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Gene Review

CCR5  -  chemokine (C-C motif) receptor 5...

Homo sapiens

Synonyms: C-C CKR-5, C-C chemokine receptor type 5, CC-CKR-5, CCCKR5, CCR-5, ...
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Disease relevance of CCR5

  • The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates [1].
  • A 32-base pair inactivating deletion in CCR5 (delta 32) common to Northern European populations has been associated with reduced, but not absolute, HIV-1 transmission risk and delayed disease progression [2].
  • Because vMIP-II could inhibit cell entry of human immunodeficiency virus (HIV) mediated through CCR3 and CCR5 as well as CXCR4, this protein may serve as a lead for development of broad-spectrum anti-HIV agents [3].
  • Signaling from both CCR5 and CXCR4 is mediated by pertussis toxin (PTX)-sensitive G(i) proteins and is not required for HIV-1 entry [4].
  • Expression of CCR5 and RANTES may be important in the modulation of hepatic inflammation and response to interferon therapy in chronic hepatitis C [5].

Psychiatry related information on CCR5

  • We also found that CCR5 is the predominant coreceptor used for infection of human adult microglia by the HIV type 1 dementia isolates HIV-1DS-br, HIV-1RC-br, and HIV-1YU-2, since the anti-CCR5 antibody 2D7 was able to dramatically inhibit microglial infection by both wild-type and single-round luciferase pseudotype reporter viruses [6].
  • MIP-1beta is a CC-chemokine that plays a role in inflammation and host defense mechanisms by interacting with its specific receptor CCR5 [7].
  • Here we address whether CCR5 or CXCR4 tropism of the predominant viral strain detected before or on combination antiretroviral therapy (ART) explains why some human immunodeficiency virus (HIV)-infected patients who begin ART with advanced HIV disease retain low interferon (IFN)-gamma responses, despite recovery of CD4(+) T cell counts [8].
  • RESULTS: All constructed cell lines expressing the various CXCR4 glycomutants showed similar permissiveness for the X4-monotropic virus and no change in the coreceptor specificity that allows infection of a CCR5-dependent R5-monotropic virus [9].
  • The identified human antibodies to CCR5 define an alloantigen that may cause allograft rejection in a mismatch situation even in individuals with no history of blood transfusions or i.v. drug abuse [10].

High impact information on CCR5

  • These studies identify a distinct subset of CD4-induced HIV-1 neutralizing antibodies that closely emulate CCR5 and demonstrate that tyrosine sulfation can contribute to the potency and diversity of the human humoral response [11].
  • Tyrosine sulfation of human antibodies contributes to recognition of the CCR5 binding region of HIV-1 gp120 [11].
  • Like that of CCR5, antibody association with gp120 is dependent on sulfate moieties, enhanced by CD4, and inhibited by sulfated CCR5-derived peptides [11].
  • The extent of genetic variation in the CCR5 gene [12].
  • A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors [13].

Chemical compound and disease context of CCR5

  • Utilization of CCR3 and CCR5 on the target cell depended upon the sequence of the third variable (V3) region of the HIV-1 gp120 exterior envelope glycoprotein [1].
  • These results represent a detailed analysis of the multiple sulfation reaction of a peptide substrate by TPSTs and provide a structural basis for understanding the role of tyrosine sulfation of CCR5 in HIV-1 coreceptor and chemokine receptor function [14].
  • Stimulation with heat-killed extracts of Mycobacterium tuberculosis down-modulated cell surface expression of CCR5 on gammadelta T cells in a macrophage-dependent manner, while synthetic phosphoantigen isopentenyl pyrophosphate and CCR5 ligands directly triggered CCR5 down-modulation on gammadelta T cells [15].
  • Both the CCR5-specific monoclonal antibody 2D7 and TAK-779, a nonpeptide inhibitor of CCR5-mediated viral entry, blocked HIV-1 strain ADA infection by >80% [16].
  • AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction [17].

Biological context of CCR5

  • Here we describe the evolutionary relationships between the phenotypically important CCR5 alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-delta32 and CCR2-641 polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression [18].
  • We began this study to test whether polymorphisms in the CCR5 regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals [18].
  • A derivative of RANTES that was created by chemical modification of the amino terminus, aminooxypentane (AOP)-RANTES, did not induce chemotaxis and was a subnanomolar antagonist of CCR5 function in monocytes [19].
  • We found a rapid and extensive downregulation of CXCR4 by SDF-1alpha and of CCR5 by RANTES or the antagonist RANTES(9-68) [20].
  • T cells treated with B-oligomer did not initiate signal transduction in response to macrophage inflammatory protein (MIP)-1beta or RANTES (regulated upon activation, normal T cell expressed and secreted); however, cell surface expression of CCR5 and binding of MIP-1beta or HIV-1 to such cells were not impaired [4].

Anatomical context of CCR5


Associations of CCR5 with chemical compounds

  • In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (Mr 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca2+ signaling at nanomolar concentrations [23].
  • Tyrosine sulfation of CCR5 N-terminal peptide by tyrosylprotein sulfotransferases 1 and 2 follows a discrete pattern and temporal sequence [14].
  • The PDTC-mediated inhibition of CCR5 and CXCR4 mRNA expression was associated with decreased chemotactic responsiveness (>90% inhibition) and with a marked inhibition of surface-receptor expression [24].
  • Accordingly, H(2)O(2) and the glutathione-depleting drug buthionine sulfoximine increased to different extents CCR2, CCR5, and CXCR4 mRNA expression [24].
  • We found that CCR5 2-18 is sulfated by both TPST isoenzymes leading to a final product with four sulfotyrosine residues [14].

Physical interactions of CCR5

  • This process, triggered by CCL5 binding to CCR5, is not mediated by TNFalpha, Fas, or caspase-8 [25].
  • R5-tropic HIV-1 glycoprotein 120, but not interleukin-16, the natural agonist, or X4-tropic glycoprotein 120, inhibited MIP-1beta binding to CCR5 in the presence of monomeric and dimeric soluble CD4 [26].
  • Posttranslational sulfation of tyrosine residues in the N-terminal tail of CCR5 is critical for high affinity interaction of the receptor with the HIV-1 envelope glycoprotein gp120 in complex with CD4 [14].
  • As shown by bioluminescence resonance energy transfer experiments, CCR5 formed constitutive homo- as well as heterooligomeric complexes together with C5aR but not with the unrelated AT(1a)R in living cells [27].
  • Chemokine binding to CCR5 leads to cellular activation through pertussis toxin-sensitive heterotrimeric G proteins as well as G protein-independent signalling pathways [28].

Enzymatic interactions of CCR5

  • Activation of the chemotactic peptide receptor FPRL1 in monocytes phosphorylates the chemokine receptor CCR5 and attenuates cell responses to selected chemokines [29].

Regulatory relationships of CCR5

  • The PBMCs of patients with newly diagnosed but not with longstanding type 1 diabetes showed reduced expression of the Th1-associated chemokine receptors CCR5 (P < 0.001 vs. control subjects) and CXCR3 (P < 0.002 vs. control subjects) [30].
  • Cultured in vitro, adherent monocytes/macrophages up-regulated CCR5 and down-regulated CCR1 expression, compared to freshly-isolated monocytes [31].
  • HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood-brain barrier and up-regulates CCR5 expression on human monocytes [32].
  • IL-8 pretreatment also inhibited CCR5- but not CXCR4-mediated virus entry into MAGIC5 cells [33].
  • CCR5 lacks the Ser/IleLeu sequence required for phorbol ester-induced uptake of CXCR4 [34].
  • By comparing arg- (Rgp) and lys-gingipain (Kgp) mutants, a mutant deficient in both proteases, and the action of trypsin, P. gingivalis Rgp was strongly suggested to cleave PAR-1 and PAR-2 to up-regulate CCR5 [35].

Other interactions of CCR5

  • In children who progressed to AIDS without a shift to CXCR4 usage, all the sequential isolates were CCR5-dependent but showed a reduced sensitivity to C-C chemokines [21].
  • Viral isolates obtained during the asymptomatic stages generally used only CCR5 as a co-receptor and were inhibited by RANTES, MIP-1alpha and MIP-1beta, but not by SDF-1 [21].
  • Although subjects with CCR5 delta 32 defects had significantly reduced median viral load at study entry, providing a plausible explanation for the association with delayed progression, this association was not seen with CCR2B 64I [2].
  • Naive T cells expressed only CXC chemokine receptor (CXCR)4, whereas the majority of memory/activated T cells expressed CXCR3, and a small proportion expressed CC chemokine receptor (CCR)3 and CCR5 [36].
  • HCC-1[9-74] was a potent agonist of CCR1, CCR3, and CCR5 and promoted calcium flux and chemotaxis of T lymphoblasts, monocytes, and eosinophils [37].

Analytical, diagnostic and therapeutic context of CCR5


  1. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Choe, H., Farzan, M., Sun, Y., Sullivan, N., Rollins, B., Ponath, P.D., Wu, L., Mackay, C.R., LaRosa, G., Newman, W., Gerard, N., Gerard, C., Sodroski, J. Cell (1996) [Pubmed]
  2. The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression. Michael, N.L., Louie, L.G., Rohrbaugh, A.L., Schultz, K.A., Dayhoff, D.E., Wang, C.E., Sheppard, H.W. Nat. Med. (1997) [Pubmed]
  3. A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Kledal, T.N., Rosenkilde, M.M., Coulin, F., Simmons, G., Johnsen, A.H., Alouani, S., Power, C.A., Lüttichau, H.R., Gerstoft, J., Clapham, P.R., Clark-Lewis, I., Wells, T.N., Schwartz, T.W. Science (1997) [Pubmed]
  4. The B-oligomer of pertussis toxin deactivates CC chemokine receptor 5 and blocks entry of M-tropic HIV-1 strains. Alfano, M., Schmidtmayerova, H., Amella, C.A., Pushkarsky, T., Bukrinsky, M. J. Exp. Med. (1999) [Pubmed]
  5. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C. Promrat, K., McDermott, D.H., Gonzalez, C.M., Kleiner, D.E., Koziol, D.E., Lessie, M., Merrell, M., Soza, A., Heller, T., Ghany, M., Park, Y., Alter, H.J., Hoofnagle, J.H., Murphy, P.M., Liang, T.J. Gastroenterology (2003) [Pubmed]
  6. Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. Albright, A.V., Shieh, J.T., Itoh, T., Lee, B., Pleasure, D., O'Connor, M.J., Doms, R.W., González-Scarano, F. J. Virol. (1999) [Pubmed]
  7. Characterization of the role of the N-loop of MIP-1 beta in CCR5 binding. Bondue, A., Jao, S.C., Blanpain, C., Parmentier, M., LiWang, P.J. Biochemistry (2002) [Pubmed]
  8. Brief Report: CXCR4 or CCR5 Tropism of Human Immunodeficiency Virus Type 1 Isolates Does Not Determine the Immunological Milieu in Patients Responding to Antiretroviral Therapy. Price, P., Keane, N., Gray, L., Lee, S., Gorry, P.R., French, M.A. Viral Immunol. (2006) [Pubmed]
  9. Infection of cells expressing CXCR4 mutants lacking N-glycosylation at the N-terminal extracellular domain is enhanced for R5X4-dualtropic human immunodeficiency virus type-1. Thordsen, I., Polzer, S., Schreiber, M. BMC Infect. Dis. (2002) [Pubmed]
  10. The CCR5 receptor acts as an alloantigen in CCR5Delta32 homozygous individuals: identification of chemokineand HIV-1-blocking human antibodies. Ditzel, H.J., Rosenkilde, M.M., Garred, P., Wang, M., Koefoed, K., Pedersen, C., Burton, D.R., Schwartz, T.W. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  11. Tyrosine sulfation of human antibodies contributes to recognition of the CCR5 binding region of HIV-1 gp120. Choe, H., Li, W., Wright, P.L., Vasilieva, N., Venturi, M., Huang, C.C., Grundner, C., Dorfman, T., Zwick, M.B., Wang, L., Rosenberg, E.S., Kwong, P.D., Burton, D.R., Robinson, J.E., Sodroski, J.G., Farzan, M. Cell (2003) [Pubmed]
  12. The extent of genetic variation in the CCR5 gene. Ansari-Lari, M.A., Liu, X.M., Metzker, M.L., Rut, A.R., Gibbs, R.A. Nat. Genet. (1997) [Pubmed]
  13. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Doranz, B.J., Rucker, J., Yi, Y., Smyth, R.J., Samson, M., Peiper, S.C., Parmentier, M., Collman, R.G., Doms, R.W. Cell (1996) [Pubmed]
  14. Tyrosine sulfation of CCR5 N-terminal peptide by tyrosylprotein sulfotransferases 1 and 2 follows a discrete pattern and temporal sequence. Seibert, C., Cadene, M., Sanfiz, A., Chait, B.T., Sakmar, T.P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  15. Patterns of chemokine receptor expression on peripheral blood gamma delta T lymphocytes: strong expression of CCR5 is a selective feature of V delta 2/V gamma 9 gamma delta T cells. Glatzel, A., Wesch, D., Schiemann, F., Brandt, E., Janssen, O., Kabelitz, D. J. Immunol. (2002) [Pubmed]
  16. Human Mast cell progenitors can be infected by macrophagetropic human immunodeficiency virus type 1 and retain virus with maturation in vitro. Bannert, N., Farzan, M., Friend, D.S., Ochi, H., Price, K.S., Sodroski, J., Boyce, J.A. J. Virol. (2001) [Pubmed]
  17. Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist. Princen, K., Hatse, S., Vermeire, K., Aquaro, S., De Clercq, E., Gerlach, L.O., Rosenkilde, M., Schwartz, T.W., Skerlj, R., Bridger, G., Schols, D. J. Virol. (2004) [Pubmed]
  18. Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Mummidi, S., Ahuja, S.S., Gonzalez, E., Anderson, S.A., Santiago, E.N., Stephan, K.T., Craig, F.E., O'Connell, P., Tryon, V., Clark, R.A., Dolan, M.J., Ahuja, S.K. Nat. Med. (1998) [Pubmed]
  19. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Simmons, G., Clapham, P.R., Picard, L., Offord, R.E., Rosenkilde, M.M., Schwartz, T.W., Buser, R., Wells, T.N., Proudfoot, A.E. Science (1997) [Pubmed]
  20. HIV coreceptor downregulation as antiviral principle: SDF-1alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. Amara, A., Gall, S.L., Schwartz, O., Salamero, J., Montes, M., Loetscher, P., Baggiolini, M., Virelizier, J.L., Arenzana-Seisdedos, F. J. Exp. Med. (1997) [Pubmed]
  21. In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Scarlatti, G., Tresoldi, E., Björndal, A., Fredriksson, R., Colognesi, C., Deng, H.K., Malnati, M.S., Plebani, A., Siccardi, A.G., Littman, D.R., Fenyö, E.M., Lusso, P. Nat. Med. (1997) [Pubmed]
  22. CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. He, J., Chen, Y., Farzan, M., Choe, H., Ohagen, A., Gartner, S., Busciglio, J., Yang, X., Hofmann, W., Newman, W., Mackay, C.R., Sodroski, J., Gabuzda, D. Nature (1997) [Pubmed]
  23. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Baba, M., Nishimura, O., Kanzaki, N., Okamoto, M., Sawada, H., Iizawa, Y., Shiraishi, M., Aramaki, Y., Okonogi, K., Ogawa, Y., Meguro, K., Fujino, M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  24. Redox regulation of chemokine receptor expression. Saccani, A., Saccani, S., Orlando, S., Sironi, M., Bernasconi, S., Ghezzi, P., Mantovani, A., Sica, A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  25. A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death. Mellado, M., de Ana, A.M., Moreno, M.C., Martínez, C., Rodríguez-Frade, J.M. Curr. Biol. (2001) [Pubmed]
  26. Interaction of soluble CD4 with the chemokine receptor CCR5. Wang, X., Staudinger, R. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  27. G protein-coupled receptor kinases promote phosphorylation and beta-arrestin-mediated internalization of CCR5 homo- and hetero-oligomers. Hüttenrauch, F., Pollok-Kopp, B., Oppermann, M. J. Biol. Chem. (2005) [Pubmed]
  28. Chemokine receptor CCR5: insights into structure, function, and regulation. Oppermann, M. Cell. Signal. (2004) [Pubmed]
  29. Activation of the chemotactic peptide receptor FPRL1 in monocytes phosphorylates the chemokine receptor CCR5 and attenuates cell responses to selected chemokines. Shen, W., Proost, P., Li, B., Gong, W., Le, Y., Sargeant, R., Murphy, P.M., Van Damme, J., Wang, J.M. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  30. Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes. Lohmann, T., Laue, S., Nietzschmann, U., Kapellen, T.M., Lehmann, I., Schroeder, S., Paschke, R., Kiess, W. Diabetes (2002) [Pubmed]
  31. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Trebst, C., Sørensen, T.L., Kivisäkk, P., Cathcart, M.K., Hesselgesser, J., Horuk, R., Sellebjerg, F., Lassmann, H., Ransohoff, R.M. Am. J. Pathol. (2001) [Pubmed]
  32. HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood-brain barrier and up-regulates CCR5 expression on human monocytes. Weiss, J.M., Nath, A., Major, E.O., Berman, J.W. J. Immunol. (1999) [Pubmed]
  33. Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization. Richardson, R.M., Tokunaga, K., Marjoram, R., Sata, T., Snyderman, R. J. Biol. Chem. (2003) [Pubmed]
  34. Differential regulation of CXCR4 and CCR5 endocytosis. Signoret, N., Rosenkilde, M.M., Klasse, P.J., Schwartz, T.W., Malim, M.H., Hoxie, J.A., Marsh, M. J. Cell. Sci. (1998) [Pubmed]
  35. Porphyromonas gingivalis selectively up-regulates the HIV-1 coreceptor CCR5 in oral keratinocytes. Giacaman, R.A., Nobbs, A.H., Ross, K.F., Herzberg, M.C. J. Immunol. (2007) [Pubmed]
  36. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. Sallusto, F., Lenig, D., Mackay, C.R., Lanzavecchia, A. J. Exp. Med. (1998) [Pubmed]
  37. Natural proteolytic processing of hemofiltrate CC chemokine 1 generates a potent CC chemokine receptor (CCR)1 and CCR5 agonist with anti-HIV properties. Detheux, M., Ständker, L., Vakili, J., Münch, J., Forssmann, U., Adermann, K., Pöhlmann, S., Vassart, G., Kirchhoff, F., Parmentier, M., Forssmann, W.G. J. Exp. Med. (2000) [Pubmed]
  38. Lineage-specific expression of human immunodeficiency virus (HIV) receptor/coreceptors in differentiating hematopoietic precursors: correlation with susceptibility to T- and M-tropic HIV and chemokine-mediated HIV resistance. Chelucci, C., Casella, I., Federico, M., Testa, U., Macioce, G., Pelosi, E., Guerriero, R., Mariani, G., Giampaolo, A., Hassan, H.J., Peschle, C. Blood (1999) [Pubmed]
  39. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1beta, and MIP-1alpha. Raport, C.J., Gosling, J., Schweickart, V.L., Gray, P.W., Charo, I.F. J. Biol. Chem. (1996) [Pubmed]
  40. Early reduction of immune activation in lymphoid tissue following highly active HIV therapy. Andersson, J., Fehniger, T.E., Patterson, B.K., Pottage, J., Agnoli, M., Jones, P., Behbahani, H., Landay, A. AIDS (1998) [Pubmed]
  41. Distribution of chemokine receptor CCR2 and CCR5 genotypes and their relative contribution to human immunodeficiency virus type 1 (HIV-1) seroconversion, early HIV-1 RNA concentration in plasma, and later disease progression. Tang, J., Shelton, B., Makhatadze, N.J., Zhang, Y., Schaen, M., Louie, L.G., Goedert, J.J., Seaberg, E.C., Margolick, J.B., Mellors, J., Kaslow, R.A. J. Virol. (2002) [Pubmed]
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