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Chemokine (C-C motif) receptor 5
Identifiers
Symbols CCR5; CC-CKR-5; CCCKR5; CD195; CKR-5; CKR5; CMKBR5
External IDs OMIM601373 MGI107182 HomoloGene37325 IUPHAR: CCR5 GeneCards: CCR5 Gene
Orthologs
Species Human Mouse
Entrez 1234 12774
Ensembl ENSG00000160791 ENSMUSG00000073993
UniProt P51681 Q3TDA4
RefSeq (mRNA) NM_000579 NM_009917
RefSeq (protein) NP_000570 NP_034047
Location (UCSC) Chr 3:
46.41 - 46.42 Mb
Chr 9:
123.97 - 123.98 Mb
PubMed search [1] [2]

CCR5 is a gene which encodes the CCR5 protein, "Chemokine (C-C motif) receptor 5", a member of the beta chemokine receptors family of integral membrane proteins.[1][2]

In Humans, the CCR5 gene location is on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation resulting in the Genetic deletion of the CCR5 gene. Homozygous carriers of this mutation are resistant to HIV-1 infection [3].

The CCR5 protein has also recently been designated CD195: "Cluster of differentiation" 195 (for cell surface molecules present on White blood cells). The CCR5 protein is a seven transmembrane protein [1] which functions as a chemokine receptor in the CC chemokine group. The natural chemokine ligands that bind to this receptor are RANTES, MIP-1α and MIP-1β. CCR5 is predominantly expressed on T cells, macrophages, dendritic cells and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear.

Contents

HIV

HIV uses CCR5 or another protein, CXCR4, as a co-receptor to enter its target cells. Several chemokine receptors can function as viral coreceptors, but CCR5 is likely the most physiologically important coreceptor during natural infection. The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection,[4] suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.

A number of new experimental HIV drugs, called entry inhibitors, have been designed to interfere with the interaction between CCR5 and HIV, including PRO140 (Progenics), Vicriviroc (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). A potential problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. Development of Aplaviroc has been terminated due to safety concerns (potential liver toxicity).[5]

CCR5-Δ32

CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is a genetic variant of CCR5.[6][7]

CCR5-Δ32 is a deletion mutation of a gene that has a specific impact on the function of T cells. CCR5-Δ32 is widely dispersed throughout Northern Europe and in those of Northern European descent. It has been hypothesized that this allele was favored by natural selection during the Black Death. This coalescence date is contradicted by purported evidence of CCR5-Δ32 in Bronze Age samples, at levels comparable to the modern European population.[8] Research from The University of California at Berkeley published in 2003 indicates that smallpox may be another candidate for the high level of the mutation in the European population.[6]

The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV. Yersinia pestis was demonstrated in the laboratory not to associate with CCR5. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is largely dispensable. However, CCR5 apparently plays a role in mediating resistance to West Nile virus infection in humans, as CCR5-Δ32 individuals have shown to be disproportionately at higher risk of West Nile virus in studies,[9] indicating that not all of the functions of CCR5 may be compensated by other receptors.

While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV R5 entry; two copies of this allele provide strong protection against HIV infection.[10] This allele is found in 5-14% of Europeans but is rare in Africans and Asians.[11] Multiple studies of HIV-infected persons have shown that presence of one copy of this allele delays progression to the condition of AIDS by about 2 years. CCR5-Δ32 decreases the number of CCR5 proteins on the outside of the CD4 cell, which can have a large effect on the HIV disease progression rates. It is possible that a person with the CCR5-Δ32 receptor allele will not be infected with HIV R5 strains. Several commercial testing companies offer tests for CCR5-Δ32.

In 2008, German doctors announced that an HIV-infected leukemia patient had received a bone marrow transplant from a donor who is homozygous for the CCR5-Δ32 trait. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.[12][13] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors.[14] However, this is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.[15] In 2009, researchers at the University of Pennsylvania began enrolling HIV-positive patients in a clinical trial in which the patients' cells will be genetically modified to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.[16][17]

Interactions

CCR5 has been shown to interact with CCL5[18][19][20] and CCL3L1.[21][19]

See also

References

  1. ^ a b Genetics Home Reference
  2. ^ Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M (March 1996). "Molecular cloning and functional expression of a new human CC-chemokine receptor gene". Biochemistry 35 (11): 3362–7. doi:10.1021/bi952950g. PMID 8639485.  
  3. ^ Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, et al. (1996) Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382: 722–725
  4. ^ Anderson J, Akkina R (2007). "Complete Knockdown of CCR5 by lentiviral vector-expressed siRNAs and protection of transgenic macrophages against HIV-1 infection". Gene Therapy 14 (14): 1287–1297. doi:10.1038/sj.gt.3302958. PMID 17597795.  
  5. ^ aidsmap.com | Maraviroc
  6. ^ a b Galvani AP, Slatkin M (December 2003). "Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele". Proc. Natl. Acad. Sci. U.S.A. 100 (25): 15276–9. doi:10.1073/pnas.2435085100. PMID 14645720.  
  7. ^ Stephens J et al. (1998). "Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes" (PDF). Am J Hum Genet 62 (6): 1507–15. doi:10.1086/301867. PMID 9585595. http://www.broad.mit.edu/mpg/popgen/pubs/1998_AJHG_CCR5.pdf.  
  8. ^ Philip W. Hedrick; Brian C. Verrelli (June 2006). "‘Ground truth’ for selection on CCR5-Δ32". Trends in Genetics 22 (6): 293–6. doi:10.1016/j.tig.2006.04.007. PMID 16678299.  
  9. ^ Glass WG, McDermott DH, Lim JK, Lekhong S, Yu SF, Frank WA, Pape J, Cheshier RC, Murphy PM (January 2006). "CCR5 deficiency increases risk of symptomatic West Nile virus infection". J. Exp. Med. 203 (1): 35–40. doi:10.1084/jem.20051970. PMID 16418398.  
  10. ^ "Biologists discover why 10 percent of Europeans are safe from HIV infection". PhysOrg.com. March 2005. http://www.physorg.com/news3333.html. Retrieved 2007-04-10.  
  11. ^ Pardis C. Sabeti; Emily Walsh, Steve F. Schaffner, Patrick Varilly, Ben Fry, Holli B. Hutcheson, Mike Cullen, Tarjei S. Mikkelsen, Jessica Roy, Nick Patterson, Richard Cooper, David Reich, David Altshuler, Stephen O’Brien, Eric S. Lander (November 2005). "The case for selection at CCR5-Delta32". PLoS Biology 3 (11): e378. doi:10.1371/journal.pbio.0030378. PMID 16248677.  
  12. ^ "A Doctor, a Mutation and a Potential Cure for AIDS". WSJ. November 2008. http://online.wsj.com/article/SB122602394113507555.html. Retrieved 2008-11-10.  
  13. ^ Hütter G, Nowak D, Mossner M, et al. (February 2009). "Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation". N. Engl. J. Med. 360 (7): 692–8. doi:10.1056/NEJMoa0802905. PMID 19213682.  
  14. ^ "Man appears free of HIV after stem cell transplant". CNN. 2009-02-11. http://www.cnn.com/2009/HEALTH/02/11/health.hiv.stemcell/index.html?eref=rss_latest. Retrieved 2009-02-11.  
  15. ^ Agrawal L, Lu XH, Qingwen J, VanHorn-Ali Z, Nicolescu IV, McDermott DH, Murphy PM, Alkhatib G (March 2004). "Role for CCR5 Delta 32 protein in resistance to R5, R5X4, and X4 human immunodeficiency virus type 1 in primary CD4(+) cells". J. Virology 78 (5): 2277-2287. PMID 14963124. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC369216/pdf/1304.pdf.  
  16. ^ "Autologous T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728 for HIV (Zinc-Finger)". NIH. 2009-12-09. http://clinicaltrials.gov/ct2/show/NCT00842634?term=806383&rank=1. Retrieved 2009-12-30.  
  17. ^ Nicholas Wade (2009-12-28). "In New Way to Edit DNA, Hope for Treating Disease". NYT. http://www.nytimes.com/2009/12/29/health/research/29zinc.html. Retrieved 2009-12-30.  
  18. ^ Slimani, Hocine; Charnaux Nathalie, Mbemba Elisabeth, Saffar Line, Vassy Roger, Vita Claudio, Gattegno Liliane (Oct. 2003). "Interaction of RANTES with syndecan-1 and syndecan-4 expressed by human primary macrophages". Biochim. Biophys. Acta (Netherlands) 1617 (1-2): 80–8. ISSN 0006-3002. PMID 14637022.  
  19. ^ a b Struyf, S; Menten P, Lenaerts J P, Put W, D'Haese A, De Clercq E, Schols D, Proost P, Van Damme J (Jul. 2001). "Diverging binding capacities of natural LD78beta isoforms of macrophage inflammatory protein-1alpha to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils". Eur. J. Immunol. (Germany) 31 (7): 2170–8. ISSN 0014-2980. PMID 11449371.  
  20. ^ Proudfoot, A E; Fritchley S, Borlat F, Shaw J P, Vilbois F, Zwahlen C, Trkola A, Marchant D, Clapham P R, Wells T N (Apr. 2001). "The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity". J. Biol. Chem. (United States) 276 (14): 10620–6. doi:10.1074/jbc.M010867200. ISSN 0021-9258. PMID 11116158.  
  21. ^ Miyakawa, Toshikazu; Obaru Kenshi, Maeda Kenji, Harada Shigeyoshi, Mitsuya Hiroaki (Feb. 2002). "Identification of amino acid residues critical for LD78beta, a variant of human macrophage inflammatory protein-1alpha, binding to CCR5 and inhibition of R5 human immunodeficiency virus type 1 replication". J. Biol. Chem. (United States) 277 (7): 4649–55. doi:10.1074/jbc.M109198200. ISSN 0021-9258. PMID 11734558.  

Further reading

  • Wilkinson D (1997). "Cofactors provide the entry keys. HIV-1". Curr. Biol. 6 (9): 1051–3. doi:10.1016/S0960-9822(02)70661-1. PMID 8805353.  
  • Broder CC, Dimitrov DS (1997). "HIV and the 7-transmembrane domain receptors". Pathobiology 64 (4): 171–9. doi:10.1159/000164032. PMID 9031325.  
  • Choe H, Martin KA, Farzan M, et al. (1998). "Structural interactions between chemokine receptors, gp120 Env and CD4". Semin. Immunol. 10 (3): 249–57. doi:10.1006/smim.1998.0127. PMID 9653051.  
  • Sheppard HW, Celum C, Michael NL, et al. (2002). "HIV-1 infection in individuals with the CCR5-Delta32/Delta32 genotype: acquisition of syncytium-inducing virus at seroconversion". J. Acquir. Immune Defic. Syndr. 29 (3): 307–13. PMID 11873082.  
  • Freedman BD, Liu QH, Del Corno M, Collman RG (2004). "HIV-1 gp120 chemokine receptor-mediated signaling in human macrophages". Immunol. Res. 27 (2-3): 261–76. doi:10.1385/IR:27:2-3:261. PMID 12857973.  
  • Esté JA (2004). "Virus entry as a target for anti-HIV intervention". Curr. Med. Chem. 10 (17): 1617–32. doi:10.2174/0929867033457098. PMID 12871111.  
  • Gallo SA, Finnegan CM, Viard M, et al. (2003). "The HIV Env-mediated fusion reaction". Biochim. Biophys. Acta 1614 (1): 36–50. doi:10.1016/S0005-2736(03)00161-5. PMID 12873764.  
  • Zaitseva M, Peden K, Golding H (2003). "HIV coreceptors: role of structure, posttranslational modifications, and internalization in viral-cell fusion and as targets for entry inhibitors". Biochim. Biophys. Acta 1614 (1): 51–61. doi:10.1016/S0005-2736(03)00162-7. PMID 12873765.  
  • Lee C, Liu QH, Tomkowicz B, et al. (2004). "Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways". J. Leukoc. Biol. 74 (5): 676–82. doi:10.1189/jlb.0503206. PMID 12960231.  
  • Yi Y, Lee C, Liu QH, et al. (2004). "Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications for neuropathogenesis". J. Neurovirol. 10 Suppl 1: 91–6. PMID 14982745.  
  • Seibert C, Sakmar TP (2004). "Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs". Curr. Pharm. Des. 10 (17): 2041–62. doi:10.2174/1381612043384312. PMID 15279544.  
  • Cutler CW, Jotwani R (2006). "Oral mucosal expression of HIV-1 receptors, co-receptors, and alpha-defensins: tableau of resistance or susceptibility to HIV infection?". Adv. Dent. Res. 19 (1): 49–51. doi:10.1177/154407370601900110. PMID 16672549.  
  • Ajuebor MN, Carey JA, Swain MG (2006). "CCR5 in T cell-mediated liver diseases: what's going on?". J. Immunol. 177 (4): 2039–45. PMID 16887960.  
  • Lipp M, Müller G (2006). "Shaping up adaptive immunity: the impact of CCR7 and CXCR5 on lymphocyte trafficking". Verhandlungen der Deutschen Gesellschaft für Pathologie 87: 90–101. PMID 16888899.  
  • Balistreri CR, Caruso C, Grimaldi MP, et al. (2007). "CCR5 receptor: biologic and genetic implications in age-related diseases". Ann. N. Y. Acad. Sci. 1100: 162–72. doi:10.1196/annals.1395.014. PMID 17460174.  
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