NIAID Home NIAID Searchable Chemical Database Division of Aids Default NIAID Searchable Chemical Database Classes of Drugs Cellular Target Index of Drugs FDA Approved Drugs Viral Targets Viral Life Cycle Introduction Database for Anti-HIV Compounds - Clickable Menu Bar

NIAID HIV/OI Searchable Chemical Database

NIAID/DAIDS Searchable Chemical Database



CCR5

CCR5* (CC chemokine receptor 5), is the major co-receptor for macrophage-tropic (M-tropic) HIV-1 strains (1, 5, 7, 8, 10; reviewed in 4), and also appears to be the major co-receptor for microglial tropic HIV-1 primary isolates (22). CCR5 is a G-protein-coupled, 7-transmembrane domain receptor whose putative physiological ligands are the chemokinesMacrophage Inflammatory Protein-1a(MIP-1a), MIP-1b, and Regulated upon Activation, Normal T Expressed, and Secreted (RANTES) (1, 6, 7, 9). CCR5, also known as CKR-5 and CMKBR5# (systematic Human Genome nomenclature), is expressed in dendritic cells (13, 19), in previously activated memory T-cells (3), in microglia (14, 21) and in tissue macrophages (23). Although a single domain, consisting of the second extracellular loop, appears to be predominantly responsible for chemokine binding, multiple extracellular domains of CCR5 are involved HIV-1 co-receptor activity (24). Several charged and uncharged residues in the tyrosine-rich amino-terminal extracellular domain and several charged residues in the second and third extracellular loops of CCR5 have been shown to be important for gp120 recognition (8,10,11, 15, 18, 24).


Several compounds with anti-HIV-1 activity are thought to function through perturbation of CCR5 co-receptor activity. These include the natural ligands for CCR5: MIP-1a, MIP-1b, and RANTES (5), as well as the modified analogue AOP-RANTES (22), the truncated peptides RANTES[9-68] (2) and RANTES[3-68] (17), and surprisingly, a decapeptide based on residues 1-10 of RANTES (16).


MCP-2, a ligand for CCR1, CCR2b, and CCR5, is also able to block infection by CCR5-tropic HIV-1 strains in PBMCs (12). Anti-CCR5 antibodies have also shown potent anti-HIV-1 activity in-vitro (24).


* Hyperlink to Genbank entry.

#Hyperlink to The Genome Database (GDB).


References

  1. ALKHATIB, G.; COMBADIERE, C.; BRODER, C.C.; FENG, Y.; KENNEDY, P.E.; MURPHY, P.M.; BERGER, E.A., CC CKRS: A RANTES, MIP-1 ALPHA, MIP-1 BETA RECEPTOR AS A FUSION COFACTOR FOR MACROPHAGE-TROPIC HIV-1. SCIENCE 272(5270):1955-1958(1996).
  2. ARENZANA-SEISDEDOS, F.; VIRELIZIER, J.L.; ROUSSET, D.; CLARK-LEWIS I.; LOETSCHER, P.; MOSER, B.; BAGGIOLINI, M., HIV BLOCKED BY CHEMOKINE ANTAGONIST. NATURE 383(6599):400(1996).
  3. BLEUL, C.C.; WU, L.; HOXIE, J.A.; SPRINGER, T.A.; MACKAY, C.R., THE HIV CORECEPTORS CXCR4 AND CCR5 ARE DIFFERENTIALLY EXPRESSED AND REGULATED ON HUMAN T LYMPHOCYTES. PROC NATL ACAD SCI USA 94(5):1925-1930(1997).
  4. CHOE, H.; FARZAN, M.; SUN, Y.; SULLIVAN, N.; ROLLINS, B.; PONATH, P.D.; WU, L.J.; MACKAY, C.R.; LAROSA, G.; NEWMAN, W.; GERARD, N.; GERARD, C.; SODROSKI, J., THE BETA-CHEMOKINE RECEPTORS CCR3 AND CCR5 FACILITATE INFECTION BY PRIMARY HIV-1 ISOLATES. CELL 85(7):1135-1148(1996).
  5. COCCHI, F.; DEVICO, A.L.; GARZINO-DEMO, A.; ARYA, S.K.; GALLO, R.C.; LUSSO, P., IDENTIFICATION OF RANTES, MIP-1-ALPHA, AND MIP-1-BETA AS THE MAJOR HIV-SUPPRESSIVE FACTORS PRODUCED BY CD8(+) T-CELLS. SCIENCE 270(5243):1811-1815(1995).
  6. DENG, H.; LIU, R.; ELLMEIER, W.; CHOE, S.; UNUTMAZ, D.; BURKHART, M.; DIMARZIO, P.; MARMON, S.; SUTTON, R.E.; HILL, C.M.; DAVIS, C.B.; PEIPER, S.C.; SCHALL, T.J.; LITTMAN, D.R.; LANDAU, N.R., IDENTIFICATION OF A MAJOR CO-RECEPTOR FOR PRIMARY ISOLATES OF HIV-1. NATURE 381(6584):661-666(1996).
  7. DORANZ, B.J.; RUCKER, J.; YI, Y.J.; SMYTH, R.J.; SAMSON, M.; PEIPER, S.C.; PARMENTIER, M.; COLLMAN, R.G.; DOMS, R.W., 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. CELL 85(7):1149-1158(1996).
  8. DORANZ, B.J.; LU, Z.H.; RUCKER, J.; ZHANG, T.Y.; SHARRON, M.; CEN, Y.H.; WANG, Z.X.; GUO, H.H.; DU, J.G.; ACCAVITI, M.A.; DOMS, R.W.; PEIPER, S.C., TWO DISTINCT CCR5 DOMAINS CAN MEDIATE CORECEPTOR USAGE BY HUMAN IMMUNODEFICIENCY VIRUS TYPE 1. J VIROL 71(9):6305-6314(1997).
  9. DRAGIC, T.; LITWIN, V.; ALLAWAY, G.P.; MARTIN, S.R.; HUANG, Y.X.; NAGASHIMA, K.A.; CAYANAN, C.; MADDON, P.J.; KOUP, R.A.; MOORE, J.P.; PAXTON, W.A.,HIV-1 ENTRY INTO CD4(+) CELLS IS MEDIATED BY THE CHEMOKINE RECEPTOR CC-CKR-5. NATURE 381(6584):667-673(1996).
  10. DRAGIC, T.; TRKOLA, A.; LIN, S.W.; NAGASHIMA, K.A.; KAJUMO, F.; ZHAO, L.; OLSON, W.C.; WU, L.J.; MACKAY, C.R.; ALLAWAY, G.P.; SAKMAR ,T.P.; MOORE, J.P.; MADDON, P.J., AMINO-TERMINAL SUBSTITUTIONS IN THE CCR5 CORECEPTOR IMPAIR GP120 BINDING AND HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 ENTRY. J VIROL 72(1):279-285(1998).
  11. FARZAN, M.; CHOE, H.; VACA, L.; MARTIN, K.; SUN,Y.; DESJARDINS, E.; RUFFING, N.; WU, L.J.; WYATT, R.; GERARD, N.; GERARD, C.; SODROSKI, J., A TYROSINE-RICH REGION IN THE N TERMINUS OF CCR5 IS IMPORTANT FOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 ENTRY AND MEDIATES AN ASSOCIATION BETWEEN GP120 AND CCR5. J VIROL 72(2):1160-1164(1998).
  12. GONG, W.H.; HOWARD, O.M.Z.; TURPIN, J.A.; GRIMM, M.C.; UEDA, H.; GRAY, P.W.; RAPORT, C.J.; OPPENHEIM, J.J.; WANG, J.M., MONOCYTE CHEMOTACTIC PROTEIN-2 ACTIVATES CCR5 AND BLOCKS CD4/CCR5-MEDIATED HIV-1 ENTRY/REPLICATION J BIOL CHEM 273(8):428904292(1998).
  13. GRANELLI-PIPERNO, A.; MOSER, B.; POPE, M.; CHEN, D.; WEI, Y.; ISDELL, F.; O'DOHERTY, U.; PAXTON, W.; KOUP, R.; MOJSOV, S.; BHARDWAJ, N.; CLARK-LEWIS, I.; BAGGIOLINI, M.; STEINMAN, R.M.; EFFICIENT INTERACTION OF HIV-1 WITH PURIFIED DENDRITIC CELLS VIA MULTIPLE CHEMOKINE CORECEPTORS. J EXP MED 184(6):2433-2438(1996).
  14. HE, J.L.; CHEN, Y.Z.; FARZAN, M.; CHOE, H.Y.; OHAGEN, A.; GARTNER, S.; BUSCIGLIO, J.; YANG, X.Y.; HOFMANN, W.; NEWMAN, W.; MACKAY, C.R.; SODROSKI, J.; GABUZDA, D.; CCR3 AND CCR5 ARE CO-RECEPTORS FOR HIV-1 INFECTION OF MICROGLIA. NATURE 385(6617):645-649(1997).
  15. KUHMANN, S.E.; PLATT, E.J.; KOZAK, S.L.; KABAT, D.; POLYMORPHISMS IN THE CCR5 GENES OF AFRICAN GREEN MONKEYS AND MICE IMPLICATE SPECIFIC AMINO ACIDS IN INFECTIONS BY SIMIAN AND HUMAN IMMUNODEFICIENCY VIRUSES. J VIROL 71(11):8642-8656(1997).
  16. NISHIYAMA, Y.; MURAKAMI, T.; KURITA, K.; YAMAMOTO, N.; SYNTHESIS OF SOME PEPTIDES CORRESPONDING TO THE ACTIVE REGION OF RANTES FOR CHEMOTAXIS AND EVALUATION OF THEIR ANTI-HUMAN IMMUNODEFICIENCY VIRUS-1 ACTIVITY. CHEM PHARM BULL 45(12):2125-2127(1997).
  17. PROOST, P.; DE MEESTER, I.; SCHOLS, D.; STRUYF, S.; LAMBEIR, A.M.; WUYTS, A.; OPDENAKKER, G.; DE CLERCQ, E.; SCHARPE, S. VAN DAMME,J.; AMINO-TERMINAL TRUNCATION OF CHEMOKINES BY CD26/DIPEPTIDYLPEPTIDASE IV - CONVERSION OF RANTES INTO A POTENT INHIBITOR OF MONOCYTE CHEMOTAXIS AND HIV-1-INFECTION. J BIOL CHEM 273(13):7222-7227(1998).
  18. RABUT, G.E.E.; KONNER, J.A.; KAJUMO, F.; MOORE, J.P.; DRAGIC, T.; ALANINE SUBSTITUTIONS OF POLAR AND NONPOLAR RESIDUES IN THE AMINO-TERMINAL DOMAIN OF CCR5 DIFFERENTLY IMPAIR ENTRY OF MACROPHAGE- AND DUALTROPIC ISOLATES OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1. J VIROL 72(4):3464-3468(1998).
  19. RUBBERT, A.; COMBADIERE, C.; OSTROWSKI, M.; ARTHOS, J.; DYBUL, M.; MACHADO, E,, COHN, M.A.; HOXIE, J.A.; MURPHY, P.M.; FAUCI, A.S.; WEISSMAN, D.; DENDRITIC CELLS EXPRESS MULTIPLE CHEMOKINE RECEPTORS USED AS CORECEPTORS FOR HIV ENTRY. J IMMUNOL 160(8):3933-3941(1998).
  20. SCHOLS, D.; STRUYF, S.; VANDAMME, J.; ESTE, J.A.; HENSON, G.; DECLERCQ, E.; INHIBITION OF T-TROPIC HIV STRAINS BY SELECTIVE ANTAGONIZATION OF THE CHEMOKINE RECEPTOR CXCR4. J EXP MED 186(8):1383-1388(1997).
  21. SHIEH, J.T.C.; ALBRIGHT, A.V.; SHARRON, M.; GARTNER, S.; STRIZKI, J.; DOMS, R.W.; GONZALEZ-SCARANO, F.; CHEMOKINE RECEPTOR UTILIZATION BY HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 ISOLATES THAT REPLICATE IN MICROGLIA. J VIROL 72(5):4243-4249(1998).
  22. SIMMONS, G.; CLAPHAM, P.R.; PICARD, L.; OFFORD, R.E.; ROSENKILDE, M.M.; SCHWARTZ,T.W.; BUSER, R.; WELLS, T.N.C.; PROUDFOOT, A.E.I.; POTENT INHIBITION OF HIV-1 INFECTIVITY IN MACROPHAGES AND LYMPHOCYTES BY A NOVEL CCR5 ANTAGONIST. SCIENCE 276(5310):276-279(1997).
  23. WU, L.J.; PAXTON, W.A.; KASSAM, N.; RUFFING, N.; ROTTMAN, J.B.; SULLIVAN, N.; CHOE, H.; SODROSKI, J.; NEWMAN, W.; KOUP, R.A.; MACKAY, C.R.; CCR5 LEVELS AND EXPRESSION PATTERN CORRELATE WITH INFECTABILITY BY MACROPHAGE-TROPIC HIV-1, IN VITRO. J EXP MED 185(9):1681-1691(1997).
  24. WU, L.J.; LAROSA, G.; KASSAM, N.; GORDON, C.J.; HEATH, H.; RUFFING, N.; CHEN, H.; HUMBLIAS, J.; SAMSON, M.; PARMENTIER, M.; MOORE, J.P.; MACKAY, C.R.; INTERACTION OF CHEMOKINE RECEPTOR CCR5 WITH ITS LIGANDS: MULTIPLE DOMAINS FOR HIV-1 GP120 BINDING AND A SINGLE DOMAIN FOR CHEMOKINE BINDING. J EXP MED 186(8):1373-1381(1997).




Home | 

Privacy Statement | 

Help

comments: chemweb@niaid.nih.gov