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Inhibitors of Viral Entry

  • Tom Melby
  • Mike Westby
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 189)

The entry of viruses into target cells involves a complex series of sequential steps, with opportunities for inhibition at every stage. Entry inhibitors exert their biological properties by inhibiting protein—protein interactions either within the viral envelope (Env) glycoproteins or between viral Env and host-cell receptors. The nature of resistance to entry inhibitors also differs from compounds inhibiting enzymatic targets due to their different modes of action and the relative variability in Env sequences both temporally and between patients. Two drugs that target HIV-1 entry, enfuvirtide and maraviroc, are now licensed for treatment of HIV-1 infection. The efficacy of these drugs validates entry as a point of intervention in viral life cycles and, in the context of HIV treatment, contributes to the growing armamentarium of antivirals which, in multidrug combinations, can effectively inhibit viral replication and prevent disease progression.

Keywords

CCR5 Antagonist Entry Inhibitor Optimize Background Therapy Optimize Background Toro Study 
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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References

  1. Abel S, Van der Ryst E, Muihead GJ, Rosario A, Edgington A, Weissgerber G (2003) Pharmacokinetics of single and multiple oral doses of UK-427,857 — A novel CCR5 antagonist in healthy olunteers. In: 10th conference on retroviruses and opportunistic infections. Boston, MAGoogle Scholar
  2. Aghokeng AF, Ewane L, Awazi B, Nanfack A, Delaporte E, Zekeng L, Peeters M (2005) Enfuvirtide binding domain is highly conserved in non-B HIV type 1 strains from Cameroon, West Central Africa. AIDS Res Hum Retroviruses 21:430–433PubMedGoogle Scholar
  3. Aquaro S, D'Arrigo R, Svicher V, Perri GD, Caputo SL, Visco-Comandini U, Santoro M, Bertoli A, Mazzotta F, Bonora S, Tozzi V, Bellagamba R, Zaccarelli M, Narciso P, Antinori A, Perno CF (2006) Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment. J Antimicrob Chemother 58:714–722PubMedGoogle Scholar
  4. 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
  5. Baba M, Miyake H, Wang X, Okamotoand M, Takashima K (2006) Isolation and characterization of human immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652. Antimicrob Agents Chemother 51:707–715PubMedGoogle Scholar
  6. Berger EA, Doms RW, Fenyo EM, Korber BT, Littman DR, Moore JP, Sattentau QJ, Schuitemaker H, Sodroski J, Weiss RA (1998) A new classification for HIV-1. Nature 391:240PubMedGoogle Scholar
  7. Berson JF, Long D, Doranz BJ, Rucker J, Jirik FR, Doms RW (1996) A seven-transmembrane domain receptor involved in fusion and entry of T-cell-tropic human immunodeficiency virus type 1 strains. J Virol 70:6288–6295PubMedGoogle Scholar
  8. Brasseur R, Cornet B, Burny A, Vandenbranden M, Ruysschaert JM (1988) Mode of insertion into a lipid membrane of the N-terminal HIV gp41 peptide segment. AIDS Res Hum Retroviruses 4:83–90PubMedGoogle Scholar
  9. Brumme ZL, Goodrich J, Mayer HB, Brumme CJ, Henrick BM, Wynhoven B, Asselin JJ, Cheung PK, Hogg RS, Montaner JS, Harrigan PR (2005) Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals. J Infect Dis 192:466–474PubMedGoogle Scholar
  10. Carmona R, Perez-Alvarez L, Munoz M, Casado G, Delgado E, Sierra M, Thomson M, Vega Y, Vazquez de Parga E, Contreras G, Medrano L, Najera R (2005) Natural resistance-associated mutations to Enfuvirtide (T20) and polymorphisms in the gp41 region of different HIV-1 genetic forms from T20 naive patients. J Clin Virol 32:248–253PubMedGoogle Scholar
  11. Castonguay LA, Weng Y, Adolfsen W, Di Salvo J, Kilburn R, Caldwell CG, Daugherty BL, Finke PE, Hale JJ, Lynch CL, Mills SG, MacCoss M, Springer MS, DeMartino JA (2003) Binding of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines to human CCR5: a molecular modeling-guided mutagenesis study of the binding pocket. Biochemistry 42:1544–1550PubMedGoogle Scholar
  12. Chan DC, Kim PS (1998) HIV entry and its inhibition. Cell 93:681–684PubMedGoogle Scholar
  13. Chan DC, Fass D, Berger JM, Kim PS (1997) Core structure of gp41 from the HIV envelope glycoprotein. Cell 89:263–273PubMedGoogle Scholar
  14. 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 95:15613–15617PubMedGoogle Scholar
  15. 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
  16. Chibo D, Roth N, Roulet V, Skrabal K, Gooey M, Carolan L, Nicholls J, Papadakis A, Birch C (2007) Virological fitness of HIV in patients with resistance to enfuvirtide. Aids 21:1974–1977PubMedGoogle Scholar
  17. Cilliers T, Patience T, Pillay C, Papathanasopoulos M, Morris L (2004) Sensitivity of HIV type 1 subtype C isolates to the entry inhibitor T-20. AIDS Res Hum Retroviruses 20:477–482PubMedGoogle Scholar
  18. 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
  19. Cohen C, DeJesus E, Mills A, Pierone Jr G, Kumar P, Ruane P, Elion R, Fusco G, Levy R, Solomon K, Erickson-Viitanen S (2007) Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy. In: 4th international AIDS society conference, Sydney, Australia, 22–25 July 2007. Abstract TUAB106Google Scholar
  20. Collier AC, Coombs RW, Katzenstein D, Holodniy M, Gibson J, Mordenti J, Izu AE, Duliege AM, Ammann AJ, Merigan T et al (1995) Safety, pharmacokinetics, and antiviral response of CD4-immunoglobulin G by intravenous bolus in AIDS and AIDS-related complex. J Acquir Immune Defic Syndr Hum Retrovirol 10:150–156PubMedGoogle Scholar
  21. 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 312:763–767PubMedGoogle Scholar
  22. Deeks SG, Lu J, Hoh R, Neilands TB, Beatty G, Huang W, Liegler T, Hunt P, Martin JN, Kuritzkes DR (2007) Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen. J Infect Dis 195:387–391PubMedGoogle Scholar
  23. Dejucq N, Simmons G, Clapham PR (2000) T-cell line adaptation of human immunodeficiency virus type 1 strain SF162: effects on envelope, vpu and macrophage-tropism. J Gen Virol 81:2899–2904PubMedGoogle Scholar
  24. 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
  25. 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 74:8358–8367PubMedGoogle Scholar
  26. 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 75:8605–8614PubMedGoogle Scholar
  27. Dimitrov AS, Louis JM, Bewley CA, Clore GM, Blumenthal R (2005) Conformational changes in HIV-1 gp41 in the course of HIV-1 envelope glycoprotein-mediated fusion and inactivation. Biochemistry 44:12471–12479PubMedGoogle Scholar
  28. Dorn CP, Finke PE, Oates B, Budhu RJ, Mills SG, MacCoss M, Malkowitz L, Springer MS, Daugherty BL, Gould SL, DeMartino JA, Siciliano SJ, Carella A, Carver G, Holmes K, Danzeisen R, Hazuda D, Kessler J, Lineberger J, Miller M, Schleif WA, Emini EA (2001) Antagonists of the human CCR5 receptor as anti-HIV-1 agents, part 1: discovery and initial structure-activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes. Bioorg Med Chem Lett 11:259–264PubMedGoogle Scholar
  29. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R, Armour D, Price D, Stammen B, Wood A, Perros M (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 49:4721–4732PubMedGoogle Scholar
  30. Dorr P, Westby M, McFadyen L, Mori J, Davis J, Perruccio F, Jones R, Stupple P, Middleton D, Perros M (2008) PF-232798, a second generation oral CCR5 antagonist. In: 15th conference on retroviruses and opportunistic infections, Boston, USA, 3–6 February. Abstract 737Google Scholar
  31. 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
  32. 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 USA 97:5639–5644PubMedGoogle Scholar
  33. Dwyer JJ, Wilson KL, Davison DK, Freel SA, Seedorff JE, Wring SA, Tvermoes NA, Matthews TJ, Greenberg ML, Delmedico MK (2007) Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus. Proc Natl Acad Sci USA 104:12772–12777PubMedGoogle Scholar
  34. Erickson-Viitanen S, Abremski1 K, Solomon K, Levy R, Lam E, Whitcomb JM, Lloyd Jr R, Mathis R, Reeves J, Burns D (2008) Co-receptor tropism, ENV genotype, and in vitro susceptibility to CCR5 antagonists during a 14-day monotherapy study with INCB9471. In: 15th conference on retroviruses and opportunistic infections, Boston, USA, February 3–6. Abstract 862Google Scholar
  35. Este JA (2002) Sch-351125 and Sch-350634. Curr Opin Investig Drugs 3:379–383PubMedGoogle Scholar
  36. Etemad-Moghadam B, Rhone D, Steenbeke T, Sun Y, Manola J, Gelman R, Fanton JW, Racz P, Tenner-Racz K, Axthelm MK, Letvin NL, Sodroski J (2001) Membrane-fusing capacity of the human immunodeficiency virus envelope proteins determines the efficiency of CD4+ T-cell depletion in macaques infected by a simian-human immunodeficiency virus. J Virol 75:5646–5655Google Scholar
  37. Fatkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AI, Saag MS, Goebel FD, Rockstroh JK, Dezube BJ, Jenkins TM, Medhurst C, Sullivan JF, Ridgway C, Abel S, James IT, Youle M, van der Ryst E (2005) Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 11:1170–1172PubMedGoogle Scholar
  38. 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
  39. Furuta RA, Wild CT, Weng Y, Weiss CD (1998) Capture of an early fusion-active conformation of HIV-1 gp41. Nat Struct Biol 5:276–279PubMedGoogle Scholar
  40. Gallaher WR (1987) Detection of a fusion peptide sequence in the transmembrane protein of human immunodeficiency virus. Cell 50:327–328PubMedGoogle Scholar
  41. Greenberg ML, Cammack N (2004) Resistance to enfuvirtide, the first HIV fusion inhibitor. J Antimicrob Chemother 54:333–340PubMedGoogle Scholar
  42. Hanna G, Lalezari J, Hellinger J, Wohl D, Masterson T, Fiske W, Kadow J, Lin 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 a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. In: 11th conference on retroviruses and opportunistic infections, San Francisco, CAGoogle Scholar
  43. Harrigan PR, Montaner JS, Wegner SA, Verbiest W, Miller V, Wood R, Larder BA (2001) Worldwide variation in HIV-1 phenotypic susceptibility in untreated individuals: biologically relevant values for resistance testing. Aids 15:1671–1677PubMedGoogle Scholar
  44. Harrowe G, Cheng-Mayer C (1995) Amino acid substitutions in the V3 loop are responsible for adaptation to growth in transformed T-cell lines of a primary human immunodeficiency virus type 1. Virology 210:490–494PubMedGoogle Scholar
  45. 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 77:1666–1671PubMedGoogle Scholar
  46. Hendrix C (2004) Safety, phamacokinetics and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr 37:1253–1262PubMedGoogle Scholar
  47. Heredia A, Gilliam B, DeVico A, Le N, Bamba D, Flinko R, Lewis G, Gallo RC, Redfield RR (2007) CCR5 density levels on primary CD4 T cells impact the replication and Enfuvirtide susceptibility of R5 HIV-1. Aids 21:1317–1322PubMedGoogle Scholar
  48. Ho HT, Fan L, Nowicka-Sans B, McAuliffe B, Li CB, Yamanaka G, Zhou N, Fang H, Dicker I, Dalterio R, Gong YF, Wang T, Yin Z, Ueda Y, Matiskella J, Kadow J, Clapham P, Robinson J, Colonno R, Lin PF (2006) Envelope conformational changes induced by human immunodeficiency virus type 1 attachment inhibitors prevent CD4 binding and downstream entry events. J Virol 80:4017–4025PubMedGoogle Scholar
  49. Holguin A, Faudon JL, Labernardiere JL, Soriano V (2007) Susceptibility of HIV-1 non-B subtypes and recombinant variants to Enfuvirtide. J Clin Virol 38:176–180PubMedGoogle Scholar
  50. Jacobson JM, Lowy I, Fletcher CV, O'Neill TJ, Tran DN, Ketas TJ, Trkola A, Klotman ME, Maddon PJ, Olson WC, Israel RJ (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 182:326–329PubMedGoogle Scholar
  51. Ji C, Brandt M, Dioszegi M, Jekle A, Schwoerer S, Challand S, Zhang J, Chen Y, Zautke L, Achhammer G, Baehner M, Kroetz S, Heilek-Snyder G, Schumacher R, Cammack N, Sankuratri S (2007) Novel CCR5 monoclonal antibodies with potent and broad-spectrum anti-HIV activities. Antiviral Res 74:125–137PubMedGoogle Scholar
  52. Jiang S, Lin K, Strick N, Neurath AR (1993) Inhibition of HIV-1 infection by a fusion domain binding peptide from the HIV-1 envelope glycoprotein GP41. Biochem Biophys Res Commun 195:533–538PubMedGoogle Scholar
  53. Kadow J, Wang HG, Lin PF (2006) Small-molecule HIV-1 gp120 inhibitors to prevent HIV-1 entry: an emerging opportunity for drug development. Curr Opin Investig Drugs 7:721–726PubMedGoogle Scholar
  54. Karlsson GB, Halloran M, Schenten D, Lee J, Racz P, Tenner-Racz K, Manola J, Gelman R, Etemad-Moghadam B, Desjardins E, Wyatt R, Gerard NP, Marcon L, Margolin D, Fanton J, Axthelm MK, Letvin NL, Sodroski J (1998) The envelope glycoprotein ectodomains determine the efficiency of CD4+ T lymphocyte depletion in simian- human immunodeficiency virus-infected macaques. J Exp Med 188:1159–1171PubMedGoogle Scholar
  55. Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, Alldredge L, Hunter E, Lambert D, Bolognesi D, Matthews T, Johnson MR, Nowak MA, Shaw GM, Saag MS (1998) Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4:1302–1307PubMedGoogle Scholar
  56. Kilby JM, Lalezari JP, Eron JJ, Carlson M, Cohen C, Arduino RC, Goodgame JC, Gallant JE, Volberding P, Murphy RL, Valentine F, Saag MS, Nelson EL, Sista PR, Dusek A (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 Retro-viruses 18:685–693Google Scholar
  57. Kitchen CM, Lu J, Suchard MA, Hoh R, Martin JN, Kuritzkes DR, Deeks SG (2006) Continued evolution in gp41 after interruption of enfuvirtide in subjects with advanced HIV type 1 disease. AIDS Res Hum Retroviruses 22:1260–1266PubMedGoogle Scholar
  58. Kitrinos K, Labranche C, Stanhope M, Madsen H, Demarest J (2005) Clonal analysis detects preexisting R5X4-tropic virus in patient demonstrating population-level tropism switch on 873140 monotherapy. Antivir Ther 10:S68Google Scholar
  59. 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 L AV. Nature 312:767–768PubMedGoogle Scholar
  60. 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 276:1391–1397PubMedGoogle Scholar
  61. Kuritzkes DR, Jacobson J, Powderly WG, Godofsky E, DeJesus E, Haas F, Reimann KA, Larson JL, Yarbough PO, Curt V, Shanahan WR Jr (2004) Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 189:286–291PubMedGoogle Scholar
  62. Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393:648–659PubMedGoogle Scholar
  63. Labrosse B, Morand-Joubert L, Goubard A, Rochas S, Labernardiere JL, Pacanowski J, Meynard JL, Hance AJ, Clavel F, Mammano F (2006) Role of the envelope genetic context in the development of enfuvirtide resistance in human immunodeficiency virus type 1-infected patients. J Virol 80:8807–8819PubMedGoogle Scholar
  64. Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine F, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J (2003a) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in non- nucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8:279–287Google Scholar
  65. Lalezari JP, Eron JJ, Carlson M, Cohen C, DeJesus E, Arduino RC, Gallant JE, Volberding P, Murphy RL, Valentine F, Nelson EL, Sista PR, Dusek A, Kilby JM (2003b) A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy. Aids 17:691–698Google Scholar
  66. Lalezari JP, Henry K, O'Hearn M, Montaner JS, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ Jr, Chung J, DeMasi R, Donatacci L, Drobnes C, Delehanty J, Salgo M (2003c) Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 348:2175–2185Google Scholar
  67. Lalezari JP, Bellos NC, Sathasivam K, Richmond GJ, Cohen CJ, Myers RA Jr, Henry DH, Raskino C, Melby T, Murchison H, Zhang Y, Spence R, Greenberg ML, Demasi RA, Miralles GD (2005b) T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen. J Infect Dis 191:1155–1163Google Scholar
  68. Lalezari J, Zhang Y, DeMasi R, Salgo M, Miralles G, Team TT-S (2004) Long term safety of T-1249, a potent inhibitor of HIV fusion. In: 44th interscience conference on antimicrobial agents and chemotherapy (ICAAC), WA, USAGoogle Scholar
  69. Lalezari J, Thompson M, Kumar P, Piliero P, Davey R, Patterson K, Shachoy-Clark A, Adkison K, Demarest J, Lou Y, Berrey M, Piscitelli S (2005a) Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults. Aids 19:1443–1448Google Scholar
  70. Lalezari J, Goodrich J, DeJesus E, Lampiris H, Gulick R, Saag M, Ridgway C, McHale M, van der Ryst E, Mayer H (2007) Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of aphase 2b/3 study in the US and Canada. In: 14th conference on retroviruses and opportunistic infections, Los Angeles, USA, February 25–28. Abstract 104bLBGoogle Scholar
  71. Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M, Katlama C, Stellbrink HJ, Delfraissy JF, Lange J, Huson L, DeMasi R, Wat C, Delehanty J, Drobnes C, Salgo M (2003) Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 348:2186–2195PubMedGoogle Scholar
  72. Lewis M, Simpson P, Fransen S, Huang W, Whitcomb JM, Mosley M, Robertson DL, Mansfield R, Ciaramella G, Westby M (2007) CXCR4-using virus detected in patients receiving maraviroc in the Phase III studies MOTIVATE 1 and 2 originates from a pre-existing minority of CXCR4-using virus. Antivir Ther 12:S65Google Scholar
  73. Lin PF, Blair W, Wang T, Spicer T, Guo Q, Zhou N, Gong YF, Wang HG, Rose R, Yamanaka G, Robinson B, Li CB, Fridell R, Deminie C, Demers G, Yang Z, Zadjura L, Meanwell N, Colonno R (2003) A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc Natl Acad Sci USA 100:11013–11018PubMedGoogle Scholar
  74. 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
  75. 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 280:11259–11273PubMedGoogle Scholar
  76. 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 78:4628–4637PubMedGoogle Scholar
  77. Lu M, Blacklow SC, Kim PS (1995) A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat Struct Biol 2:1075–1082PubMedGoogle Scholar
  78. 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
  79. Maeda K, Nakata H, Koh Y, Miyakawa T, Ogata H, Takaoka Y, Shibayama S, Sagawa K, Fukushima D, Moravek J, Koyanagi Y, Mitsuya H (2004a) Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J Virol 78:8654–8662Google Scholar
  80. Maeda K, Ogata H, Harada S, Tojo Y, Miyakawa T, Nakata H, Takaoka Y, Shibayama S, Sagawa K, Daikichi F, Moravek J, Arnold E, Mitsuya H (2004b) Determination of binding sites of a unique CCR5 inhibitor AK602 on human CCR5. In: 11th conference on retroviruses and opportunistic infections, San Francisco, CAGoogle Scholar
  81. 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
  82. Malashkevich VN, Chan DC, Chutkowski CT, Kim PS (1998) Crystal structure of the simian immunodeficiency virus (SIV) gp41 core: conserved helical interactions underlie the broad inhibitory activity of gp41 peptides. Proc Natl Acad Sci USA 95:9134–9139PubMedGoogle Scholar
  83. Marcelin AG, Reynes J, Yerly S, Ktorza N, Segondy M, Piot JC, Delfraissy JF, Kaiser L, Perrin L, Katlama C, Calvez V (2004) Characterization of genotypic determinants in HR-1 and HR-2 gp41 domains in individuals with persistent HIV viraemia under T-20. Aids 18:1340–1342PubMedGoogle Scholar
  84. Marozsan AJ, Kuhmann SE, Morgan T, Herrera C, Rivera-Troche E, Xu S, Baroudy BM, Strizki J, Moore JP (2005) Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D). Virology 338:182–199PubMedGoogle Scholar
  85. Mayer H, van der Ryst E, Saag M, Clotet B, Fatkenheuer G, Clumeck N, Turner K, Goodrich J (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: 16th international AIDS conference, Toronto, Canada, 13–18 August. Abstract THLB0215Google Scholar
  86. Melby T, DeMasi R, Miralles G, Heilek-Snyder G, Greenberg M (2005) Evolution of enfuvirtide resistance in longitudinal samples obtained after continued enfuvirtide dosing post-virological failure. In: 14th international drug resistance workshop, QC, Canada. Antiviral therapy, Suppl 1Google Scholar
  87. Melby T, Despirito M, Demasi R, Heilek-Snyder G, Greenberg ML, Graham N (2006a) HIV-1 coreceptor use in triple-class treatment-experienced patients: baseline prevalence, correlates, and relationship to enfuvirtide response. J Infect Dis 194:238–246Google Scholar
  88. Melby T, Sista P, Demasi R, Kirkland T, Roberts N, Salgo M, Heilek-Snyder G, Cammack N, Matthews TJ, Greenberg ML (2006b) 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 22:375–385Google Scholar
  89. Melby T, Demasi R, Cammack N, Miralles GD, Greenberg ML (2007a) Evolution of genotypic and phenotypic resistance during chronic treatment with the fusion inhibitor T-1249. AIDS Res Hum Retroviruses 23:1366–1373Google Scholar
  90. Melby TE, Despirito M, Demasi RA, Heilek G, Thommes JA, Greenberg ML, Graham N (2007b) Association between specific enfuvirtide resistance mutations and CD4 cell response during enfuvirtide-based therapy. Aids 21:2537–2539Google Scholar
  91. 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 151:413–424PubMedGoogle Scholar
  92. 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 48:3253–3259PubMedGoogle Scholar
  93. Miller SA, Tollefson S, Crowe JE Jr, Williams JV, Wright DW (2007) Examination of a fusogenic hexameric core from human metapneumovirus and identification of a potent synthetic peptide inhibitor from the heptad repeat 1 region. J Virol 81:141–149PubMedGoogle Scholar
  94. Mink M, Mosier SM, Janumpalli S, Davison D, Jin L, Melby T, Sista P, Erickson J, Lambert D, Stanfield-Oakley SA, Salgo M, Cammack N, Matthews T, Greenberg ML (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 79:12447–12454PubMedGoogle Scholar
  95. Mirsaliotis A, Lamb D, Brighty DW (2008) Nonhelical leash and alpha-helical structures determine the potency of a peptide antagonist of human T-cell leukemia virus entry. J Virol 82:4965–4973PubMedGoogle Scholar
  96. Mori J, Mosley M, Lewis M, Simpson P, Tomas J, Huang W, Whitcomb JM, Ciaramella G, Westby M (2007) Characterization of maraviroc resistance in patients failing treatment with CCR5-tropic virus in MOTIVATE 1 and MOTIVATE 2. Antivir Ther 12:S12Google Scholar
  97. Moyle GJ, Wildfire A, Mandalia S, Mayer H, Goodrich J, Whitcomb J, Gazzard BG (2005) Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection. J Infect Dis 191:866–872PubMedGoogle Scholar
  98. Mueller A, Strange PG (2004) The chemokine receptor, CCR5. Int J Biochem Cell Biol 36:35–38PubMedGoogle Scholar
  99. 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 140:315–323Google Scholar
  100. Munoz-Barroso I, Salzwedel K, Hunter E, Blumenthal R (1999) Role of the membrane-proximal domain in the initial stages of human immunodeficiency virus type 1 envelope glycoprotein-mediated membrane fusion. J Virol 73:6089–6092Google Scholar
  101. Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC (2006) Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents Chemother 50:3289–3296PubMedGoogle Scholar
  102. Nelson M, Arasteh K, Clotet B, Cooper DA, Henry K, Katlama C, Lalezari JP, Lazzarin A, Montaner JS, O'Hearn M, Piliero PJ, Reynes J, Trottier B, Walmsley SL, Cohen C, Eron JJ Jr, Kuritzkes DR, Lange J, Stellbrink HJ, Delfraissy JF, Buss NE, Donatacci L, Wat C, Smiley L, Wilkinson M, Valentine A, Guimaraes D, Demasi R, Chung J, Salgo MP (2005) Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr 40:404–412PubMedGoogle Scholar
  103. Nelson M, Fatkenheuer G, Konourina I, Lazzarin A, Clumeck N, Horban A, Tawadrous M, Sullivan J, Mayer H, van der Ryst E (2007) Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results In: 14th conference on retroviruses and opportunistic infections, Los Angeles, USA, February 25–28. Abstract 104aLBGoogle Scholar
  104. Nishikawa M, Takashima K, Nishi T, Furuta RA, Kanzaki N, Yamamoto Y, Fujisawa J (2005) Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5. Antimicrob Agents Chemother 49:4708–4715PubMedGoogle Scholar
  105. Pastore C, Ramos A, Mosier DE (2004) Intrinsic obstacles to human immunodeficiency virus type 1 coreceptor switching. J Virol 78:7565–7574PubMedGoogle Scholar
  106. Pastore C, Nedellec R, Ramos A, Pontow S, Ratner L, Mosier DE (2006) Human immunodeficiency virus type 1 coreceptor switching: V1/V2 gain-of-fitness mutations compensate for V3 loss-of-fitness mutations. J Virol 80:750–758PubMedGoogle Scholar
  107. Platt EJ, Durnin JP, Kabat D (2005) Kinetic factors control efficiencies of cell entry, efficacies of entry inhibitors, and mechanisms of adaptation of human immunodeficiency virus. J Virol 79:4347–4356PubMedGoogle Scholar
  108. Poveda E, Rodes B, Lebel-Binay S, Faudon JL, Jimenez V, Soriano V (2005) Dynamics of enfuvir-tide resistance in HIV-infected patients during and after long-term enfuvirtide salvage therapy. J Clin Virol 34:295–301PubMedGoogle Scholar
  109. Pugach P, Marozsan AJ, Ketas TJ, Landes EL, Moore JP, Kuhmann SE (2007) HIV-1 clones resistant to a small molecule CCR5 inhibitor use the inhibitor-bound form of CCR5 for entry. Virology 361:212–228PubMedGoogle Scholar
  110. Quintana FJ, Gerber D, Kent SC, Cohen IR, Shai Y (2005) HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T cell activation. J Clin Invest 115:2149–2158PubMedGoogle Scholar
  111. 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
  112. 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
  113. Reeves JD, Lee F-H, 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 79:4991–4999PubMedGoogle Scholar
  114. 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
  115. Rizzuto CD, Wyatt R, Hernandez-Ramos N, Sun Y, Kwong PD, Hendrickson WA, Sodroski J (1998) A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 280:1949–1953PubMedGoogle Scholar
  116. Russell D, Bakhtyari A, Jazrawi RP, Whitlock L, Ridgway C, McHale M, Abel S (2003) Multiple dose study to investigate the safety of UK-427,857 (100 mg or 300 mg) BID for 28 days in healthy males and females. In: 43rd interscience conference on antimicrobial agents and chemotherapy, Chicago, IL, USAGoogle Scholar
  117. Saez-Cirion A, Nir S, Lorizate M, Agirre A, Cruz A, Perez-Gil J, Nieva JL (2002) Sphingomyelin and cholesterol promote HIV-1 gp41 pretransmembrane sequence surface aggregation and membrane restructuring. J Biol Chem 277:21776–21785Google Scholar
  118. 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
  119. 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
  120. Seibert C, Ying W, Gavrilov S, Tsamis F, Kuhmann SE, Palani A, Tagat JR, Clader JW, McCombie SW, Baroudy BM, Smith SO, Dragic T, Moore JP, Sakmar TP (2006) Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Virology 349:41–54PubMedGoogle Scholar
  121. Shearer WT, Israel RJ, Starr S, Fletcher CV, Wara D, Rathore M, Church J, DeVille J, Fenton T, Graham B, Samson P, Staprans S, McNamara J, Moye J, Maddon PJ, Olson WC (2000) Recombinant CD4-IgG2 in human immunodeficiency virus type 1-infected children: phase 1/2 study. The Pediatric AIDS Clinical Trials Group Protocol 351 Study Team. J Infect Dis 182:1774–1779PubMedGoogle Scholar
  122. Sista PR, Melby T, Davison D, Jin L, Mosier S, Mink M, Nelson EL, DeMasi R, Cammack N, Salgo MP, Matthews TJ, Greenberg ML (2004) Characterization of determinants of genotypic and phenotypic resistance to enfuvirtide in baseline and on-treatment HIV-1 isolates. Aids 18:1787–1794PubMedGoogle Scholar
  123. 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 USA 98:12718–12723PubMedGoogle Scholar
  124. Strizki JM, Tremblay C, Xu S, Wojcik L, Wagner N, Gonsiorek W, Hipkin RW, Chou CC, Pugliese-Sivo C, Xiao Y, Tagat JR, Cox K, Priestley T, Sorota S, Huang W, Hirsch M, Reyes GR, Baroudy BM (2005) Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob Agents Chemother 49:4911–4919PubMedGoogle Scholar
  125. Tan K, Liu J-H, Wang J-H, Shen S, Lu M (1997) Atomic structure of a thermostable subdomain of HIV-1gp41. Proc Natl Acad Sci USA94:12303–12308PubMedGoogle Scholar
  126. Trkola A, Ketas TJ, Nagashima KA, Zhao L, Cilliers T, Morris L, Moore JP, Maddon PJ, Olson WC (2001) Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J Virol 75:579–588PubMedGoogle Scholar
  127. 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 USA 99:395–400PubMedGoogle Scholar
  128. Tsibris AMN, Gulick RM, Su Z, Hughes MD, Flexner C, Wilkin T, Gross R, Hirsch M, Skolnick PR, Coakley E, Greaves WL, Kuritzkes DR (2007) In vivo emergence of HIV-1 resistance to the CCR5 antagonist vicriviroc: findings from ACTG A5211. Antivir Ther 12:S15Google Scholar
  129. Veiga S, Henriques S, Santos NC, Castanho M (2004) Putative role of membranes in the HIV fusion inhibitor enfuvirtide mode of action at the molecular level. Biochem J 377:107–110PubMedGoogle Scholar
  130. Walker DK, Abel S, Comby P, Muirhead GJ, Nedderman AN, Smith DA (2005) Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Drug Metab Dispos 33:587–595PubMedGoogle Scholar
  131. 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 67:1268–1282PubMedGoogle Scholar
  132. 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 46:1896–1905PubMedGoogle Scholar
  133. Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC (1997) Atomic structure of the ectodomain from HIV-1 gp41. Nature 387:426–430PubMedGoogle Scholar
  134. 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 80:4909–4920PubMedGoogle Scholar
  135. Westby M, Smith-Burchnell C, Mori J, Lewis M, Mosley M, Stockdale M, Dorr P, Ciaramella G, Perros M (2007) Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 81:2359–2371PubMedGoogle Scholar
  136. Whitcomb JM, Huang W, Fransen S, Limoli K, Toma J, Wrin T, Chappey C, Kiss LD, Paxinos EE, Petropoulos CJ (2007) Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism. Antimicrob Agents Chemother 51:566–575PubMedGoogle Scholar
  137. 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 89:10537–10541PubMedGoogle Scholar
  138. 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
  139. Wood A, Armour D (2005) The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. Prog Med Chem 43:239–271PubMedGoogle Scholar
  140. Wyatt R, Sodroski J (1998) The HIV-1 envelope glycoproteins: fusogens, antigens, and immuno-gens. Science 280:1884–1888PubMedGoogle Scholar
  141. Wyatt R, Kwong PD, Desjardins E, Sweet RW, Robinson J, Hendrickson WA, Sodroski JG (1998) The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 393:705–711PubMedGoogle Scholar
  142. Xu L, Pozniak A, Wildfire A, Stanfield-Oakley SA, Mosier SM, Ratcliffe D, Workman J, Joall A, Myers R, Smit E, Cane PA, Greenberg ML, Pillay D (2005) Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41. Antimicrob Agents Chemother 49:1113–1119PubMedGoogle Scholar
  143. 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 78:5448–5457PubMedGoogle Scholar
  144. Zhang XQ, Sorensen M, Fung M, Schooley RT (2006) Synergistic in vitro antiretroviral activity of a humanized monoclonal anti-CD4 antibody (TNX-355) and enfuvirtide (T-20). Antimicrob Agents Chemother 50:2231–2233PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Virology Communications Specialist101 E. Ellerbee St. DurhamUSA
  2. 2.Pfizer Global R&DSandwich LaboratoriesKentUK

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