Future clinical prospects for entry inhibitors

  • Sonya L. Heath
  • J. Michael Kilby
Part of the Milestones in Drug Therapy book series (MDT)


Some of the earliest attempts to develop HIV therapies involved agents intended to block viral entry into host cells, but only very recently and only once (with the FDA approval of a membrane fusion inhibitor, enfuvirtide, in 2003) has this strategic approach resulted in a commercially available agent. Indeed, for more than 15 years, from 1987 to 2003, all available antiretroviral therapies targeted one of two HW-encoded enzymes, reverse transcriptase (RT) or protease, which are critical components of later steps in the viral life cycle. Increasingly convenient combinations of RT and protease inhibitors (PI) have proven capable of potently suppressing viral replication and have dramatically improved the outlook for many HIV-infected patients. However, the sustained success of these enzyme inhibitors has been limited somewhat by selection for drug-resistant viral isolates, the necessity of strict dosing adherence, and the potential for toxicity. Thus, there remains a critical need for development of new therapeutic classes involving mechanisms of action distinctly different from RT and PI drugs. There is preliminary evidence demonstrating that viral entry inhibitors have potential to be safe and effective additions to the HIV armamentarium, and this class would be expected to have a low risk of cross-resistance with conventional antiretroviral drugs.


West Nile Virus Antimicrob Agent CCR5 Antagonist Fusion Inhibitor Entry Inhibitor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    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
  2. 2.
    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
  3. 3.
    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
  4. 4.
    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
  5. 5.
    Mitsuya H, Looney DJ, Kuno S, Ueno R, Wong-Staal F, Broder S (1988) Dextran sulfate suppression of viruses in the HIV family: inhibition of virion binding to CD4+ cells. Science 240: 646–649PubMedCrossRefGoogle Scholar
  6. 6.
    Flexner C, Barditch-Crovo PA, Kornhauser DM, Farzadegan H, Nerhood LJ, Chaisson RE, Bell KM, Lorentsen KJ, Hendrix CW, Petty BG et al. (1991) Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection. Antimicrob Agents Chemother 35: 2544–2550PubMedGoogle Scholar
  7. 7.
    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
  8. 8.
    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
  9. 9.
    Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, Maddon PJ, Allaway GP, Sakmar TP, Henson G, De Clercq E et al. (1998) AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 4: 72–77PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    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
  12. 12.
    Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, Pugach P, Xu S, Wojcik L, Tagat J et al. (2002) HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci USA 99: 395–400PubMedCrossRefGoogle Scholar
  13. 13.
    Mayer H, Rest EV, Saag MS (2006) Safety and efficacy of maraviroc, a novel CCR5 antagonist, when used in combination with optimised background therapy for the treatment of antiretroviral-experienced subjects infected with dual/mixed tropic HIV-1: 24-week results of a phase 2b exploratory trial. International AIDS Society Toronto, THLB-0215Google Scholar
  14. 14.
    Kilby JM, Eron JJ (2003) Novel therapies based on mechanisms of HIV-1 cell entry. N Engl J Med 348: 2228–2238PubMedCrossRefGoogle Scholar
  15. 15.
    Dubay JW, Roberts SJ, Brody B, Hunter E (1992) Mutations in the leucine zipper of the human immunodeficiency virus type 1 transmembrane glycoprotein affect fusion and infectivity. J Virol 66: 4748–4756PubMedGoogle Scholar
  16. 16.
    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
  17. 17.
    Kilby JM, Lalezari JP, Eron JJ, Carlson M, Cohen C, Arduino RC, Goodgame JC, Gallant JE, Volberding P, Murphy RL et al. (2002) The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res Hum Retroviruses 18: 685–693PubMedCrossRefGoogle Scholar
  18. 18.
    Lalezari JP, Eron JJ, Carlson M, Cohen C, DeJesus E, Arduino RC, Gallant JE, Volberding P, Murphy RL, Valentine F et al. (2003) A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy. AIDS 17: 691–698PubMedCrossRefGoogle Scholar
  19. 19.
    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
  20. 20.
    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
  21. 21.
    Bourgarit A, Lascoux C, Palmer P, Tuleja E, Pintado C, Farge D, Sereni D (2006) First-line use of enfuvirtide-containing HAART regimen with dramatic clinical and immunological improvement in three cases. AIDS 20: 471–473PubMedGoogle Scholar
  22. 22.
    Greaves W, R L, Fatkenheuer G (2006) Late virologic breakthrough in treatment-naive patients on a regimen of Combivir + viriviroc. 13th Conference on Retroviruses and Opportunistic Infections, Denver, COGoogle Scholar
  23. 23.
    Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, Johnson M, Johnson D, Lalonde R, Japour A et al. (2002) Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 346: 2039–2046PubMedCrossRefGoogle Scholar
  24. 24.
    Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, Stryker R, Johnson P, Labriola DF, Farina D et al. (1999) Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 341: 1865–1873PubMedCrossRefGoogle Scholar
  25. 25.
    Meng TC, Fischl MA, Cheeseman SH, Spector SA, Resnick L, Boota A, Petrakis T, Wright B, Richman DD (1995) Combination therapy with recombinant human soluble CD4-immunoglobulin G and zidovudine in patients with HIV infection: a phase I study. J Acquir Immune Defic Syndr Hum Retrovirol 8: 152–160PubMedGoogle Scholar
  26. 26.
    Baba M, Pauwels R, Balzarini J, Arnout J, Desmyter J, De Clercq E (1988) Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro. Proc Natl Acad Sci USA 85: 6132–6136PubMedCrossRefGoogle Scholar
  27. 27.
    Castagna A, Biswas P, Beretta A, Lazzarin A (2005) The appealing story of HIV entry inhibitors: from discovery of biological mechanisms to drug development. Drugs 65: 879–904PubMedCrossRefGoogle Scholar
  28. 28.
    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
  29. 29.
    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
  30. 30.
    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
  31. 31.
    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
  32. 32.
    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
  33. 33.
    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
  34. 34.
    Delmedico M, Bray B, Cammack N (2006) Next generation HIV peptide fusion inhibitor candidates achieve potent, durable suppression of virus replication in vitro and improved pharmacokinetic properties. 13th Conference on Retroviruses and Opportunistic Infections, Denver, COGoogle Scholar
  35. 35.
    Cote HC, Yip B, Asselin JJ, Chan JW, Hogg RS, Harrigan PR, O’Shaughnessy MV, Montaner JS (2003) Mitochondrial:nuclear DNA ratios in peripheral blood cells from human immunodeficiency virus (HIV)-infected patients who received selected HIV antiretroviral drug regimens. J Infect Dis 187: 1972–1976PubMedCrossRefGoogle Scholar
  36. 36.
    Montaner JS, Cote HC, Harris M, Hogg RS, Yip B, Chan JW, Harrigan PR, O’Shaughnessy MV (2003) Mitochondrial toxicity in the era of HAART: evaluating venous lactate and peripheral blood mitochondrial DNA in HIV-infected patients taking antiretroviral therapy. J Acquir Immune Defic Syndr 34Suppl 1: S85–90PubMedGoogle Scholar
  37. 37.
    Carr A, Cooper DA (2000) Adverse effects of antiretroviral therapy. Lancet 356: 1423–1430PubMedCrossRefGoogle Scholar
  38. 38.
    Nolan D (2003) Metabolic complications associated with HIV protease inhibitor therapy. Drugs 63: 2555–2574PubMedCrossRefGoogle Scholar
  39. 39.
    Powderly WG (2002) Long-term exposure to lifelong therapies. J Acquir Immune Defic Syndr 29Suppl 1: S28–40PubMedGoogle Scholar
  40. 40.
    Moreland LW, Bucy RP, Koopman WJ (1995) Regeneration of T cells after chemotherapy. N Engl J Med 332: 1651–1652PubMedGoogle Scholar
  41. 41.
    Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355: 1018–1028PubMedCrossRefGoogle Scholar
  42. 42.
    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: 367–377PubMedCrossRefGoogle Scholar
  43. 43.
    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
  44. 44.
    Favorova OO, Andreewski TV, Boiko AN, Sudomoina MA, Alekseenkov AD, Kulakova OG, Slanova AV, Gusev EI (2002) The chemokine receptor CCR5 deletion mutation is associated with MS in HLA-DR4-positive Russians. Neurology 59: 1652–1655PubMedGoogle Scholar
  45. 45.
    Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382: 635–638PubMedCrossRefGoogle Scholar
  46. 46.
    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
  47. 47.
    Deeks SG (2006) Challenges of developing R5 inhibitors in antiretroviral naive HIV-infected patients. Lancet 367: 711–713PubMedCrossRefGoogle Scholar
  48. 48.
    Ball RA, Kinchelow T (2003) Injection site reactions with the HIV-1 fusion inhibitor enfuvirtide. J Am Acad Dermatol 49: 826–831PubMedCrossRefGoogle Scholar
  49. 49.
    Maggi P, Ladisa N, Cinori E, Altobella A, Pastore G, Filotico R (2004) Cutaneous injection site reactions to long-term therapy with enfuvirtide. J Antimicrob Chemother 53: 678–681PubMedCrossRefGoogle Scholar
  50. 50.
    Harris M, Joy R, Larsen G, Valyi M, Walker E, Frick LW, Palmatier RM, Wring SA, Montaner JS (2006) Enfuvirtide plasma levels and injection site reactions using a needle-free gas-powered injection system (Biojector). AIDS 20: 719–723PubMedCrossRefGoogle Scholar
  51. 51.
    Fridland A, Connelly MC, Robbins BL (2000) Cellular factors for resistance against antiretroviral agents. Antiviral Ther 5: 181–185Google Scholar
  52. 52.
    Lucia MB, Rutella S, Leone G, Vella S, Cauda R (2001) HIV-protease inhibitors contribute to Pglycoprotein efflux function defect in peripheral blood lymphocytes from HIV-positive patients receiving HAART. J Acquir Immune Defic Syndr 27: 321–330PubMedGoogle Scholar
  53. 53.
    Madani N, Perdigoto AL, Srinivasan K, Cox JM, Chruma JJ, LaLonde J, Head M, Smith AB 3rd, Sodroski JG (2004) Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155. J Virol 78: 3742–3752PubMedCrossRefGoogle Scholar
  54. 54.
    Duensing T, Fung M, Lewis S (2006) In vitro characterization of HIV isolated from patients treated with the entry inhibitor TNX-355. 13th Conference on Retroviruses and Opportunistic Infections, Denver, COGoogle Scholar
  55. 55.
    Amara A, Gall SL, Schwartz O, Salamero J, Montes M, Loetscher P, Baggiolini M, Virelizier JL, Arenzana-Seisdedos F (1997) HIV coreceptor downregulation as antiviral principle: SDF-1alphadependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. J Exp Med 186: 139–146PubMedCrossRefGoogle Scholar
  56. 56.
    Briz V, Poveda E, Soriano V (2006) HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 57: 619–627PubMedCrossRefGoogle Scholar
  57. 57.
    Rimsky LT, Shugars DC, Matthews TJ (1998) Determinants of human immunodeficiency virus type 1 resistance to gp41-derived inhibitory peptides. J Virol 72: 986–993PubMedGoogle Scholar
  58. 58.
    Derdeyn CA, Decker JM, Sfakianos JN, Wu X, O’Brien WA, Ratner L, Kappes JC, Shaw GM, Hunter E (2000) Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J Virol 74: 8358–8367PubMedCrossRefGoogle Scholar
  59. 59.
    Derdeyn CA, Decker JM, Sfakianos JN, Zhang Z, O’Brien WA, Ratner L, Shaw GM, Hunter E (2001) Sensitivity of human immunodeficiency virus type 1 to fusion inhibitors targeted to the gp41 first heptad repeat involves distinct regions of gp41 and is consistently modulated by gp120 interactions with the coreceptor. J Virol 75: 8605–8614PubMedCrossRefGoogle Scholar
  60. 60.
    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 of enfuvirtide in vitro. J Virol 79: 12447–12454PubMedCrossRefGoogle Scholar
  61. 61.
    Melby T, Sista P, DeMasi R, Kirkland T, Roberts N, Salgo M, Heilek-Snyder G, Cammack N, Matthews TJ, Greenberg ML (2006) Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2. AIDS Res Hum Retroviruses 22: 375–385PubMedCrossRefGoogle Scholar
  62. 62.
    Xu L, Pozniak A, Wildfire A, Stanfield-Oakley SA, Mosier SM, Ratcliffe D, Workman J, Joall A, Myers R, Smit E et al. (2005) Emergence and evolution of enfuvirtide resistance following longterm therapy involves heptad repeat 2 mutations within gp41. Antimicrob Agents Chemother 49: 1113–1119PubMedCrossRefGoogle Scholar
  63. 63.
    Menzo S, Castagna A, Monachetti A, Hasson H, Danise A, Carini E, Bagnarelli P, Lazzarin A, Clementi M (2004) Genotype and phenotype patterns of human immunodeficiency virus type 1 resistance to enfuvirtide during long-term treatment. Antimicrob Agents Chemother 48: 3253–3259PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2007

Authors and Affiliations

  • Sonya L. Heath
    • 1
  • J. Michael Kilby
    • 1
  1. 1.Department of Medicine, Division of Infectious Diseases, 1917 ClinicUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations