Inhibitors that target fusion

  • Wei Wang 
  • Carol D. Weiss
Part of the Milestones in Drug Therapy book series (MDT)


The process of viral entry offers several advantages for drug intervention. Targeting extracellular events eliminates challenges in ensuring adequate drug delivery into cells. Disabling HIV before integration of viral DNA into host cells also prevents the potential for establishment of viral persistence in longlived cells. Recent progress in understanding the molecular basis of the HIV entry process points to new therapeutic strategies. In this chapter, we focus on agents that target the step of virus-cell fusion from a mechanistic point of view. Issues related to product development of fusion inhibitors for eventual clinical use are covered in the Chapter by Greenberg.


Human Immunodeficiency Virus Type Coiled Coil Heptad Repeat Fusion Inhibitor Entry 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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    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: 184–187PubMedCrossRefGoogle Scholar
  2. 2.
    Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W et al. (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384: 179–183PubMedCrossRefGoogle Scholar
  3. 3.
    Eckert DM, Kim PS (2001) Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem 70: 777–810PubMedCrossRefGoogle Scholar
  4. 4.
    Gallo SA, Finnegan CM, Viard M, Raviv Y, Dimitrov A, Rawat SS, Puri A, Durell S, Blumenthal R (2003) The HIV Env-mediated fusion reaction. Biochim Biophys Acta 1614: 36–50PubMedCrossRefGoogle Scholar
  5. 5.
    Muster T, Guinea R, Trkola A, Purtscher M, Klima A, Steindl F, Palese P, Katinger H (1994) Cross-neutralizing activity against divergent human immunodeficiency virus type 1 isolates induced by the gp41 sequence ELDKWAS. J Virol 68: 4031–4034PubMedGoogle Scholar
  6. 6.
    Zwick MB, Labrijn AF, Wang M, Spenlehauer C, Saphire EO, Binley JM, Moore JP, Stiegler G, Katinger H, Burton DR, Parren PW (2001) Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. J Virol 75: 10892–10905PubMedCrossRefGoogle Scholar
  7. 7.
    Lu M, Blacklow SC, Kim PS (1995) A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat Struct Biol 2: 1075–1082PubMedCrossRefGoogle Scholar
  8. 8.
    Chan DC, Fass D, Berger JM, Kim PS (1997) Core structure of gp41 from the HIV envelope glycoprotein. Cell 89: 263–273PubMedCrossRefGoogle Scholar
  9. 9.
    Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC (1997) Atomic structure of the ectodomain from HIV-1 gp41. Nature 387: 426–430PubMedCrossRefGoogle Scholar
  10. 10.
    Tan K, Liu J, Wang J, Shen S, Lu M (1997) Atomic structure of a thermostable subdomain of HIV-1 gp41. Proc Natl Acad Sci USA 94: 12303–12308PubMedCrossRefGoogle Scholar
  11. 11.
    Carr CM, Kim PS (1993) A spring-loaded mechanism for the conformational changes of influenza hemagglutinin. Cell 73: 823–832PubMedCrossRefGoogle Scholar
  12. 12.
    Melikyan GB, Markosyan RM, Hemmati H, Delmedico MK, Lambert DM, Cohen FS (2000) Evidence that the transition of HIV-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion. J Cell Biol 151: 413–424PubMedCrossRefGoogle Scholar
  13. 13.
    Furuta RA, Wild CT, Weng Y, Weiss CD (1998) Capture of an early fusion-active conformation of HIV-1 gp41. Nat Struct Biol 5: 276–279PubMedCrossRefGoogle Scholar
  14. 14.
    He Y, Vassell R, Zaitseva M, Nguyen N, Yang Z, Weng Y, Weiss CD (2003) Peptides trap the human immunodeficiency virus type 1 envelope glycoprotein fusion intermediate at two sites. J Virol 77: 1666–1671PubMedCrossRefGoogle Scholar
  15. 15.
    Wild C, Oas T, McDanal C, Bolognesi D, Matthews T (1992) A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition. Proc Natl Acad Sci USA 89: 10537–10541PubMedCrossRefGoogle Scholar
  16. 16.
    Jiang S, Lin K, Strick N, Neurath AR (1993) HIV-1 inhibition by a peptide. Nature 365: 113PubMedCrossRefGoogle Scholar
  17. 17.
    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
  18. 18.
    Chan DC, Kim PS (1998) HIV entry and its inhibition. Cell 93: 681–684PubMedCrossRefGoogle Scholar
  19. 19.
    Wild C, Greenwell T, Shugars D, Rimksy-Clark L, Matthews T (1995) The inhibitory activity of an HIV type 1 peptide correlates with its ability to interact with a leucine zipper structure. AIDS Res Hum Retroviruses 11: 323–325PubMedCrossRefGoogle Scholar
  20. 20.
    Chen C-H, 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
  21. 21.
    Bewley CA, Louis JM, Ghirlando R, Clore GM (2002) Design of a novel peptide inhibitor of HIV fusion that disrupts the internal trimeric coiled-coil of gp41. J Biol Chem Google Scholar
  22. 22.
    Debnath AK (2006) Progress in identifying peptides and small-molecule inhibitors targeted to gp41 of HIV-1. Expert Opin Investig Drugs 15: 465–478PubMedCrossRefGoogle Scholar
  23. 23.
    Kazmierski WM, Kenakin TP, Gudmundsson KS (2006) Peptide, peptidomimetic and small-molecule drug discovery targeting HIV-1 host-cell attachment and entry through gp120, gp41, CCR5 and CXCR4. Chem Biol Drug Des 67: 13–26PubMedCrossRefGoogle Scholar
  24. 24.
    Wild CT, Shugars DC, Greenwell TK, McDanal CB, Matthews TJ (1994) Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 are potent inhibitors of virus infection. Proc Natl Acad Sci USA 91: 9770–9774PubMedCrossRefGoogle Scholar
  25. 25.
    Kilby JM, Hopkins S, Venetta TM, Di Massimo 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
  26. 26.
    Chan DC, Chutkowski CT, Kim PS (1998) Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. Proc Natl Acad Sci USA 95: 15613–15617PubMedCrossRefGoogle Scholar
  27. 27.
    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
  28. 28.
    Wei X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM, Saag MS, Wu X, Shaw GM, Kappes JC (2002) Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46: 1896–1905PubMedCrossRefGoogle Scholar
  29. 29.
    Koshiba T, Chan DC (2003) The prefusogenic intermediate of HIV-1 gp41 contains exposed Cpeptide regions. J Biol Chem 278: 7573–7579PubMedCrossRefGoogle Scholar
  30. 30.
    Root MJ, Hamer DH (2003) Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein. Proc Natl Acad Sci USA 100: 5016–5021PubMedCrossRefGoogle Scholar
  31. 31.
    Kilgore NR, Salzwedel K, Reddick M, Allaway GP, Wild CT (2003) Direct evidence that C-peptide inhibitors of human immunodeficiency virus type 1 entry bind to the gp41 N-helical domain in receptor-activated viral envelope. J Virol 77: 7669–7672PubMedCrossRefGoogle Scholar
  32. 32.
    Trivedi VD, Cheng SF, Wu CW, Karthikeyan R, Chen CJ, Chang DK (2003) The LLSGIV stretch of the N-terminal region of HIV-1 gp41 is critical for binding to a model peptide, T20. Protein Eng 16: 311–317PubMedCrossRefGoogle Scholar
  33. 33.
    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
  34. 34.
    Nameki D, Kodama E, Ikeuchi M, Mabuchi N, Otaka A, Tamamura H, Ohno M, Fujii N, Matsuoka M (2005) Mutations conferring resistance to human immunodeficiency virus type 1 fusion inhibitors are restricted by gp41 and Rev-responsive element functions. J Virol 79: 764–770PubMedCrossRefGoogle Scholar
  35. 35.
    Lawless MK, Barney S, Guthrie KI, Bucy TB, Petteway SR Jr, Merutka G (1996) HIV-1 membrane fusion mechanism: structural studies of the interactions between biologically-active peptides from gp41. Biochemistry 35: 13697–13708PubMedCrossRefGoogle Scholar
  36. 36.
    Wexler-Cohen Y, Johnson BT, Puri A, Blumenthal R, Shai Y (2006) Structurally altered peptides reveal an important role for N-terminal heptad repeat binding and stability in the inhibitory action of HIV-1 peptide DP178. J Biol Chem 281: 9005–9010PubMedCrossRefGoogle Scholar
  37. 37.
    Munoz-Barroso I, Durell S, Sakaguchi K, Appella E, Blumenthal R (1998) Dilation of the human immunodeficiency virus-1 envelope glycoprotein fusion pore revealed by the inhibitory action of a synthetic peptide from gp41. J Cell Biol 140: 315–323PubMedCrossRefGoogle Scholar
  38. 38.
    Kliger Y, Gallo SA, Peisajovich SG, Munoz-Barroso I, Avkin S, Blumenthal R, Shai Y (2001) Mode of action of an antiviral peptide from HIV-1. Inhibition at a post-lipid mixing stage. J Biol Chem 276: 1391–1397PubMedCrossRefGoogle Scholar
  39. 39.
    Liu S, Lu H, Niu J, Xu Y, Wu S, Jiang S (2005) Different from the HIV fusion inhibitor C34, the anti-HIV drug Fuzeon (T-20) inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120. J Biol Chem 280: 11259–11273PubMedCrossRefGoogle Scholar
  40. 40.
    Alam SM, Paleos CA, Liao HX, Scearce R, Robinson J, Haynes BF (2004) An inducible HIV type 1 gp41 HR-2 peptide-binding site on HIV type 1 envelope gp120. AIDS Res Hum Retroviruses 20: 836–845PubMedCrossRefGoogle Scholar
  41. 41.
    Yuan W, Craig S, Si Z, Farzan M, Sodroski J (2004) CD4-induced T-20 binding to human immunodeficiency virus type 1 gp120 blocks interaction with the CXCR4 coreceptor. J Virol 78: 5448–5457PubMedCrossRefGoogle Scholar
  42. 42.
    Dwyer JJ, Hasan A, Wilson KL, White JM, Matthews TJ, Delmedico MK (2003) The hydrophobic pocket contributes to the structural stability of the N-terminal coiled coil of HIV gp41 but is not required for six-helix bundle formation. Biochemistry 42: 4945–4953PubMedCrossRefGoogle Scholar
  43. 43.
    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
  44. 44.
    Armand-Ugon M, Gutierrez A, Clotet B, Este JA (2003) HIV-1 resistance to the gp41-dependent fusion inhibitor C-34. Antiviral Res 59: 137–142PubMedCrossRefGoogle Scholar
  45. 45.
    Lalezari JP, Bellos NC, Sathasivam K, Richmond GJ, Cohen CJ, Myers RA, Henry DH, Raskino C, Melby T, Murchison H et al. (2005) T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen. J Infect Dis 191: 1155–1163PubMedCrossRefGoogle Scholar
  46. 46.
    Menzo S, Castagna A, Monachetti A, Hasson H, Danise A, Carini E, Bagnarelli P, Lazzarin A, Clementi M (2004) Resistance and replicative capacity of HIV-1 strains selected in vivo by longterm enfuvirtide treatment. New Microbiol 27: 51–61PubMedGoogle Scholar
  47. 47.
    Reeves JD, Lee FH, Miamidian JL, Jabara CB, Juntilla MM, Doms RW (2005) Enfuvirtide resistance mutations: impact on human immunodeficiency virus envelope function, entry inhibitor sensitivity, and virus neutralization. J Virol 79: 4991–4999PubMedCrossRefGoogle Scholar
  48. 48.
    Judice JK, Tom JY, Huang W, Wrin T, Vennari J, Petropoulos CJ, McDowell RS (1997) Inhibition of HIV type 1 infectivity by constrained alpha-helical peptides: implications for the viral fusion mechanism. Proc Natl Acad Sci USA 94: 13426–13430PubMedCrossRefGoogle Scholar
  49. 49.
    Jin BS, Ryu JR, Ahn K, Yu YG (2000) Design of a peptide inhibitor that blocks the cell fusion mediated by glycoprotein 41 of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 16: 1797–1804PubMedCrossRefGoogle Scholar
  50. 50.
    Sia SK, Carr PA, Cochran AG, Malashkevich VN, Kim PS (2002) Short constrained peptides that inhibit HIV-1 entry. Proc Natl Acad Sci USA 99: 14664–14669PubMedCrossRefGoogle Scholar
  51. 51.
    Otaka A, Nakamura M, Nameki D, Kodama E, Uchiyama S, Nakamura S, Nakano H, Tamamura H, Kobayashi Y, Matsuoka M, Fujii N (2002) Remodeling of gp41-C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells. Angew Chem Int Ed Engl 41: 2937–2940PubMedCrossRefGoogle Scholar
  52. 52.
    Wang S, York J, Shu W, Stoller MO, Nunberg JH, Lu M (2002) Interhelical interactions in the gp41 core: implications for activation of HIV-1 membrane fusion. Biochemistry 41: 7283–7292PubMedCrossRefGoogle Scholar
  53. 53.
    Eckert DM, Malashkevich VN, Hong LH, Carr PA, Kim PS (1999) Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket. Cell 99: 103–115PubMedCrossRefGoogle Scholar
  54. 54.
    Ferrer M, Kapoor TM, Strassmaier T, Weissenhorn W, Skehel JJ, Oprian D, Schreiber SL, Wiley DC, Harrison SC (1999) Selection of gp41-mediated HIV-1 cell entry inhibitors from biased combinatorial libraries of non-natural binding elements. Nat Struct Biol 6: 953–960PubMedCrossRefGoogle Scholar
  55. 55.
    Debnath AK, Radigan L, Jiang S (1999) Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1. J Med Chem 42: 3203–3209PubMedCrossRefGoogle Scholar
  56. 56.
    Jiang S, Lin K, Zhang L, Debnath AK (1999) A screening assay for antiviral compounds targeted to the HIV-1 gp41 core structure using a conformation-specific monoclonal antibody. J Virol Methods 80: 85–96PubMedCrossRefGoogle Scholar
  57. 57.
    Jiang S, Debnath AK (2000) A salt bridge between an N-terminal coiled coil of gp41 and an antiviral agent targeted to the gp41 core is important for anti-HIV-1 activity. Biochem Biophys Res Commun 270: 153–157PubMedCrossRefGoogle Scholar
  58. 58.
    Armand-Ugon M, Clotet-Codina I, Tintori C, Manetti F, Clotet B, Botta M, Este JA (2005) The anti-HIV activity of ADS-J1 targets the HIV-1 gp120. Virology 343: 141–149PubMedCrossRefGoogle Scholar
  59. 59.
    Zhao Q, Ernst JT, Hamilton AD, Debnath AK, Jiang S (2002) XTT formazan widely used to detect cell viability inhibits HIV type 1 infection in vitro by targeting gp41. AIDS Res Hum Retroviruses 18: 989–997PubMedCrossRefGoogle Scholar
  60. 60.
    Jiang S, Lu H, Liu S, Zhao Q, He Y, Debnath AK (2004) N-Substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob Agents Chemother 48: 4349–4359PubMedCrossRefGoogle Scholar
  61. 61.
    Labrosse B, Pleskoff O, Sol N, Jones C, Henin Y, Alizon M (1997) Resistance to a drug blocking human immunodeficiency virus type 1 entry (RPR103611) is conferred by mutations in gp41. J Virol 71: 8230–8236PubMedGoogle Scholar
  62. 62.
    Jin BS, Lee WK, Ahn K, Lee MK, Yu YG (2005) High-throughput screening method of inhibitors that block the interaction between 2 helical regions of HIV-1 gp41. J Biomol Screen 10: 13–19PubMedCrossRefGoogle Scholar
  63. 63.
    Lipinski CA (2000) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44: 235–249PubMedCrossRefGoogle Scholar
  64. 64.
    Eckert DM, Kim PS (2001) Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region. Proc Natl Acad Sci USA 98: 11187–11192PubMedCrossRefGoogle Scholar
  65. 65.
    Lu M, Kim PS (1997) A trimeric structural subdomain of the HIV-1 transmembrane glycoprotein. J Biomol Struct Dyn 15: 465–471PubMedGoogle Scholar
  66. 66.
    Bianchi E, Finotto M, Ingallinella P, Hrin R, Carella AV, Hou XS, Schleif WA, Miller MD, Geleziunas R, Pessi A (2005) Covalent stabilization of coiled coils of the HIV gp41 N region yields extremely potent and broad inhibitors of viral infection. Proc Natl Acad Sci USA 102: 12903–12908PubMedCrossRefGoogle Scholar
  67. 67.
    Root MJ, Kay MS, Kim PS (2001) Protein design of an HIV-1 entry inhibitor. Science 291: 884–888PubMedCrossRefGoogle Scholar
  68. 68.
    Louis JM, Bewley CA, Clore GM (2001) Design and properties of N(CCG)-gp41, a chimeric gp41 molecule with nanomolar HIV fusion inhibitory activity. J Biol Chem 276: 29485–29489PubMedCrossRefGoogle Scholar
  69. 69.
    Greenberg M, Cammack N, Salgo M, Smiley L (2004) HIV fusion and its inhibition in antiretroviral therapy. Rev Med Virol 14: 321–337PubMedCrossRefGoogle Scholar
  70. 70.
    Greenberg ML, Cammack N (2004) Resistance to enfuvirtide, the first HIV fusion inhibitor. J Antimicrob Chemother 54: 333–340PubMedCrossRefGoogle Scholar
  71. 71.
    Sista PR, Melby T, Davison D, Jin L, Mosier S, Mink M, Nelson EL, De Masi R, Cammack N 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
  72. 72.
    Perez-Alvarez L, Carmona R, Ocampo A, Asorey A, Miralles C, Perez de Castro S, Pinilla M, Contreras G, Taboada JA, Najera (2006) Long-term monitoring of genotypic and phenotypic resistance to T20 in treated patients infected with HIV-1. J Med Virol 78: 141–147PubMedCrossRefGoogle Scholar
  73. 73.
    Baldwin CE, Sanders RW, Deng Y, Jurriaans S, Lange JM, Lu M, Berkhout B (2004) Emergence of a drug-dependent human immunodeficiency virus type 1 variant during therapy with the T20 fusion inhibitor. J Virol 78: 12428–12437PubMedCrossRefGoogle Scholar
  74. 74.
    Xu L, Pozniak A, Wildfire A, Stanfield-Oakley SA, Mosier SM, Ratcliffe D, Workman J, Joall A, Myers R, Smit T 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
  75. 75.
    Jenwitheesuk E, Samudrala R (2005) Heptad-repeat-2 mutations enhance the stability of the enfuvirtide-resistant HIV-1 gp41 hairpin structure. Antiviral Ther 10: 893–900Google Scholar
  76. 76.
    Poveda E, Rodes B, Lebel-Binay S, Faudon JL, Jimenez V, Soriano V (2005) Dynamics of enfuvirtide resistance in HIV-infected patients during and after long-term enfuvirtide salvage therapy. J Clin Virol 34: 295–301PubMedCrossRefGoogle Scholar
  77. 77.
    Lu J, Sista P, Giguel F, Greenberg M, Kuritzkes DR (2004) Relative replicative fitness of human immunodeficiency virus type 1 mutants resistant to Enfuvirtide (T-20). J Virol 78: 4628–4637PubMedCrossRefGoogle Scholar
  78. 78.
    Lohrengel S, Hermann F, Hagmann I, Oberwinkler H, Scrivano L, Hoffmann C, von Laer D, Dittmar MT (2005) Determinants of human immunodeficiency virus type 1 resistance to membrane-anchored gp41-derived peptides. J Virol 79: 10237–10246PubMedCrossRefGoogle Scholar
  79. 79.
    Neumann T, Hagmann I, Lohrengel S, Heil ML, Derdeyn CA, Krausslich HG, Dittmar MT (2005) T20-insensitive HIV-1 from naive patients exhibits high viral fitness in a novel dual-color competition assay on primary cells. Virology 333: 251–262PubMedCrossRefGoogle Scholar
  80. 80.
    Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M, Pohlmann, 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
  81. 81.
    Beausejour Y, Tremblay MJ (2004) Susceptibility of HIV type 1 to the fusion inhibitor T-20 is reduced on insertion of host intercellular adhesion molecule 1 in the virus membrane. J Infect Dis 190: 894–902PubMedCrossRefGoogle 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: 5476–5485PubMedCrossRefGoogle Scholar
  83. 83.
    Miller MD, Hazuda DJ (2004) HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications. Drug Resist Updat 7: 89–95PubMedCrossRefGoogle Scholar
  84. 84.
    Desmezieres E, Gupta N, Vassell R, He Y, Peden K, Sirota L, Yang Z, Wingfield P, Weiss CD (2005) HIV gp41 escape mutants: Cross-resistance to peptide inhibitors of HIV fusion and altered receptor activation of gp120. J Virol 79: 4774–4781PubMedCrossRefGoogle Scholar
  85. 85.
    Steger HK, Kaur J, Reeves J, Doms RW, Root MJ (2005) Keystone Symposium HIV Pathogenesis, abstract no. 346Google Scholar
  86. 86.
    Hanna SL, Yang C, Owen SM, Lal RB (2002) Variability of critical epitopes within HIV-1 heptad repeat domains for selected entry inhibitors in HIV-infected populations worldwide. AIDS 16: 1603–1608PubMedCrossRefGoogle Scholar
  87. 87.
    Labrosse B, Labernardiere J-L, Dam E, Trouplin V, Skrabal K, Clavel F, Mammano F (2003) Baseline susceptibility of primary human immunodeficiency virus type 1 to entry inhibitors. J Virol 77: 1610–1613PubMedCrossRefGoogle Scholar
  88. 88.
    Chinnadurai R, Munch J, Kirchhoff F (2005) Effect of naturally-occurring gp41 HR1 variations on susceptibility of HIV-1 to fusion inhibitors. AIDS 19: 1401–1405PubMedCrossRefGoogle Scholar
  89. 89.
    Sanders RW, Korber B, Lu M, Berkhout B, Moore JP (2002) Mutational analysis and natural variability of the gp41 ectodomain. In: Kuiken C, Foley B, Freed E, Hahn B, Marx P, McCutchan F, Mellors J, Wolinsky S, Korber B (eds): HIV sequence compendium 2002. Los Alamos National Laboratory Theoretical Biology and Biophysics Group, Los Alamos, 43–68Google Scholar
  90. 90.
    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
  91. 91.
    Heil ML, Decker JM, Sfakianos JN, Shaw GM, Hunter E, Derdeyn CA (2004) Determinants of human immunodeficiency virus type 1 baseline susceptibility to the fusion inhibitors enfuvirtide and T-649 reside outside the peptide interaction site. J Virol 78: 7582–7589PubMedCrossRefGoogle Scholar
  92. 92.
    Barretina J, Blanco J, Bonjoch A, Llano A, Clotet B, Este JA (2004) Immunological and virological study of enfuvirtide-treated HIV-positive patients. AIDS 18: 1673–1682PubMedCrossRefGoogle Scholar
  93. 93.
    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
  94. 94.
    Ji H, Shu W, Burling FT, Jiang S, Lu M (1999) Inhibition of human immunodeficiency virus type 1 infectivity by the gp41 core: role of a conserved hydrophobic cavity in membrane fusion. J Virol 73: 8578–8586PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2007

Authors and Affiliations

  • Wei Wang 
    • 1
  • Carol D. Weiss
    • 1
  1. 1.Food and Drug AdministrationCenter for Biologics Evaluation and ResearchBethesdaUSA

Personalised recommendations