HIV-1 Coreceptors and Their Inhibitors

  • N. Ray
  • R. W. Doms
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 303)


Entry of human immunodeficiency virus (HIV) into target cells is mediated by the viral Envelope glycoprotein (Env) and its coordinated interaction with a receptor (CD4) and a coreceptor (usually the chemokine receptors CCR5 or CXCR4). This review describes the identification of chemokine receptors as coreceptors for HIV-1 Env-mediated fusion, the determinants of chemokine receptor usage, and the impact of nonfunctional chemokine receptor alleles on HIV-1 resistance and disease progression. Due to the important role of chemokine receptors in HIV-1 entry, inhibitors of these coreceptors are good candidates for blocking entry and development of antiretroviral therapies. We discuss the different CCR5- and CXCR4-based antiretroviral drugs that have been developed thus far, highlighting the most promising drug candidates. Resistance to these coreceptor inhibitors as well as the impact of these drugs on clinical monitoring and treatment are also discussed.


Chemokine Receptor CCR5 Inhibitor Coreceptor Switching Coreceptor Antagonist Chemokine Receptor Usage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Aarons E, Beddows S, Willingham T, Wu L, Koup R (2001) Adaptation to blockade of human immunodeficiency virus type 1 entry imposed by the anti-CCR5 monoclonal antibody 2D7. Virology 287:382–390PubMedGoogle Scholar
  2. 2.
    Abel S, Van der Ryst E, Muirhead GJ, Rosario M, Edgington A, Weissgerber G (2003) Pharmacokinetics of single and multiple oral doses of UK-427,857—a novel CCR5 antagonist in healthy volunteers [abstr]. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections, 10–14 February 2003. Abstr 556Google Scholar
  3. 3.
    Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA (1996) CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272:1955–1958PubMedGoogle Scholar
  4. 4.
    Ashorn PA, Berger EA, Moss B (1990) Human immunodeficiency virus envelope glycoprotein/CD4-mediated fusion of nonprimate cells with human cells. J Virol 64:2149–2156PubMedGoogle Scholar
  5. 5.
    Baba M, Kanzaki N, Miyake H, Wang X, Takashima K, Teshima K, Shiraishi M, Iizawa Y (2005) TAK-652, a novel small molecule CCR5 antagonist with potent anti-HIV-1 activity. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections, 22–25 February 2005, Boston. Abstr 541Google Scholar
  6. 6.
    Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, Shiraishi M, Aramaki Y, Okonogi K, Ogawa Y, Meguro K, Fujino M (1999) A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 96:5698–5703PubMedGoogle Scholar
  7. 7.
    Bazan HA, Alkhatib G, Broder CC, Berger EA (1998) Patterns of CCR5, CXCR4, and CCR3 usage by envelope glycoproteins from human immunodeficiency virus type 1 primary isolates. J Virol 72:4485–4491PubMedGoogle Scholar
  8. 8.
    Berger EA, Murphy PM, Farber JM (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17:657–700PubMedGoogle Scholar
  9. 9.
    Bieniasz PD, Fridell RA, Aramori I, Ferguson SS, Caron MG, Cullen BR (1997) HIV-1-induced cell fusion is mediated by multiple regions within both the viral envelope and the CCR-5 co-receptor. EMBO J 16:2599–2609PubMedGoogle Scholar
  10. 10.
    Biti R, Ffrench R, Young J, Bennetts B, Stewart G, Liang T (1997) HIV-1 infection in an individual homozygous for the CCR5 deletion allele. Nat Med 3:252–253PubMedGoogle Scholar
  11. 11.
    Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA (1996) The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382:829–833PubMedGoogle Scholar
  12. 12.
    Bleul CC, Wu L, Hoxie JA, Springer TA, Mackay CR (1997) The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci USA 94:1925–1930PubMedGoogle Scholar
  13. 13.
    Brambilla A, Villa C, Rizzardi G, Veglia F, Ghezzi S, Lazzarin A, Cusini M, Muratori S, Santagostino E, Gringeri A, Louie LG, Sheppard HW, Poli G, Michael NL, Pantaleo G, Vicenzi E (2000) Shorter survival of SDF1-3′A/3′A homozygotes linked to CD4+ T cell decrease in advanced human immunodeficiency virus type 1 infection. J Infect Dis 182:311–315PubMedGoogle Scholar
  14. 14.
    Broder CC, Dimitrov DS, Blumenthal R, Berger EA (1993) The block to HIV-1 envelope glycoprotein-mediated membrane fusion in animal cells expressing human CD4 can be overcome by a human cell component(s). Virology 193:483–491PubMedGoogle Scholar
  15. 15.
    Chen CH, Matthews TJ, McDanal CB, Bolognesi DP, Greenberg ML(1995) Amolecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion. J Virol 69:3771–3777PubMedGoogle Scholar
  16. 16.
    Chen Z, Kwon D, Jin Z, Monard S, Telfer P, Jones MS, Lu CY, Aguilar RF, Ho DD, Marx PA (1998) Natural infection of a homozygous delta24 CCR5 redcapped mangabey with an R2b-tropic simian immunodeficiency virus. J Exp Med 188:2057–2065PubMedGoogle Scholar
  17. 17.
    Chesebro B, Nishio J, Perryman S, Cann A, O’Brien W, Chen IS, Wehrly K (1991) Identification of human immunodeficiency virus envelope gene sequences influencing viral entry into CD4-positive HeLa cells, T-leukemia cells, and macrophages. J Virol 65:5782–5789PubMedGoogle Scholar
  18. 18.
    Chesebro B, Wehrly K, Nishio J, Perryman S (1992) Macrophage-tropic human immunodeficiency virus isolates from different patients exhibit unusual V3 envelope sequence homogeneity in comparison with T-cell-tropic isolates: definition of critical amino acids involved in cell tropism. J Virol 66:6547–6554PubMedGoogle Scholar
  19. 19.
    Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85:1135–148PubMedGoogle Scholar
  20. 20.
    Clapham PR, Blanc D, Weiss RA (1991) Specific cell surface requirements for the infection of CD4-positive cells by human immunodeficiency virus types 1 and 2 and by Simian immunodeficiency virus. Virology 181:703–715PubMedGoogle Scholar
  21. 21.
    Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P (1995) Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:1811–1815PubMedGoogle Scholar
  22. 22.
    Cocchi F, DeVico AL, Garzino-Demo A, Cara A, Gallo RC, Lusso P (1996) The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nat Med 2:1244–1247PubMedGoogle Scholar
  23. 23.
    Connor RI, Mohri H, Cao Y, Ho DD(1993) Increased viral burden and cytopathicity correlate temporally with CD4+ T-lymphocyte decline and clinical progression in human immunodeficiency virus type 1-infected individuals. J Virol 67:1772–1777PubMedGoogle Scholar
  24. 24.
    [Reference deleted in proof]Google Scholar
  25. 25.
    Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR (1997) Change in coreceptor use coreceptor use correlates with disease progression in HIV-1-infected individuals. J Exp Med 185:621–628PubMedGoogle Scholar
  26. 26.
    De Clercq E (2003) The bicyclam AMD3100 story. Nat Rev Drug Discov 2:581–587PubMedGoogle Scholar
  27. 27.
    De Jong JJ, De Ronde A, Keulen W, Tersmette M, Goudsmit J (1992) Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution. J Virol 66:6777–6780PubMedGoogle Scholar
  28. 28.
    de Jong JJ, Goudsmit J, Keulen W, Klaver B, Krone W, Tersmette M, de Ronde A (1992) Human immunodeficiency virus type 1 clones chimeric for the envelope V3 domain differ in syncytium formation and replication capacity. JVirol 66:757–765Google Scholar
  29. 29.
    de Vreese K, Kofler-Mongold V, Leutgeb C, Weber V, Vermeire K, Schacht S, Anne J, de Clercq E, Datema R, Werner G (1996) Themolecular target of bicyclams, potent inhibitors of human immunodeficiency virus replication. J Virol 70:689–696PubMedGoogle Scholar
  30. 30.
    Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O’Brien SJ (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:1856–1862PubMedGoogle Scholar
  31. 31.
    Demarest J, Adkison K, Sparks S, Shachoy-Clark A, Schell K, Reddy S, Fang L, O’Mara K, Shibayama S, Piscitelli S (2004) Single and multiple dose escalation study to investigate the safety, pharmacokinetics, and receptor binding of GW873140, a novel CCR5 receptor antagonist in healthy subjects. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections, 8–11 February 2004, San Francisco. Abstr 139Google Scholar
  32. 32.
    Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661–666PubMedGoogle Scholar
  33. 33.
    Deng HK, Unutmaz D, KewalRamani VN, Littman DR (1997) Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature 388:296–300PubMedGoogle Scholar
  34. 34.
    Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, Maddon PJ, Allaway GP, Sakmar TP, Henson G, De Clercq E, Moore JP (1998) AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 4:72–77PubMedGoogle Scholar
  35. 35.
    Doranz BJ, Filion LG, Diaz-Mitoma F, Sitar DS, Sahai J, Baribaud F, Orsini MJ, Benovic JL, Cameron W, Doms RW(2001) Safe use of the CXCR4 inhibitor ALX40-4C in humans. AIDS Res Hum Retroviruses 17:475–486PubMedGoogle Scholar
  36. 36.
    Doranz BJ, Grovit-Ferbas K, Sharron MP, Mao SH, Goetz MB, Daar ES, Doms RW, O’Brien WA (1997) A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor. J Exp Med 186:1395–1400PubMedGoogle Scholar
  37. 37.
    Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Peiper SC, Parmentier M, Collman RG, Doms RW (1996) 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 85:1149–1158PubMedGoogle Scholar
  38. 38.
    Dorr P, Macartney M, Rickett G, Smith-Burchnell C, Dobbs S, Mori J, Griffin P, Lok J, Irvine R, Westby M, Hitchcock C, Stammen B, et al (2003) UK-427,857, a novel small molecule HIV entry inhibitor is a specific antagonist of the chemokine receptor CCR5. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections, 10–14 February 2003, Boston. Abstr 12Google Scholar
  39. 39.
    Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA (1996) HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381:667–673PubMedGoogle Scholar
  40. 40.
    Dragic T, Trkola A, Thompson DA, Cormier EG, Kajumo FA, Maxwell E, Lin SW, Ying W, Smith SO, Sakmar TP, Moore JP (2000) A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci U S A 97:5639–5644PubMedGoogle Scholar
  41. 41.
    Este JA, Cabrera C, Blanco J, Gutierrez A, Bridger G, Henson G, Clotet B, Schols D, De Clercq E (1999) Shift of clinical human immunodeficiency virus type 1 isolates from X4 to R5 and prevention of emergence of the syncytium-inducing phenotype by blockade of CXCR4. J Virol 73:5577–5585PubMedGoogle Scholar
  42. 42.
    [Reference deleted in proof]Google Scholar
  43. 43.
    Feng Y, Broder CC, Kennedy PE, Berger EA (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272:872–877PubMedGoogle Scholar
  44. 44.
    Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, Nibbs RJ, Freedman BI, Quinones MP, Bamshad MJ, Murthy KK, Rovin BH, Bradley W, Clark RA, Anderson SA, O’Connell RJ, Agan BK, Ahuja SS, Bologna R, Sen L, Dolan MJ, Ahuja SK (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307:1434–1440PubMedGoogle Scholar
  45. 45.
    Gorry PR, Zhang C, Wu S, Kunstman K, Trachtenberg E, Phair J, Wolinsky S, Gabuzda D (2002) Persistence of dual-tropic HIV-1 in an individual homozygous for the CCR5 Delta 32 allele. Lancet 359:1832–1834PubMedGoogle Scholar
  46. 46.
    Gotoh K, Yoshimori M, Kanbara K, Tamamura H, Kanamoto T, Mochizuki K, Fujii N, Nakashima H (2001) Increase of R5 HIV-1 infection and CCR5 expression in T cells treated with high concentrations of CXCR4 antagonists and SDF-1. J Infect Chemother 7:28–36PubMedGoogle Scholar
  47. 47.
    Hendel H, Henon N, Lebuanec H, Lachgar A, Poncelet H, Caillat-Zucman S, Winkler CA, Smith MW, Kenefic L, O’Brien S, Lu W, Andrieu JM, Zagury D, Schachter F, Rappaport J, Zagury JF (1998) Distinctive effects of CCR5, CCR2, and SDF1 genetic polymorphisms in AIDS progression. J Acquir Immune Defic Syndr Hum Retrovirol 19:381–386PubMedGoogle Scholar
  48. 48.
    Hendrix C, Collier AC, Lederman M, Pollard R, Brown S, Glesby M, et al (2002) Calandra for the AMD-3100 HIV Study Group. AMD-3100 CXCR4 receptor blocker fails to reduce HIV viral load by > 1 log following 10-day continuous infusion. 9th Conference on Retroviruses and Opportunistic Infections, Seattle. Abstr 391Google Scholar
  49. 49.
    Hoffman TL, Stephens EB, Narayan O, Doms RW (1998) HIV type I envelope determinants for use of the CCR2b, CCR3, STRL33, and APJ coreceptors. Proc Natl Acad Sci U S A 95:11360–11365PubMedGoogle Scholar
  50. 50.
    Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, Kang S, Ceradini D, Jin Z, Yazdanbakhsh K, Kunstman K, Erickson D, Dragon E, Landau NR, Phair J, Ho DD, Koup RA (1996) The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 2:1240–1243PubMedGoogle Scholar
  51. 51.
    Hwang SS, Boyle TJ, Lyerly HK, Cullen BR (1991) Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science 253:71–74PubMedGoogle Scholar
  52. 52.
    Iizawa Y, Kanzaki N, Takashima K, Miyake H, Tagawa Y, Sugihara Y, Baba M (2003) Anti-HIV-1 activity of TAK-220, a small molecule CCR5 antagonist. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections, 10–14 February 2003, Boston. Abstr 11Google Scholar
  53. 53.
    Ioannidis JP, Rosenberg PS, Goedert JJ, Ashton LJ, Benfield TL, Buchbinder SP, Coutinho RA, Eugen-Olsen J, Gallart T, Katzenstein TL, Kostrikis LG, Kuipers H, Louie LG, Mallal SA, Margolick JB, Martinez OP, Meyer L, Michael NL, Operskalski E, Pantaleo G, Rizzardi GP, Schuitemaker H, Sheppard HW, Stewart GJ, Theodorou ID, Ullum H, Vicenzi E, Vlahov D, Wilkinson D, Workman C, Zagury JF, O’Brien TR (2001) Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3′A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data. Ann Intern Med 135:782–795PubMedGoogle Scholar
  54. 54.
    Kanbara K, Sato S, Tanuma J, Tamamura H, Gotoh K, Yoshimori M, Kanamoto T, Kitano M, Fujii N, Nakashima H (2001) Biological and genetic characterization of a human immunodeficiency virus strain resistant to CXCR4 antagonist T134. AIDS Res Hum Retroviruses 17:615–622PubMedGoogle Scholar
  55. 55.
    Kostrikis LG, Huang Y, Moore JP, Wolinsky SM, Zhang L, Guo Y, Deutsch L, Phair J, Neumann AU, Ho DD (1998) A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promotermutation. Nat Med 4:350–353PubMedGoogle Scholar
  56. 56.
    Lederman MM, Veazey RS, Offord R, Mosier DE, Dufour J, Mefford M, Piatak M Jr, Lifson JD, Salkowitz JR, Rodriguez B, Blauvelt A, Hartley O (2004) Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 306:485–487PubMedGoogle Scholar
  57. 57.
    Lee B, Doranz BJ, Rana S, Yi Y, Mellado M, Frade JM, Martinez AC, O’Brien SJ, Dean M, Collman RG, Doms RW (1998) Influence of the CCR2-V64I polymorphism on human immunodeficiency virus type 1 coreceptor activity and on chemokine receptor function of CCR2b, CCR3, CCR5, and CXCR4. JVirol 72:7450–7458Google Scholar
  58. 58.
    Lee B, Sharron M, Montaner LJ, Weissman D, Doms RW (1999) Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci USA 96:5215–5220PubMedGoogle Scholar
  59. 59.
    [Reference deleted in proof]Google Scholar
  60. 60.
    Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86:367–377PubMedGoogle Scholar
  61. 61.
    Maddon PJ, Dalgleish AG, McDougal JS, Clapham PR, Weiss RA, Axel R (1986) The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47:333–348PubMedGoogle Scholar
  62. 62.
    Maeda K, Nakata H, Koh Y, Miyakawa T, Ogata H, Takaoka Y, Shibayama S, Sagawa K, Fukushima D, Moravek J, Koyanagi Y, Mitsuya H (2004) Spiro-diketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J Virol 78:8654–8662PubMedGoogle Scholar
  63. 63.
    Maeda K, Nakata H, Ogata H, Koh Y, Miyakawa T, Mitsuya H (2004) The current status of, and challenges in, the development of CCR5 inhibitors as therapeutics for HIV-1 infection. Curr Opin Pharmacol 4:447–452PubMedGoogle Scholar
  64. 64.
    Maeda K, Yoshimura K, Shibayama S, Habashita H, Tada H, Sagawa K, Miyakawa T, Aoki M, Fukushima D, Mitsuya H (2001) Novel low molecular weight spirodike-topiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5. J Biol Chem 276:35194–35200PubMedGoogle Scholar
  65. 65.
    Maeda Y, Foda M, Matsushita S, Harada S (2000) Involvement of both the V2 and V3 regions of the CCR5-tropic human immunodeficiency virus type 1 envelope in reduced sensitivity to macrophage inflammatory protein 1alpha. J Virol 74:1787–1793PubMedGoogle Scholar
  66. 66.
    Magierowska M, Theodorou I, Debre P, Sanson F, Autran B, Riviere Y, Charron D, Costagliola D (1999) Combined genotypes of CCR5, CCR2, SDF1, and HLA genes can predict the long-term nonprogressor status in human immunodeficiency virus-1-infected individuals. Blood 93:936–941PubMedGoogle Scholar
  67. 67.
    McDermott DH, Zimmerman PA, Guignard F, Kleeberger CA, Leitman SF, Murphy PM (1998) CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS). Lancet 352:866–870PubMedGoogle Scholar
  68. 68.
    Meyer L, Magierowska M, Hubert JB, Theodorou I, van Rij R, Prins M, de Roda Husman AM, Coutinho R, Schuitemaker H (1999) CC-chemokine receptor variants, SDF-1 polymorphism, and disease progression in 720 HIV-infected patients. SEROCO Cohort. Amsterdam Cohort Studies on AIDS. Aids 13:624–626Google Scholar
  69. 69.
    Michael NL, Chang G, Louie LG, Mascola JR, Dondero D, Birx DL, Sheppard HW (1997) The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat Med 3:338–340PubMedGoogle Scholar
  70. 70.
    Michael NL, Nelson JA, KewalRamani VN, Chang G, O’Brien SJ, Mascola JR, Volsky B, Louder M, White GC 2nd, Littman DR, Swanstrom R, O’Brien TR (1998) Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32. J Virol 72:6040–6047PubMedGoogle Scholar
  71. 71.
    Miedema F, Meyaard L, Koot M, Klein MR, Roos MT, Groenink M, Fouchier RA, Van’t Wout AB, Tersmette M, Schellekens PT, et al (1994) Changing virus-host interactions in the course of HIV-1 infection. Immunol Rev 140:35–72PubMedGoogle Scholar
  72. 72.
    Moore JP, Doms RW (2003) The entry of entry inhibitors: a fusion of science and medicine. Proc Natl Acad Sci U S A 100:10598–10602PubMedGoogle Scholar
  73. 73.
    Mosier DE, Picchio GR, Gulizia RJ, Sabbe R, Poignard P, Picard L, Offord RE, Thompson DA, Wilken J (1999) Highly potent RANTES analogues either prevent CCR5-using human immunodeficiency virus type 1 infection in vivo or rapidly select for CXCR4-using variants. J Virol 73:3544–3550PubMedGoogle Scholar
  74. 74.
    Mummidi S, Ahuja SS, Gonzalez E, Anderson SA, Santiago EN, Stephan KT, Craig FE, O’Connell P, Tryon V, Clark RA, Dolan MJ, Ahuja SK (1998) Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nat Med 4:786–793PubMedGoogle Scholar
  75. 75.
    Murakami T, Nakajima T, Koyanagi Y, Tachibana K, Fujii N, Tamamura H, Yoshida N, Waki M, Matsumoto A, Yoshie O, Kishimoto T, Yamamoto N, Nagasawa T (1997) A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection. J Exp Med 186:1389–1393PubMedGoogle Scholar
  76. 76.
    Nakata H, Koh Y, Maeda K, Takaoka Y, Tamamura H, Fujii N, Mitsuya H (2005) Greater synergistic anti-HIV effects upon combinations of a CCR5 inhibitor AK602/ONO4128/GW873140 with CXCR4 inhibitors than with other anti-HIV drugs. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections, 22–25 February 2005, Boston. Abstr 543Google Scholar
  77. 77.
    O’Brien TR, Winkler C, Dean M, Nelson JA, Carrington M, Michael NL, White GC 2nd (1997) HIV-1 infection in a man homozygous for CCR5 delta 32. Lancet 349:1219PubMedGoogle Scholar
  78. 78.
    Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B (1996) The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382:833–835PubMedGoogle Scholar
  79. 79.
    Paxton WA, Martin SR, Tse D, O’Brien TR, Skurnick J, VanDevanter NL, Padian N, Braun JF, Kotler DP, Wolinsky SM, Koup RA (1996) Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure. Nat Med 2:412–417PubMedGoogle Scholar
  80. 80.
    Pozniak AL, Fatkenheuer G, Johnson M, Hoepelman IM, Rockstroh J, Goebel F, Abel S, James I, Rosario M, Medhurst C, et al (2003) Presented at the 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago. Abstr H-443Google Scholar
  81. 81.
    Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M, Pohlmann S, Sfakianos JN, Derdeyn CA, Blumenthal R, Hunter E, Doms RW (2002) Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA 99:16249–16254PubMedGoogle Scholar
  82. 82.
    Reeves JD, Miamidian JL, Biscone MJ, Lee FH, Ahmad N, Pierson TC, Doms RW (2004) Impact of mutations in the coreceptor binding site on human immunodeficiency virus type 1 fusion, infection, and entry inhibitor sensitivity. J Virol 78:5476–5485PubMedGoogle Scholar
  83. 83.
    Reynes J, Rouzier R, Kanouni T, Baillat V, Baroudy B, Keung A, Hogan C, Markowitz M, Laughlin M (2002) Safety and antiviral effects of a CCR5 receptor antagonist in HIV-1-infected subjects. Presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle. Abstr 1Google Scholar
  84. 84.
    Rizzardi GP, Morawetz RA, Vicenzi E, Ghezzi S, Poli G, Lazzarin A, Pantaleo G (1998) CCR2 polymorphism and HIV disease. Swiss HIV Cohort. Nat Med 4:252–253PubMedGoogle Scholar
  85. 85.
    Ross TM, Cullen BR (1998) The ability of HIV type 1 to use CCR-3 as a coreceptor is controlled by envelope V1/V2 sequences acting in conjunction with a CCR-5 tropic V3 loop. Proc Natl Acad Sci U S A 95:7682–7686PubMedGoogle Scholar
  86. 86.
    Rucker J, Edinger AL, Sharron M, Samson M, Lee B, Berson JF, Yi Y, Margulies B, Collman RG, Doranz BJ, Parmentier M, Doms RW (1997) Utilization of chemokine receptors, orphan receptors, and herpesvirus-encoded receptors by diverse human and simian immunodeficiency viruses. J Virol 71:8999–9007PubMedGoogle Scholar
  87. 87.
    [Reference deleted in proof]Google Scholar
  88. 88.
    Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G, Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ, Collman RG, Doms RW, Vassart G, Parmentier M (1996) Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382:722–725PubMedGoogle Scholar
  89. 89.
    Schols D, Este JA, Cabrera C, De Clercq E (1998) T-cell-line-tropic human immunodeficiency virus type 1 that is made resistant to stromal cell-derived factor 1alpha contains mutations in the envelope gp120 but does not show a switch in coreceptor use. J Virol 72:4032–4037PubMedGoogle Scholar
  90. 90.
    Schols D, Struyf S, Van Damme J, Este JA, Henson G, De Clercq E (1997) Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J Exp Med 186:1383–1388PubMedGoogle Scholar
  91. 91.
    Schuitemaker H, Koot M, Kootstra NA, Dercksen MW, de Goede RE, van Steenwijk RP, Lange JM, Schattenkerk JK, Miedema F, Tersmette M (1992) Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol 66:1354–1360PubMedGoogle Scholar
  92. 92.
    Schurmann D, Rouzier R, Nougarede R, Reynes J, Fatkenheuer G, Raffi F, Michelet C, Tarral A, Hoffmann C, Kiunke J, Sprenger H, vanLier J, Sansone A, Jackson M, Laughlin M (2004) Antiviral activity of a CCR5 receptor antagonist. Presented at the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco. Abstract 140LBGoogle Scholar
  93. 93.
    Sharron M, Pohlmann S, Price K, Lolis E, Tsang M, Kirchhoff F, Doms RW, Lee B (2000) Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes. Blood 96:41–49PubMedGoogle Scholar
  94. 94.
    Shioda T, Levy JA, Cheng-Mayer C (1992) Small amino acid changes in the V3 hypervariable region of gp120 can affect the T-cell-line and macrophage tropism of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 89:9434–9438PubMedGoogle Scholar
  95. 95.
    Simmons G, Reeves JD, Hibbitts S, Stine JT, Gray PW, Proudfoot AE, Clapham PR (2000) Co-receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands. Immunol Rev 177:112–126PubMedGoogle Scholar
  96. 96.
    Simmons G, Wilkinson D, Reeves JD, Dittmar MT, Beddows S, Weber J, Carnegie G, Desselberger U, Gray PW, Weiss RA, Clapham PR (1996) Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry. J Virol 70:8355–8360PubMedGoogle Scholar
  97. 97.
    Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, Goedert JJ, O’Brien TR, Jacobson LP, Kaslow R, Buchbinder S, Vittinghoff E, Vlahov D, Hoots K, Hilgartner MW, O’Brien SJ (1997) Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science 277:959–965PubMedGoogle Scholar
  98. 98.
    Smyth RJ, Yi Y, Singh A, Collman RG (1998) Determinants of entry cofactor utilization and tropism in a dualtropic human immunodeficiency virus type 1 primary isolate. J Virol 72:4478–4484PubMedGoogle Scholar
  99. 99.
    Speck RF, Wehrly K, Platt EJ, Atchison RE, Charo IF, Kabat D, Chesebro B, Goldsmith MA (1997) Selective employment of chemokine receptors as human immunodeficiency virus type 1 coreceptors determined by individual amino acids within the envelope V3 loop. J Virol 71:7136–7139PubMedGoogle Scholar
  100. 100.
    Strizki JM, Xu S, Wagner NE, Wojcik L, Liu J, Hou Y, Endres M, Palani A, Shapiro S, Clader JW, Greenlee WJ, Tagat JR, McCombie S, Cox K, Fawzi AB, Chou CC, Pugliese-Sivo C, Davies L, Moreno ME, Ho DD, Trkola A, Stoddart CA, Moore JP, Reyes GR, Baroudy BM (2001) SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proc Natl Acad Sci U S A 98:12718–12723PubMedGoogle Scholar
  101. 101.
    Takeuchi Y, Akutsu M, Murayama K, Shimizu N, Hoshino H (1991) Host range mutant of human immunodeficiency virus type 1: modification of cell tropism by a single point mutation at the neutralization epitope in the env gene. J Virol 65:1710–1718PubMedGoogle Scholar
  102. 102.
    Tersmette M, de Goede RE, Al BJ, Winkel IN, Gruters RA, Cuypers HT, Huisman HG, Miedema F (1988) Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-inducing isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J Virol 62:2026–2032PubMedGoogle Scholar
  103. 103.
    Theodorou I, Meyer L, Magierowska M, Katlama C, Rouzioux C (1997) HIV-1 infection in an individual homozygous for CCR5 delta 32. Seroco Study Group. Lancet 349:1219–1220PubMedGoogle Scholar
  104. 104.
    Tremblay CL, Giguel F, Hicks JL, Chou TC, Lizawa Y, Sugihara Y, Hirsch MS (2003) TAK-220, a novel small molecule inhibitor of CCR5 has favourable anti-HIV the interactions with other antiretrovirals in vitro. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections, 10–14 February 2003, Boston. Abstr 562Google Scholar
  105. 105.
    Trkola A, Dragic T, Arthos J, Binley JM, Olson WC, Allaway GP, Cheng-Mayer C, Robinson J, Maddon PJ, Moore JP (1996) CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature 384:184–187PubMedGoogle Scholar
  106. 106.
    Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, Pugach P, Xu S, Wojcik L, Tagat J, Palani A, Shapiro S, Clader JW, McCombie S, Reyes GR, Baroudy BM, Moore JP (2002) HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci U S A 99:395–400PubMedGoogle Scholar
  107. 107.
    van Rij RP, Broersen S, Goudsmit J, Coutinho RA, Schuitemaker H (1998) The role of a stromal cell-derived factor-1 chemokine gene variant in the clinical course of HIV-1 infection. Aids 12:F85–90PubMedGoogle Scholar
  108. 108.
    Veazey RS, Klasse PJ, Ketas TJ, Reeves JD, Piatak M Jr, Kunstman K, Kuhmann SE, Marx PA, Lifson JD, Dufour J, Mefford M, Pandrea I, Wolinsky SM, Doms RW, DeMartino JA, Siciliano SJ, Lyons K, Springer MS, Moore JP (2003) Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian-human immunodeficiency virus infection. J ExpMed 198:1551–1562Google Scholar
  109. 109.
    Westby M, Smith-Burchnell C, Hamilton D, Mori J, Macartney M, Robas N, Irvine B, Fidock M, Perruccio F, Mills J, Burt K, Barber C, Stephenson P, Dorr P, Perros M (2005) Structurally-related HIV co-receptor antagonists bind to similar regions of CCR5 but have differential activities against UK-427,857-resistant primary isolates. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections, 22–25 February 2005, Boston. Abstr 96Google Scholar
  110. 110.
    Willey SJ, Reeves JD, Hudson R, Miyake K, Dejucq N, Schols D, De Clercq E, Bell J, McKnight A, Clapham PR (2003) Identification of a subset of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains able to exploit an alternative coreceptor on untransformed human brain and lymphoid cells. J Virol 77:6138–6152PubMedGoogle Scholar
  111. 111.
    Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert JJ, O’Brien TR, Jacobson LP, Detels R, Donfield S, Willoughby A, Gomperts E, Vlahov D, Phair J, O’Brien SJ (1998) Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 279:389–393PubMedGoogle Scholar
  112. 112.
    Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, Gerard C, Sodroski J (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384:179–183PubMedGoogle Scholar
  113. 113.
    Zhang Y, Lou B, Lal RB, Gettie A, Marx PA, Moore JP (2000) Use of inhibitors to evaluate coreceptor usage by simian and simian/human immunodeficiency viruses and human immunodeficiency virus type 2 in primary cells. J Virol 74:6893–6910PubMedGoogle Scholar
  114. 114.
    Zhang YJ, Dragic T, Cao Y, Kostrikis L, Kwon DS, Littman DR, Kewal Ramani VN, Moore JP (1998) Use of coreceptors other than CCR5 by non-syncytium-inducing adult and pediatric isolates of human immunodeficiency virus type 1 is rare in vitro. J Virol 72:9337–9344PubMedGoogle Scholar
  115. 115.
    Zhang YJ, Zhang L, Ketas T, Korber BT, Moore JP (2001) HIV type 1 molecular clones able to use the Bonzo/STRL-33 coreceptor for virus entry. AIDS Res Hum Retroviruses 17:217–227PubMedGoogle Scholar
  116. 116.
    Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, Ho DD (1993) Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261:1179–1181PubMedGoogle Scholar
  117. 117.
    Zimmerman PA, Buckler-White A, Alkhatib G, Spalding T, Kubofcik J, Combadiere C, Weissman D, Cohen O, Rubbert A, Lam G, Vaccarezza M, Kennedy PE, Kumaraswami V, Giorgi JV, Detels R, Hunter J, Chopek M, Berger EA, Fauci AS, Nutman TB, Murphy PM (1997) Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol Med 3:23–36PubMedGoogle Scholar
  118. 118.
    Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595–599PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • N. Ray
    • 1
  • R. W. Doms
    • 1
  1. 1.Department of MicrobiologyUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations