic segment containing the closely-linked LD78-alpha and AT744.1 (SCYA4; 182284) genes is duplicated in the genome of many individuals. These authors designated the nonallelic genes 464.2 (LD78-beta) and AT744.2 (603782), respectively. The 464.2 and 744.2 genes are also closely linked to each other.
In review of the MIP1 genes, Menten et al. (2002) stated that the CCL3L1 gene encodes a 93-amino acid preprotein. The mature protein contains 70 amino acids and has a calculated molecular mass of about 7.8 kD. CCL3L1 shares 96% amino acid identity with CCL3. Although the CCL3 gene exists as a single copy per haploid genome, the copy number of the CCL3L1 gene varies among individuals.
Using real-time PCR of genomic DNA, Townson et al. (2002) found that the copy number per diploid genome of the CCL3L1 gene in 100 Caucasian individuals ranged from 0 to 10. Most individuals (49%) had 2 copies of the CCL3L1 gene, while 10 to 20% had 1, 3, or 4 copies.
Genome assembly (build 35.1) indicated that there is a nearly identical duplicated locus, CCL3L3 (609467), in the same region (Scott, 2005).
Nibbs et al. (1999) found that LD78-beta bound CCR5 (601373) with 6-fold higher affinity than LD78-alpha. It also bound the promiscuous beta-chemokine receptor D6 (CCBP2; 602648) with 15- to 20-fold higher affinity. LD78-beta inhibited human immunodeficiency virus (HIV)-1 entry into CCR5-expressing cells better than RANTES (CCL5; 187011), a potent HIV-1 entry inhibitor. Nibbs et al. (1999) found that the enhanced activity of LD78-beta was due to the presence of a proline at position 2 of the mature CCL3L1 protein.
In a review, Menten et al. (2002) noted that CCL3L1 is a potent ligand for CCR5, a major coreceptor for macrophage-tropic, also called R5 (short for CCR5)-tropic, strains of HIV-1. Like other CCR5 ligands, CCL3L1 may be a dominant HIV-suppressive chemokine. Menten et al. (2002) stated that, although CCL3 and CCL3L1 are 96% identical, CCL3L1 is 30-fold more potent at inhibiting R5 HIV-1 infection compared with CCL3.
Townson et al. (2002) found that lipopolysaccharide stimulation of peripheral blood mononuclear cells from 35 individuals increased expression of CCL3L1 mRNA. Samples with higher CCL3L1 copy number had a consistent and significant increase in the ratio of CCL3L1 mRNA to CCL3 mRNA, which is transcribed from a gene not subject to duplication. A high CCL3L1 copy number also correlated with increased functional chemokine production as measured by increased protein secreted to the culture medium of activated cells and increased chemotactic response by CCR5-expressing cells.
The CCL3L1 gene contains 3 exons and spans about 1.9 kb (Menten et al., 2002).
Hirashima et al. (1992) mapped the 3 LD78 genes to chromosome 17q21.1-q21.3 by in situ hybridization and somatic cell hybrid analysis. Naruse et al. (1996) mapped LD78-beta to a cluster of other CC cytokines on chromosome 17q11.2 using a panel of somatic cell hybrids with known deletions. The deduced order of genes from a YAC contig assembled for the region is: cen--NF1 (613113)--(MCP3 (158106), MCP1 (158105), NCC1 (601391), I-309 (182281))--Y1741 breakpoint--RANTES (187011)--(LD78-gamma, AT744.2, LD78-beta)--(NCC3 (601393), NCC2 (601392), AT744.1, LD78-alpha)--NCC4 (601394)--RARA (180240)--tel. The authors were unable to determine the order of the genes within parentheses in their study.
Role in Human Immunodeficiency Virus-1 Susceptibility
Gonzalez et al. (2005) examined the effect of CCL3L1 copy number, which varies due to segmental duplication on chromosome 17q, on susceptibility to HIV-1. Mean CCL3L1 copy number varied in different population groups, being generally highest in Africans, followed by East Asians, Amerindians, Central/South Asians, Middle Easterners, and Europeans. Cloning and characterization of the chimpanzee CCL3L1 gene led to the observation that this species has a substantially higher copy number than any human population. Individual susceptibility to HIV-1, however, was related not to the absolute copy number but to having a CCL3L1 copy number lower than the population-specific average. Susceptibility was even greater in individuals having disease-accelerating CCR5 genotypes, and Gonzalez et al. (2005) showed that CCR5 protein expression is, in part, influenced by CCL3L1. Gonzalez et al. (2005) concluded that CCL3L1 dose plays a central role in HIV/AIDS pathogenesis and suggested that the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.
Ahuja et al. (2008) found that variations in CCL3L1 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.
Studies by Urban et al. (2009), Bhattacharya et al. (2009), and Field et al. (2009) called into question the findings of Gonzalez et al. (2005) and Ahuja et al. (2008). In response, He et al. (2009) pointed out methodologic and epidemiologic differences that might account for the discrepancies. In a commentary, Shrestha et al. (2009) pointed out that accurately counting gene copy number beyond 2 will require better amplification and sequencing techniques than the inherently difficult methods currently available.
Ahuja, S. K., Kulkarni, H., Catano, G., Agan, B. K., Camargo, J. F., He, W., O'Connell, R. J., Marconi, V. C., Delmar, J., Eron, J., Clark, R. A., Frost, S., Martin, J., Ahuja, S. S., Deeks, S. G., Little, S., Richman, D., Hecht, F. M., Dolan, M. J. CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals. Nature Med. 14: 413-420, 2008. [PubMed: 18376407] [Full Text: https://doi.org/10.1038/nm1741]
Bhattacharya, T., Stanton, J., Kim, E.-Y., Kunstman, K. J., Phair, J. P., Jacobson, L. P., Wolinsky, S. M. CCL3L1 and HIV/AIDS susceptibility. (Letter) Nature Med. 15: 1112-1115, 2009. [PubMed: 19812561] [Full Text: https://doi.org/10.1038/nm1009-1112]
Blum, S., Forsdyke, R. E., Forsdyke, D. R. Three human homologs of a murine gene encoding an inhibitor of stem cell proliferation. DNA Cell Biol. 9: 589-602, 1990. [PubMed: 2271120] [Full Text: https://doi.org/10.1089/dna.1990.9.589]
Field, S. F., Howson, J. M. M., Maier, L. M., Walker, S., Walker, N. M., Smyth, D. J., Armour, J. A. L., Clayton, D. G., Todd, J. A. Experimental aspects of copy number variant assays at CCL3L1. (Letter) Nature Med. 15: 1115-1117, 2009. [PubMed: 19812562] [Full Text: https://doi.org/10.1038/nm1009-1115]
Gonzalez, E., Kulkarni, H., Bolivar, H., Mangano, A., Sanchez, R., Catano, G., Nibbs, R. J., Freedman, B. I., Quinones, M. P., Bamshad, M. J., Murthy, K. K., Rovin, B. H., and 12 others. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307: 1434-1440, 2005. [PubMed: 15637236] [Full Text: https://doi.org/10.1126/science.1101160]
He, W., Kulkarni, H., Castiblanco, J., Shimizu, C., Aluyen, U., Maldonado, R., Carrillo, A., Griffin, M., Lipsitt, A., Beachy, L., Shostakovich-Koretskaya, L., Mangono, A., and 9 others. Reply to Urban et al., Bhattacharya et al., Field et al. (Letter) Nature Med. 15: 1117-1120, 2009. [PubMed: 19812563] [Full Text: https://doi.org/10.1038/nm1009-1117]
Hirashima, M., Ono, T., Nakao, M., Nishi, H., Kimura, A., Nomiyama, H., Hamada, F., Yoshida, M. C., Shimada, K. Nucleotide sequence of the third cytokine LD78 gene and mapping of all three LD78 gene loci to human chromosome 17. DNA Seq. 3: 203-212, 1992. [PubMed: 1296815] [Full Text: https://doi.org/10.3109/10425179209034019]
Irving, S. G., Zipfel, P. F., Balke, J., McBride, O. W., Morton, C. C., Burd, P. R., Siebenlist, U., Kelly, K. Two inflammatory mediator cytokine genes are closely linked and variably amplified on chromosome 17q. Nucleic Acids Res. 18: 3261-3270, 1990. [PubMed: 1972563] [Full Text: https://doi.org/10.1093/nar/18.11.3261]
Menten, P., Wuyts, A., Van Damme, J. Macrophage inflammatory protein-1. Cytokine Growth Factor Rev. 13: 455-481, 2002. [PubMed: 12401480] [Full Text: https://doi.org/10.1016/s1359-6101(02)00045-x]
Nakao, M., Nomiyama, H., Shimada, K. Structures of human genes coding for cytokine LD78 and their expression. Molec. Cell. Biol. 10: 3646-3658, 1990. [PubMed: 1694014] [Full Text: https://doi.org/10.1128/mcb.10.7.3646-3658.1990]
Naruse, K., Ueno, M., Satoh, T., Nomiyama, H., Tei, H., Takeda, M., Ledbetter, D. H., Van Coillie, E., Opdenakker, G., Gunge, N., Sakaki, Y., Iio, M., Miura, R. A YAC contig of the human CC chemokine genes clustered on chromosome 17q11.2. Genomics 34: 236-240, 1996. [PubMed: 8661057] [Full Text: https://doi.org/10.1006/geno.1996.0274]
Nibbs, R. J. B., Yang, J., Landau, N. R., Mao, J.-H., Graham, G. J. LD78-beta, a non-allelic variant of human MIP-1-alpha (LD78-alpha), has enhanced receptor interactions and potent HIV suppressive activity. J. Biol. Chem. 274: 17478-17483, 1999. [PubMed: 10364178] [Full Text: https://doi.org/10.1074/jbc.274.25.17478]
Scott, A. F. Personal Communication. Baltimore, Md. 5/23/2005.
Shrestha, S., Tang, J., Kaslow, R. A. Gene copy number: learning to count past two. Nature Med. 15: 1127-1129, 2009. [PubMed: 19812568] [Full Text: https://doi.org/10.1038/nm1009-1127]
Townson, J. R., Barcellos, L. F., Nibbs, R. J. B. Gene copy number regulates the production of the human chemokine CCL3-L1. Europ. J. Immun. 32: 3016-3026, 2002. [PubMed: 12355456] [Full Text: https://doi.org/10.1002/1521-4141(2002010)32:10<3016::AID-IMMU3016>3.0.CO;2-D]
Urban, T. J., Weintrob, A. C., Fellay, J., Colombo, S., Shianna, K. V., Gumbs, C., Rotger, M., Pelak, K., Dang, K. K., Detels, R., Martinson, J. J., O'Brien, S. J., Letvin, N. L., McMichael, A. J., Haynes, B. F., Carrington, M., Telenti, A., Michael, N. L., Goldstein, D. B. CCL3L1 and HIV/AIDS susceptibility. (Letter) Nature Med. 15: 1110-1112, 2009. [PubMed: 19812560] [Full Text: https://doi.org/10.1038/nm1009-1110]