Targets for drug development — past and present

  • Roy M. Gulick
Part of the Milestones in Drug Therapy book series (MDT)


The first cases of AIDS were recognized in 1981 [1]. With the realization that patients with AIDS experienced nearly universal mortality, the search for effective treatment began urgently. This search was facilitated greatly by the discovery of the causative agent, the human immunodeficiency virus (HIV) [2, 3]. It was recognized early on that the replication cycles of other animal and human retroviruses depended on the virus-specific enzyme reverse transcriptase, and this became the first HIV drug target. Several compounds with demonstrated activity against other retroviruses were reported to have activity against HIV in vitro by inhibiting the reverse transcriptase enzyme, such as suramin [4] and ribavirin [5]. However, clinical trials of these agents ultimately showed no clinical benefits in HIV-infected patients [6, 7].


Human Immunodeficiency Virus Human Immunodeficiency Virus Infection Acquire Immune Deficiency Syndrome CCR5 Antagonist CCR5 Inhibitor 
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.


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  1. 1.
    Centers for Disease Control (1981) Pneumocystis pneumonia-Los Angeles. MMWR 30: 250–252Google Scholar
  2. 2.
    Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vezinet-Brun F, Rouzioux C et al. (1983) Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220: 868–871PubMedCrossRefGoogle Scholar
  3. 3.
    Gallo RC, Sarin PS, Gelmann EP, Robert-Guroff M, Richardson E, Kalyanaraman VS, Mann D, Sidhu GD, Stahl RE, Zolla-Pazner S et al. (1983) Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science 220: 865–867PubMedCrossRefGoogle Scholar
  4. 4.
    Mitsuya H, Popovic M, Yarchoan R, Matsushita S, Gallo RC, Broder S (1984) Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science 226: 172–174PubMedCrossRefGoogle Scholar
  5. 5.
    McCormick JB, Getchell JP, Mitchell SW, Hicks DR (1984) Ribavirin suppresses replication of lymphadenopathy-associated virus in cultures of human adult T lymphocytes. Lancet 2: 1367–1369PubMedCrossRefGoogle Scholar
  6. 6.
    Kaplan LD, Wolfe PR, Volberding PA, Feorino P, Levy JA, Abrams DI, Kiprov D, Wong R, Kaufman L, Gottlieb MS (1987) Lack of response to suramin in patients with AIDS and AIDSrelated complex. Am J Med 82: 615–620PubMedCrossRefGoogle Scholar
  7. 7.
    Spector SA, Kennedy C, McCutchan JA, Bozzette SA, Straube RG, Connor JD, Richman DD (1989) The antiviral effect of zidovudine and ribavirin in clinical trials and the use of p24 antigen levels as a virologic marker. J Infect Dis 159: 822–828PubMedGoogle Scholar
  8. 8.
    Horwitz JP, Chua J, Noel M (1964) Nucleosides V-the monomesylates of 1-2′-deoxy-B-D-lyxofuranosyl thymine. J Org Chem 29: 2076–2078CrossRefGoogle Scholar
  9. 9.
    Lin TS, Prusoff WH (1978) Synthesis and biological activity of several amino analogues of thymidine. J Med Chem 21: 109–112PubMedCrossRefGoogle Scholar
  10. 10.
    Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S (1985) 3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathyassociated virus in vitro. Proc Natl Acad Sci USA 82: 7096–7100PubMedCrossRefGoogle Scholar
  11. 11.
    Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT et al. (1987) The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317: 185–191PubMedCrossRefGoogle Scholar
  12. 12.
    Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, Skoog M, Wu JC, Shih CK, Eckner K, Hattox S, Adams J et al. (1990) Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 250: 1411–1413PubMedCrossRefGoogle Scholar
  13. 13.
    Wu JC, Warren TC, Adams J, Proudfoot J, Skiles J, Raghavan P, Perry C, Potocki I, Farina PR, Grob PM (1991) A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site. Biochemistry 30: 2022–2026PubMedCrossRefGoogle Scholar
  14. 14.
    Richman D, Rosenthal AS, Skoog M, Eckner RJ, Chou TC, Sabo JP, Merluzzi VJ (1991) BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine. Antimicrob Agents Chemother 35: 305–308PubMedGoogle Scholar
  15. 15.
    Richman DD, Havlir D, Corbeil J, Looney D, Ignacio C, Spector SA, Sullivan J, Cheeseman S, Barringer K, Pauletti D et al. (1994) Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 68: 1660–1666PubMedGoogle Scholar
  16. 16.
    Montaner JS, Reiss P, Cooper D, Vella S, Harris M, Conway B, Wainberg MA, Smith D, Robinson P, Hall D et al. (1998) A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. JAMA 279: 930–937PubMedCrossRefGoogle Scholar
  17. 17.
    Toh H, Kikuno R, Hayashida H, Miyata T, Kugimiya W, Inouye S, Yuki S, Saigo K (1985) Close structural resemblance between putative polymerase of a Drosophila transposable genetic element 17.6 and pol gene product of Moloney murine leukaemia virus. EMBO J 4: 1267–1272PubMedGoogle Scholar
  18. 18.
    Kramer RA, Schaber MD, Skalka AM, Ganguly K, Wong-Staal F, Reddy EP (1986) HTLV-III gag protein is processed in yeast cells by the virus pol-protease. Science 231: 1580–1584PubMedCrossRefGoogle Scholar
  19. 19.
    Navia MA, Fitzgerald PM, McKeever BM, Leu CT, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP (1989) Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 337: 615–620PubMedCrossRefGoogle Scholar
  20. 20.
    McQuade TJ, Tomasselli AG, Liu L, Karacostas V, Moss B, Sawyer TK, Heinrikson RL, Tarpley WG (1990) A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation. Science 247: 454–456PubMedCrossRefGoogle Scholar
  21. 21.
    Ashorn P, McQuade TJ, Thaisrivongs S, Tomasselli AG, Tarpley WG, Moss B (1990) An inhibitor of the protease blocks maturation of human and simian immunodeficiency viruses and spread of infection. Proc Natl Acad Sci USA 87: 7472–7476PubMedCrossRefGoogle Scholar
  22. 22.
    Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Krohn A et al. (1990) Rational design of peptide-based HIV proteinase inhibitors. Science 248: 358–361PubMedCrossRefGoogle Scholar
  23. 23.
    Craig JC, Duncan IB, Hockley D, Grief C, Roberts NA, Mills JS (1991) Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antiviral Res 16: 295–305PubMedCrossRefGoogle Scholar
  24. 24.
    Vacca JP, Dorsey BD, Schleif WA, Levin RB, McDaniel SL, Darke PL, Zugay J, Quintero JC, Blahy OM, Roth E et al. (1994) L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc Natl Acad Sci USA 91: 4096–4100PubMedCrossRefGoogle Scholar
  25. 25.
    Kempf D, Marsh KC, Denissen JF, McDonald E, Vasavanonda S, Flentge CA, Green BE, Fino L, Park CH, Kong XP et al. (1995) ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci USA 92: 2484–2488PubMedCrossRefGoogle Scholar
  26. 26.
    Markowitz M, Saag M, Powderly WG, Hurley AM, Hsu A, Valdes JM, Henry D, Sattler F, La Marca A, Leonard JM et al. (1995) A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 333: 1534–1539PubMedCrossRefGoogle Scholar
  27. 27.
    Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, Timpone J, Baruch A, Jones M, Facey K, Whitacre C, McAuliffe VJ et al. (1996) Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med 334: 1011–1017PubMedCrossRefGoogle Scholar
  28. 28.
    Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Richman DD, Valentine FT, Jonas L, Meibohm A et al. (1997) Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 337: 734–739PubMedCrossRefGoogle Scholar
  29. 29.
    Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, Deyton LR et al. (1997) A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 337: 725–733PubMedCrossRefGoogle Scholar
  30. 30.
    Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, Sun E, Henry D, Rode R, Potthoff A et al. (1998) Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet 351: 543–549PubMedCrossRefGoogle Scholar
  31. 31.
    Mouton Y, Alfandari S, Valette M, Cartier F, Dellamonica P, Humbert G, Lang JM, Massip P, Mechali D, Leclercq P et al. (1997) Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. AIDS 11: F101–F105PubMedCrossRefGoogle Scholar
  32. 32.
    Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338: 853–860PubMedCrossRefGoogle Scholar
  33. 33.
    Richman DD, Morton SC, Wrin T, Hellmann N, Berry S, Shapiro MF, Bozzette SA (2004) The prevalence of antiretroviral drug resistance in the United States. AIDS 18: 1393–1401PubMedCrossRefGoogle Scholar
  34. 34.
    Klatzmann D, Champagne E, Chamaret S, Gruest J, Guetard D, Hercend T, Gluckman JC, Montagnier L (1984) T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature 312: 767–768PubMedCrossRefGoogle Scholar
  35. 35.
    Dalgleish AG, Beverley PC, Clapham PR, Crawford DH, Greaves MF, Weiss RA (1984) The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312: 763–767PubMedCrossRefGoogle Scholar
  36. 36.
    McDougal JS, Kennedy MS, Sligh JM, Cort SP, Mawle A, Nicholson JK (1986) Binding of HTLVIII/LAV to T4+ T cells by a complex of the 110K viral protein and the T4 molecule. Science 231: 382–385PubMedCrossRefGoogle Scholar
  37. 37.
    Smith DH, Byrn RA, Marsters SA, Gregory T, Groopman JE, Capon DJ (1987) Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen. Science 238: 1704–1707PubMedCrossRefGoogle Scholar
  38. 38.
    Fisher RA, Bertonis JM, Meier W, Johnson VA, Costopoulos DS, Liu T, Tizard R, Walker BD, Hirsch MS, Schooley RT et al. (1988) HIV infection is blocked in vitro by recombinant soluble CD4. Nature 331: 76–78PubMedCrossRefGoogle Scholar
  39. 39.
    Hussey RE, Richardson NE, Kowalski M, Brown NR, Chang HC, Siliciano RF, Dorfman T, Walker B, Sodroski J, Reinherz EL (1988) A soluble CD4 protein selectively inhibits HIV replication and syncytium formation. Nature 331: 78–81PubMedCrossRefGoogle Scholar
  40. 40.
    Deen KC, McDougal JS, Inacker R, Folena-Wasserman G, Arthos J, Rosenberg J, Maddon PJ, Axel R, Sweet RW (1988) A soluble form of CD4 (T4) protein inhibits AIDS virus infection. Nature 331: 82–84PubMedCrossRefGoogle Scholar
  41. 41.
    Traunecker A, Luke W, Karjalainen K (1988) Soluble CD4 molecules neutralize human immunodeficiency virus type 1. Nature 331: 84–86PubMedCrossRefGoogle Scholar
  42. 42.
    Schooley RT, Merigan TC, Gaut P, Hirsch MS, Holodniy M, Flynn T, Liu S, Byington RE, Henochowicz S, Gubish E et al. (1990) Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase I-II escalating dosage trial. Ann Intern Med 112: 247–253PubMedGoogle Scholar
  43. 43.
    Kahn JO, Allan JD, Hodges TL, Kaplan LD, Arri CJ, Fitch HF, Izu AE, Mordenti J, Sherwin JE, Groopman JE et al. (1990) The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med 112: 254–261PubMedGoogle Scholar
  44. 44.
    Schacker T, Coombs RW, Collier AC, Zeh JE, Fox I, Alam J, Nelson K, Eggert E, Corey L (1994) The effects of high-dose recombinant soluble CD4 on human immunodeficiency virus type 1 viremia. J Infect Dis 169: 37–40PubMedGoogle Scholar
  45. 45.
    Schacker T, Collier AC, Coombs R, Unadkat JD, Fox I, Alam J, Wang JP, Eggert E, Corey L (1995) Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection. J Acquir Immune Defic Syndr Hum Retrovirol 9: 145–152PubMedGoogle Scholar
  46. 46.
    Daar ES, Li XL, Moudgil T, Ho DD (1990) High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. Proc Natl Acad Sci USA 87: 6574–6578PubMedCrossRefGoogle Scholar
  47. 47.
    Koot M, Keet IP, Vos AH, de Goede RE, Roos MT, Coutinho RA, Miedema F, Schellekens PT, Tersmette M (1993) Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med 118, 681–688PubMedGoogle Scholar
  48. 48.
    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: 1811–1815PubMedCrossRefGoogle Scholar
  49. 49.
    Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP et al. (1996) HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381: 667–673PubMedCrossRefGoogle Scholar
  50. 50.
    Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM et al. (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381: 661–666PubMedCrossRefGoogle Scholar
  51. 51.
    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: 872–877PubMedCrossRefGoogle Scholar
  52. 52.
    Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W et al. (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85: 1135–1148PubMedCrossRefGoogle Scholar
  53. 53.
    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: 1149–1158PubMedCrossRefGoogle Scholar
  54. 54.
    Strizki JM, Xu S, Wagner NE, Wojcik L, Liu J, Hou Y, Endres M, Palani A, Shapiro S, Clader JW et al. (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 USA 98: 12718–12723PubMedCrossRefGoogle Scholar
  55. 55.
    Reynes J, Rouzier R, Kanouni T, Kanouni T, Baillat V, Baroudy B, Keung A, Hogan C, Markowitz M, Laughlin M (2002) SCH C: Safety and antiviral effects of a CCR5 receptor antagonist in HIV-1 infected subjects. 9th Conference on Retroviruses and Opportunistic Infections 2002, Seattle, WA, February 24–28, 2002, abstract no. 1Google Scholar
  56. 56.
    Strizki JM, Tremblay C, Xu S, Wojcik L, Wagner N, Gonsiorek W, Hipkin RW, Chou CC, Pugliese-Sivo C, Xiao Y et al. (2005) Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob Agents Chemother 49: 4911–4919PubMedCrossRefGoogle Scholar
  57. 57.
    De Clercq E, Yamamoto N, Pauwels R, Baba M, Schols D, Nakashima H, Balzarini J, Debyser Z, Murrer BA, Schwartz D et al. (1992) Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event. Proc Natl Acad Sci USA. 89: 5286–5290PubMedCrossRefGoogle Scholar
  58. 58.
    De Clercq E, Yamamoto N, Pauwels R, Balzarini J, Witvrouw M, De Vreese K, Debyser Z, Rosenwirth B, Peichl P, Datema R et al. (1994) Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100. Antimicrob Agents Chemother 38: 668–674PubMedGoogle Scholar
  59. 59.
    Schols D, Este JA, Henson G, De Clercq E (1997) Bicyclams, a class of potent anti-HIV agents, are targeted at the HIV coreceptor fusin/CXCR-4. Antiviral Res 35: 147–156PubMedCrossRefGoogle Scholar
  60. 60.
    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: 72–77PubMedCrossRefGoogle Scholar
  61. 61.
    Hendrix CW, Flexner C, MacFarland RT, Giandomenico C, Fuchs EJ, Redpath E, Bridger G, Henson GW (2000) Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Antimicrob Agents Chemother 44: 1667–1673PubMedCrossRefGoogle Scholar
  62. 62.
    Hendrix CW, Collier AC, Lederman MM, Schols D, Pollard RB, Brown S, Jackson JB, Coombs RW, Glesby MJ, Flexner CW et al. (2004) Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr 37: 1253–1262PubMedCrossRefGoogle Scholar
  63. 63.
    Gallaher WR, Ball JM, Garry RF, Griffin MC, Montelaro RC (1989) A general model for the transmembrane proteins of HIV and other retroviruses. AIDS Res Hum Retroviruses 5: 431–440PubMedGoogle Scholar
  64. 64.
    Delwart EL, Mosialos G, Gilmore T (1990) Retroviral envelope glycoproteins contain a “leucine zipper”-like repeat. AIDS Res Hum Retroviruses 6: 703–706PubMedGoogle Scholar
  65. 65.
    Jiang S, Lin K, Strick N, Neurath AR (1993) HIV-1 inhibition by a peptide. Nature 365: 113PubMedCrossRefGoogle Scholar
  66. 66.
    Chen CH, Matthews TJ, McDanal CB, Bolognesi DP, Greenberg ML (1995) A molecular 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
  67. 67.
    Wild C, Greenwell T, Matthews T (1993) A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. AIDS Res Hum Retroviruses 9: 1051–1053PubMedGoogle Scholar
  68. 68.
    Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, Alldredge L, Hunter E, Lambert D, Bolognesi D et al. (1998) Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4: 1302–1307PubMedCrossRefGoogle Scholar
  69. 69.
    Lalezari JP, Henry K, O’Hearn M, Montaner JS, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ Jr et al. (2003) Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 348: 2175–2185PubMedCrossRefGoogle Scholar
  70. 70.
    Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M, Katlama C, Stellbrink HJ, Delfraissy JF, Lange J et al. (2003) Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 348: 2186–2195PubMedCrossRefGoogle Scholar
  71. 71.
    Panel on Clinical Practices for the Treatment of HIV Infection (2006) Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at <www.aids>. October 10, 2006 updateGoogle Scholar
  72. 72.
    Hammer SM, Saag MS, Schechter M, Montaner JS, Schooley RT, Jacobsen DM, Thompson MA, Carpenter CC, Fischl MA, Gazzard BG et al. (2006) Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA 296: 827–843PubMedCrossRefGoogle Scholar
  73. 73.
    Trimeris, Fuzeon Package Insert (April 2005)Google Scholar
  74. 74.
    Allaway GP, Davis-Bruno KL, Beaudry GA, Garcia EB, Wong EL, Ryder AM, Hasel KW, Gauduin MC, Koup RA, McDougal JS et al. (1995) Expression and characterization of CD4-IgG2, a novel heterotetramer that neutralizes primary HIV type 1 isolates. AIDS Res Hum Retroviruses 11: 533–539PubMedCrossRefGoogle Scholar
  75. 75.
    Jacobson JM, Lowy I, Fletcher CV, O’Neill TJ, Tran DN, Ketas TJ, Trkola A, Klotman ME, Maddon PJ, Olson WC et al. (2000) Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults. J Infect Dis 182: 326–329PubMedCrossRefGoogle Scholar
  76. 76.
    Jacobson JM, Israel RJ, Lowy I, Ostrow NA, Vassilatos LS, Barish M, Tran DN, Sullivan BM, Ketas TJ, O’Neill TJ et al. (2004) Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542. Antimicrob Agents Chemother 48: 423–429PubMedCrossRefGoogle Scholar
  77. 77.
    Shearer WT, Israel RJ, Starr S, Fletcher CV, Wara D, Rathore M, Church J, DeVille J, Fenton T, Graham B et al. (2000) Recombinant CD4-IgG2 in human immunodeficiency virus type 1-infected children: phase 1/2 study. J Infect Dis 182: 1774–1779PubMedCrossRefGoogle Scholar
  78. 78.
    Burkly LC, Olson D, Shapiro R, Winkler G, Rosa JJ, Thomas DW, Williams C, Chisholm P (1992) Inhibition of HIV infection by a novel CD4 domain 2-specific monoclonal antibody. Dissecting the basis for its inhibitory effect on HIV-induced cell fusion. J Immunol 149: 1779–1787PubMedGoogle Scholar
  79. 79.
    Kuritzkes DR, Jacobson J, Powderly WG, Godofsky E, DeJesus E, Haas F, Reimann KA, Larson JL, Yarbough PO, Curt V et al. (2004) Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 189: 286–291PubMedCrossRefGoogle Scholar
  80. 80.
    Jacobson JM, Kuritzkes DR, Godofsky E, DeJesus E, Lewis S, Jackson J, Frazier K, Fagan EA, Shanahan WR (2004) Phase 1b study of the anti-CD4 monoclonal antibody TNX-355 in HIV-1-infected subjects: safety and antiretroviral activity of multiple doses. In: abstracts of the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8–11, 2004, abstract no. 536Google Scholar
  81. 81.
    Norris D, Moreales J, Godofsky E, Garcia F, Hardwicke R, Lewis S (2006) TNX-355, in combination with optimized background regimen (OBR), achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 weeks. In: Abstracts of the XVI International AIDS Conference, Toronto, Canada, August 13–18, 2006, abstract no. THLB0218Google Scholar
  82. 82.
    Lin PF, Blair W, Wang T, Spicer T, Guo Q, Zhou N, Gong YF, Wang HG, Rose R, Yamanaka G et al. (2003) A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc Natl Acad Sci USA 100: 11013–11018PubMedCrossRefGoogle Scholar
  83. 83.
    Guo Q, Ho HT, Dicker I, Fan L, Zhou N, Friborg J, Wang T, McAuliffe BV, Wang HG, Rose RE et al. (2003) Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions. J Virol 77: 10528–10536PubMedCrossRefGoogle Scholar
  84. 84.
    Hanna G, Yan J-H, Fiske W, Materson T, Zhang D, Grasela D (2004) Safety, tolerability, and pharmacokinetics of a novel small-molecule HIV-1 attachment inhibitor, BMS-488043, after single and multiple oral doses in healthy subjects. In: Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8–11, 2004, abstract no. 535Google Scholar
  85. 85.
    Hanna G, Lalezari J, Hellinger J, Wohl D, Masterson T, Fiske W, Kadow J, Line P, Giordano M, Colonno R, Grasela D (2004) Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. In: Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8–11, 2004, abstract no. 141Google Scholar
  86. 86.
    Watson C, Jenkinson S, Kazmierski W, Kenakin T (2005) The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Mol Pharmacol 67: 1268–1282PubMedCrossRefGoogle Scholar
  87. 87.
    Demarest J, Shibayama S, Ferris R, Vavro C, St Clair M, Boone L (2004) A novel CCR5 antagonist, 873140, exhibits potent in vitro anti-HIV activity. In: Abstracts of the XV International AIDS Conference, Bangkok, Thailand, July 11–16, 2004, abstract no. WeOrA1231Google Scholar
  88. 88.
    Adkison KK, Shachoy-Clark A, Fang L, Lou Y, O’Mara K, Berrey MM, Piscitelli SC (2005) Pharmacokinetics and short-term safety of 873140, a novel CCR5 antagonist, in healthy adult subjects. Antimicrob Agents Chemother 49: 2802–2806PubMedCrossRefGoogle Scholar
  89. 89.
    Lalezari J, Thompson M, Kumar P, Piliero P, Davey R, Patterson K, Shachoy-Clark A, Adkison K, Demarest J, Lou Y et al. (2005) Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults. AIDS 19: 1443–1448PubMedCrossRefGoogle Scholar
  90. 90.
    GlaxoSmithKline Press Release (October 25, 2005)Google Scholar
  91. 91.
    Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C et al. (2005) Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 49: 4721–4732PubMedCrossRefGoogle Scholar
  92. 92.
    Price DA, Armour D, de Groot M, Leishman D, Napier C, Perros M, Stammen BL, Wood A (2006) Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc. Bioorg Med Chem Lett 16: 4633–4637PubMedCrossRefGoogle Scholar
  93. 93.
    Abel S, Russel D, Ridgway C, Muirhead G (2005) Overivew of the drug-drug interaction data for maraviroc (MVC, UK-427,857). In: Abstracts of the 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, Canada, April 28–30, 2005, abstract no. 76Google Scholar
  94. 94.
    Fatkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AI, Saag MS, Goebel FD, Rockstroh JK, Dezube BJ et al. (2005) Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 11: 1170–1172PubMedCrossRefGoogle Scholar
  95. 95.
    Mayer H (2006) Forum Working Group on Chemokine Antagonists in HIV Therapy: RoundTable 3: Focus on Lymphomas and Malignancies, Washington, DC, May 30, 2006Google Scholar
  96. 96.
    Pfizer Press Release (January 24, 2006)Google Scholar
  97. 97.
    Schurmann D, Rouzier R, Nougarede R, Reynes J, Fatkenheuer G, Raffi F, Michelet C, Tarral A, Hoffmann C, Kiunke J et al. (2004) SCH D: Antiviral activity of a CCR5 receptor antagonist. In: Abstracts for the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8–11, 2004, abstract no. 140LBGoogle Scholar
  98. 98.
    Seiberling M, Kraan M, Keung A, Martinho M, Sansone A (2005) Similar increase in SCH 417690 plasma exposure with coadministration of varying doses of ritonavir in healthy volunteers. In: Abstracts of the 3rd International AIDS Society Conference on Pathogenesis and Treatment, July 24–27, 2005, Rio de Janeiro, Brazil, abstract no. TuPe3.1B06Google Scholar
  99. 99.
    Greaves W, Landovitz R, Fatkenheuer G, Hoffmann C, Antunes F, Angel J, Boparai N, Knepp D, Keung A, Dunkle L (2006) Late virologic breakthrough in treatment-naïve patients on a regimen of Combivir + vicriviroc. In: Abstracts of the 13th Conference on Retroviruses and Opportunistic Infections, February 5–8, 2006, Denver, CO, abstract no. 161LBGoogle Scholar
  100. 100.
    Gulick R, Su Z, Flexner C, Hughes M, Skolnik P, Wilkin T, Gross R, Krambrink A, Coakley E, Greaves WL et al (2007) Phase II study of the safety and efficacy of vicriviroc, a CCR inhibitor in HIV-infected treatment experienced patients: ACTG 52. J Infect Dis (in press)Google Scholar
  101. 101.
    Martinson JJ, Chapman NH, Rees DC, Liu YT, Clegg JB. (1997) Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet 16: 100–103PubMedCrossRefGoogle Scholar
  102. 102.
    Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C et al. (1996) Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382: 722–725PubMedCrossRefGoogle Scholar
  103. 103.
    Garred P, Madsen HO, Petersen J, Marquart H, Hansen TM, Freiesleben Sorensen S, Volck B, Svejgaard A, Andersen V. (1998) CC chemokine receptor 5 polymorphism in rheumatoid arthritis. J Rheumatol 25: 1462–1465PubMedGoogle Scholar
  104. 104.
    Hellier S, Frodsham AJ, Hennig BJ, Klenerman P, Knapp S, Ramaley P, Satsangi J, Wright M, Zhang L, Thomas HC et al. (2003) Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection. Hepatology 38: 1468–1476PubMedGoogle Scholar
  105. 105.
    Fischereder M, Luckow B, Hocher B, Wuthrich RP, Rothenpieler U, Schneeberger H, Panzer U, Stahl RA, Hauser IA, Budde K et al. (2001) CC chemokine receptor 5 and renal-transplant survival. Lancet 357: 1758–1761PubMedCrossRefGoogle Scholar
  106. 106.
    Moench C, Uhrig A, Lohse AW, Otto G. (2004) CC chemokine receptor 5delta32 polymorphisma risk factor for ischemic-type biliary lesions following orthotopic liver transplantation. Liver Transpl 10: 434–439PubMedCrossRefGoogle Scholar
  107. 107.
    Glass WG, McDermott DH, Lim JK, Lekhong S, Yu SF, Frank WA, Pape J, Cheshier RC, Murphy PM. (2006) CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med 203: 35–40PubMedCrossRefGoogle Scholar
  108. 108.
    Lalezari JP, Thompson M, Kumar P, Piliero P, Davey R, Patterson K, Shachoy-Clark A, Atkison K, Demarest J, Lou Y, et al (2005) Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults. AIDS 19: 1443–1448PubMedCrossRefGoogle Scholar
  109. 109.
    Westby M, Lewis M, Whitcomb J, Youle M, Pozniak AL, James IT, Jenkins TM, Perros M, van der Ryst E. (2006) Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 80: 4909–4920PubMedCrossRefGoogle Scholar
  110. 110.
    Mayer H, van der Ryst E, Saag M, Clotet B, Fatkenheuer G, Clumeck N, Turner K, Goodrich JM. (2006) Safety and efficacy of maraviroc (MVC), a novel CCR5 antagonist, when used in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced subjects infected with dual/mixed tropic HIV-1: 24-week results of a phase 2b exploratory trial. IN: Abstracts of the XVI International AIDS Conference, Toronto, Canada, August 13–18, 2006, abstract no. THLB0215Google Scholar
  111. 111.
    Schols D, Claes S, Hatse S, Princen K, Vermeire K, De Clercq E, Skerlj R, Bridger G, Calandra G. (2003) Anti-HIV profile of AMD070, an orally bioavailble CXCR4 antagonist H. IN: Abstracts of the 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 10–14, 2003, abstract no. 563Google Scholar
  112. 112.
    Stone N, Dunaway S, Flexner C, Calandra G, Wiggins I, Conley J, Snyder S, Tierney C, Hendrix CW. (2004) Biologic activity of an orally bioavailable CXCR4 antagonist in human subjects. IN: Abstracts of the XV International AIDS Conference, Bangkok, Thailand, July 11–16, 2004, abstract no. TuPeB4475Google Scholar
  113. 113.
    Anormed Press Release (March 17, 2006)Google Scholar
  114. 114.
    Mink M, Mosier SM, Janumpalli S, Davison D, Jin L, Melby T, Sista P, Erickson J, Lambert D, Stanfield-Oakley SA et al. (2005) Impact of human immunodeficiency virus type 1 gp41 amino acid substitutions selected during enfuvirtide treatment on gp41 binding and antiviral potency enfuvirtide in vitro. J Virol 79: 12447–12454PubMedCrossRefGoogle Scholar
  115. 115.
    Eron JJ, Gulick RM, Bartlett JA, Merigan T, Arduino R, Kilby JM, Yangco B, Diers A, Drobnes C, DeMasi R et al. (2004) Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV. J Infect Dis 189: 1075–1083PubMedCrossRefGoogle Scholar
  116. 116.
    Dai SJ, Dou GF, Qiang XH, Song HF, Tang ZM, Liu DS, Liu XW, Yang LM, Zheng YT, Liang Q (2005) Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro. Acta Pharmacol Sin 26: 1274–1280PubMedCrossRefGoogle Scholar
  117. 117.
    Delmedico M, Bray B, Cammack N, Davison D, Dwyer J, Frick L, Tvermoes N, Wring S, Zhang H, Greenberg M. (2006) Next generation HIV peptide fusion inhibitor candidates achieve potent, durable suppression of virus replication in vitro and improved pharmacokinetic properties. In: Abstracts of the 13th Conference on Retroviruses and Opportunistic Infections, February 5–8, 2006, Denver, CO, abstract no. 48Google Scholar
  118. 118.
    Veazey RS, Springer MS, Marx PA, Dufour J, Klasse PJ, Moore JP. (2005) Protection of macaques from vaginal SHIV challenge by an orally delivered CCR5 inhibitor. Nat Med 11: 1293–1294PubMedCrossRefGoogle Scholar
  119. 119.
    Grinsztejn B, Nguyen BY, Katlama C, Gatell J, Lazzarin A, Vittecoq D, Gonzalez C, Chen J, Isaacs R (2006) Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Abstracts of the 13th Conference on Retroviruses and Opportunistic Infections, February 5–8, 2006, Denver, CO, abstract no. 159LBGoogle Scholar
  120. 120.
    DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, Elion R, Farthing C, Zhong L, Cheng AK et al. (2006) Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr 43: 1–5PubMedCrossRefGoogle Scholar
  121. 121.
    Smith P, Forrest A, Beatty G, Jacobson J, Lalezari J, Eron J, Pollard R, Saag M, Doto J, Martin D (2006) Pharmacokinetics/pharmacodynamics of PA-457 in a 10-day multiple dose monotherapy trial in HIV-infected patients. In: Abstracts of the 13th Conference on Retroviruses and Opportunistic Infections, February 5–8, 2006, Denver, CO, abstract no. 52Google Scholar
  122. 122.
    Tremblay CL, Kollmann C, Giguel F, Chou TC, Hirsch MS. (2000) Strong in vitro synergy between the fusion inhibitor T-20 and the CXCR4 blocker AMD-3100. J Acquir Immune Defic Syndr 25: 99–102PubMedCrossRefGoogle Scholar
  123. 123.
    Tremblay CL, Giguel F, Kollmann C, Guan Y, Chou TC, Baroudy BM, Hirsch MS. (2002) Antihuman immunodeficiency virus interactions of SCH-C (SCH 351125), a CCR5 antagonist, with other antiretroviral agents in vitro. Antimicrob Agents Chemother 46: 1336–1339PubMedCrossRefGoogle Scholar
  124. 124.
    Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M, Pohlmann S, Sfakianos JN, Derdeyn CA, Blumenthal R et al. (2002) Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA 99: 16249–16254PubMedCrossRefGoogle Scholar
  125. 125.
    Schols D, Vermeire K, Hatse S, Princen K, De Clercq E, Calandra G, Ricker S, Nelson K, Labrecque J, Bogucki D et al. (2004) In vitro anti-HIV activity profile of AMD887, a novel CCR5 antagonist, in combination with the CXCR4 inhibitor AMD 070. In: Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8–11, 2004, abstract no. 539Google Scholar
  126. 126.
    Moore JP, Kitchen SG, Pugach P, Zack JA. (2004) The CCR5 and CXCR4 coreceptors-central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 20: 111–126PubMedCrossRefGoogle Scholar
  127. 127.
    Sista PR, Melby T, Davison D, Jin L, Mosier S, Mink M, Nelson EL, DeMasi R, Cammack N, Salgo MP et al. (2004) Characterization of determinants of genotypic and phenotypic resistance to enfuvirtide in baseline and on-treatment HIV-1 isolates. AIDS 18: 1787–1794PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2007

Authors and Affiliations

  • Roy M. Gulick
    • 1
  1. 1.Cornell HIV Clinical Trials UnitWeill Medical College of Cornell UniversityNew YorkUSA

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