HIV-1 entry inhibitors as microbicides

  • Clyde E. Hart
  • Tammy Evans-Strickfaden
Part of the Milestones in Drug Therapy book series (MDT)


Sexual transmission of HIV-1 is the major route for infection of both men and women [1]. During the early phase of the HIV pandemic in the western hemisphere and industrialized world, sexual transmission of HIV was regarded as a public health concern that mostly impacted men who have sex with men (MSM) and commercial sex workers and their male clients [2]. In the developing world, however, heterosexual transmission of HIV between sex partners both outside and within the context of the commercial sex industry was identified early on as a major driving force for the catastrophic rate of infection now reported in many regions of the world [2, 3].


Human Immunodeficiency Virus Human Immunodeficiency Virus Type Simian Immunodeficiency Virus Cellulose Sulfate Human Immunodeficiency Virus Infection Rate 
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 and Prevention (2005) HIV/AIDS Surveillance Report, 2004. US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, 1–46Google Scholar
  2. 2.
    World_Health Organization (2003) The World Health Report: 2003: Shaping the Future. Chapter 3: HIV/AIDS: Confronting a Killer. World Health Organization, GenevaGoogle Scholar
  3. 3.
    UNAIDS (2006) 2006 Report on the Global AIDS Epidemic: Executive Summary. A UNAIDS 10th Anniversary Special Edition.: GenevaGoogle Scholar
  4. 4.
    Hearst N, Chen S (2004) Condom promotion for AIDS prevention in the developing world: is it working? Stud Fam Plann 35: 39–47PubMedCrossRefGoogle Scholar
  5. 5.
    Shelton JD, Halperin DT, Nantulya V, Potts M, Gayle HD, Holmes KK (2004) Partner reduction is crucial for balanced “ABC” approach to HIV prevention. BMJ 328: 891–893PubMedCrossRefGoogle Scholar
  6. 6.
    Stoneburner RL, Low-Beer D (2004) Population-level HIV declines and behavioral risk avoidance in Uganda. Science 304: 714–718PubMedCrossRefGoogle Scholar
  7. 7.
    The Gender and Development Group (2004) Integrating Gender Issues into HIV/AIDS Programs: An Operational Guide. World Bank: Washington, D.C.Google Scholar
  8. 8.
    Cookson C (1993) WHO to concentrate HIV strategy on vaginal microbicide. BMJ 307: 1375–1376PubMedGoogle Scholar
  9. 9.
    Lange JM, Karam M, Piot P (1993) Boost for vaginal microbicides against HIV. Lancet 342: 1356PubMedCrossRefGoogle Scholar
  10. 10.
    [no authors listed] (1998) Trial shows Nonoxynol 9 efficacy is questionable. AIDS Alert 13: 117–120Google Scholar
  11. 11.
    D’Cruz OJ, Uckun FM (2004) Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des 10: 315–336PubMedCrossRefGoogle Scholar
  12. 12.
    Alliance for Microbicide Development. Clinical Trials of Microbicides. 2006 [accessed 16 January 2007]; available from: Scholar
  13. 13.
    Munoz de Benito RM, Arribas Lopez JR (2006) Tenofovir disoproxil fumarate-emtricitabine coformulation for once-daily dual NRTI backbone. Expert Rev Anti Infect Ther 4: 523–535PubMedCrossRefGoogle Scholar
  14. 14.
    Van Herrewege Y, Michiels J, Van Roey J, Fransen K, Kestens L, Balzarini J, Lewi P, Vanham G, Janssen P (2004) In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother 48: 337–339PubMedCrossRefGoogle Scholar
  15. 15.
    Idemyor V (2005) Human immunodeficiency virus (HIV) entry inhibitors (CCR5 specific blockers) in development: are they the next novel therapies? HIV Clin Trials 6: 272–277PubMedCrossRefGoogle Scholar
  16. 16.
    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
  17. 17.
    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: 579–588PubMedCrossRefGoogle Scholar
  18. 18.
    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
  19. 19.
    Matthews T, Salgo M, Greenberg M, Chung J, DeMasi R, Bolognesi D (2004) Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nat Rev Drug Discov 3: 215–225PubMedCrossRefGoogle Scholar
  20. 20.
    Mayer KH, Peipert J, Fleming T, Fullem A, Moench T, Cu-Uvin S, Bentley M, Chesney M, Rosenberg Z (2001) Safety and tolerability of BufferGel, a novel vaginal microbicide, in women in the United States. Clin Infect Dis 32: 476–482PubMedCrossRefGoogle Scholar
  21. 21.
    Chang TL, Chang CH, Simpson DA, Xu Q, Martin PK, Lagenaur LA, Schoolnik GK, Ho DD, Hillier SL, Holodniy M et al. (2003) Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4. Proc Natl Acad Sci USA 100: 11672–11677PubMedCrossRefGoogle Scholar
  22. 22.
    Liu X, Lagenaur LA, Simpson DA, Essenmacher KP, Frazier-Parker CL, Liu Y, Tsai D, Rao SS, Hamer DH, Parks TP et al. (2006) Engineered vaginal lactobacillus strain for mucosal delivery of the human immunodeficiency virus inhibitor cyanovirin-N. Antimicrob Agents Chemother 50: 3250–3259PubMedCrossRefGoogle Scholar
  23. 23.
    Pusch O, Kalyanaraman R, Tucker LD, Wells JM, Ramratnam B, Boden D (2006) An anti-HIV microbicide engineered in commensal bacteria: secretion of HIV-1 fusion inhibitors by lactobacilli. AIDS 20: 1917–1922PubMedCrossRefGoogle Scholar
  24. 24.
    Bax R, K. Douville, D. McCormick, M. Rosenberg, J. Higgins, M. Dowden (2002) Microbicides-evaluating multiple formulations of C31G. Contraception 66: 365–368PubMedCrossRefGoogle Scholar
  25. 25.
    Rusert P, Kuster H, Joos B, Misselwitz B, Gujer C, Leemann C, Fischer M, Stiegler G, Katinger H, Olson WC et al. (2005) Virus isolates during acute and chronic human immunodeficiency virus type 1 infection show distinct patterns of sensitivity to entry inhibitors. J Virol 79: 8454–8469PubMedCrossRefGoogle Scholar
  26. 26.
    Boyd MR, Gustafson KR, McMahon JB, Shoemaker RH, O’Keefe BR, Mori T, Gulakowski RJ, Wu L, Rivera MI, Laurencot CM et al. (1997) Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob Agents Chemother 41: 1521–1530PubMedGoogle Scholar
  27. 27.
    Joglekar NS, Joshi SN, Navlakha SN, Katti UR, Mehendale SM (2006) Acceptability of Praneem polyherbal vaginal tablet among HIV uninfected women and their male partners in Pune, India — Phase I study. Indian J Med Res 123: 547–552PubMedGoogle Scholar
  28. 28.
    Edwards JN, Morris HB (1985) Langerhans’ cells and lymphocyte subsets in the female genital tract. Br J Obstet Gynaecol 92: 974–982PubMedGoogle Scholar
  29. 29.
    Miller CJ, Shattock RJ (2003) Target cells in vaginal HIV transmission. Microbes Infect 5: 59–67PubMedCrossRefGoogle Scholar
  30. 30.
    Hu J, Gardner MB, Miller CJ (2000) Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J Virol 74: 6087–6095PubMedCrossRefGoogle Scholar
  31. 31.
    Cummins JE, Christensen L, Lennox JL, Bush TJ, Wu Z, Malamud D, Evans-Strickfaden T, Siddig A, Caliendo AM, Hart CE et al. (2006) Mucosal innate immune factors in the female genital tract are associated with vaginal HIV-1 shedding independent of plasma viral load. AIDS Res Hum Retroviruses 22: 788–795PubMedCrossRefGoogle Scholar
  32. 32.
    Hart CE, Lennox JL, Pratt-Palmore M, Wright TC, Schinazi RF, Evans-Strickfaden T, Bush TJ, Schnell C, Conley LJ, Clancy KA et al. (1999) Correlation of human immunodeficiency virus type 1 RNA levels in blood and the female genital tract. J Infect Dis 179: 871–882PubMedCrossRefGoogle Scholar
  33. 33.
    Moulard M, Lortat-Jacob H, Mondor I, Roca G, Wyatt R, Sodroski J, Zhao L, Olson W, Kwong PD, Sattentau QJ (2000) Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp120. J Virol 74: 1948–1960PubMedCrossRefGoogle Scholar
  34. 34.
    Margolis M, Shattock R (2006) Selective transmission of CCR5-utilizing HIV-1: the ‘gatekeeper’ problem resolved? Nat Rev Microbiol 4: 312–317PubMedCrossRefGoogle Scholar
  35. 35.
    Scordi-Bello IA, Mosoian A, He C, Chen Y, Cheng Y, Jarvis GA, Keller MJ, Hogarty K, Waller DP, Profy AT et al. (2005) Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. Antimicrob Agents Chemother 49: 3607–3615PubMedCrossRefGoogle Scholar
  36. 36.
    Anderson RA, Feathergill KA, Diao XH, Cooper MD, Kirkpatrick R, Herold BC, Doncel GF, Chany CJ, Waller DP, Rencher WF et al. (2002) Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent. J Androl 23: 426–438PubMedGoogle Scholar
  37. 37.
    Neurath AR, Strick N, Li YY (2002) Anti-HIV-1 activity of anionic polymers: a comparative study of candidate microbicides. BMC Infect Dis 2: 27–38PubMedCrossRefGoogle Scholar
  38. 38.
    Dezzutti CS, James VN, Ramos A, Sullivan ST, Siddig A, Bush TJ, Grohskopf LA, Paxton L, Subbarao S, Hart CE (2004) In vitro comparison of topical microbicides for prevention of human immunodeficiency virus type 1 transmission. Antimicrob Agents Chemother 48: 3834–3844PubMedCrossRefGoogle Scholar
  39. 39.
    Fernandez-Romero JA, Thorn M, Turville SG, Titchen K, Sudol K, Li J, Miller T, Robbiani M, Maguire RA, Buckheit RW, Jr et al. (2007) Carrageenan/MIV-150 (PC-815), a combination microbicide. Sex Transm Dis 34: 9–14PubMedCrossRefGoogle Scholar
  40. 40.
    Fletcher PS, Wallace GS, Mesquita PM, Shattock RJ (2006) Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants. Retrovirology 3: 46–57PubMedCrossRefGoogle Scholar
  41. 41.
    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
  42. 42.
    Neurath AR, Strick N, Jiang S, Li YY, Debnath AK (2002) Anti-HIV-1 activity of cellulose acetate phthalate: synergy with soluble CD4 and induction of “dead-end” gp41 six-helix bundles. BMC Infect Dis 2: 6–18PubMedCrossRefGoogle Scholar
  43. 43.
    Greenhead P, Hayes P, Watts PS, Laing KG, Griffin GE, Shattock RJ (2000) Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides. J Virol 74: 5577–5586PubMedCrossRefGoogle Scholar
  44. 44.
    Weber J, Nunn A, O’Connor T, Jeffries D, Kitchen V, McCormack S, Stott J, Almond N, Stone A, Darbyshire J (2001) ‘Chemical condoms’ for the prevention of HIV infection: evaluation of novel agents against SHIV(89.6PD) in vitro and in vivo. AIDS 15: 1563–1568PubMedCrossRefGoogle Scholar
  45. 45.
    Keller MJ, Zerhouni-Layachi B, Cheshenko N, John M, Hogarty K, Kasowitz A, Goldberg CL, Wallenstein S, Profy AT, Klotman ME et al. (2006) PRO 2000 gel inhibits HIV and herpes simplex virus infection following vaginal application: a double-blind placebo-controlled trial. J Infect Dis 193: 27–35PubMedCrossRefGoogle Scholar
  46. 46.
    King JB, Stickler DJ (1991) An assessment of antiseptic bladder washout solutions using a physical model of the catheterized bladder. J Hosp Infect 18: 179–190PubMedCrossRefGoogle Scholar
  47. 47.
    Pearce-Pratt R, Phillips DM (1996) Sulfated polysaccharides inhibit lymphocyte-to-epithelial transmission of human immunodeficiency virus-1. Biol Reprod 54: 173–182PubMedCrossRefGoogle Scholar
  48. 48.
    Lu H, Zhao Q, Wallace G, Liu S, He Y, Shattock R, Neurath AR, Jiang BS (2006) Cellulose acetate 1,2-benzenedicarboxylate inhibits infection by cell-free and cell-associated primary HIV-1 isolates. AIDS Res Hum Retroviruses 22: 411–418PubMedCrossRefGoogle Scholar
  49. 49.
    Otten RA, Adams DR, Kim CN, Jackson E, Pullium JK, Lee K, Grohskopf LA, Monsour M, Butera S, Folks TM (2005) Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates. J Infect Dis 191: 164–173PubMedCrossRefGoogle Scholar
  50. 50.
    Jiang YH, Emau P, Cairns JS, Flanary L, Morton WR, McCarthy TD, Tsai CC (2005) SPL7013 gel as a topical microbicide for prevention of vaginal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses 21: 207–213PubMedCrossRefGoogle Scholar
  51. 51.
    Herold BC, Scordi-Bello I, Cheshenko N, Marcellino D, Dzuzelewski M, Francois F, Morin R, Casullo VM, Anderson RA, Chany C 2nd et al. (2002) Mandelic acid condensation polymer: novel candidate microbicide for prevention of human immunodeficiency virus and herpes simplex virus entry. J Virol 76: 11236–11244PubMedCrossRefGoogle Scholar
  52. 52.
    Coetzer M, Cilliers T, Ping LH, Swanstrom R, Morris L (2006) Genetic characteristics of the V3 region associated with CXCR4 usage in HIV-1 subtype C isolates. Virology 356: 95–105PubMedCrossRefGoogle Scholar
  53. 53.
    Fouchier RA, Groenink M. Koostra NA, Tersmette M, Huisman HG, Miedema F, Schuitemaker H (1992) Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J Virol 66: 3183–3187PubMedGoogle Scholar
  54. 54.
    Doms RW, Trono D (2000) The plasma membrane as a combat zone in the HIV battlefield. Genes Dev 14: 2677–2688PubMedCrossRefGoogle Scholar
  55. 55.
    Vives RR, Imberty A, Sattentau QJ, Lortat-Jacob H (2005) Heparan sulfate targets the HIV-1 envelope glycoprotein gp120 coreceptor binding site. J Biol Chem 280: 21353–21357PubMedCrossRefGoogle Scholar
  56. 56.
    Shattock RJ, Doms RW (2002) AIDS models: microbicides could learn from vaccines. Nat Med 8: 425PubMedCrossRefGoogle Scholar
  57. 57.
    Roben P, Moore JP, Thali M, Sodroski J, Barbas CF 3rd, Burton DR (1994) Recognition properties of a panel of human recombinant Fab fragments to the CD4 binding site of gp120 that show differing abilities to neutralize human immunodeficiency virus type 1. J Virol 68: 4821–4828PubMedGoogle Scholar
  58. 58.
    Saphire EO, Parren PW, Pantophlet R, Zwick MB, Morris GM, Rudd PM, Dwek RA, Stanfield RL, Burton DR, Wilson IA (2001) Crystal structure of a neutralizing human IGG against HIV-1: a template for vaccine design. Science 293: 1155–1159PubMedCrossRefGoogle Scholar
  59. 59.
    Sanders RW, Venturi M, Schiffner L, Kalyanaraman R, Katinger H, Lloyd KO, Kwong PD, Moore JP (2002) The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. J Virol 76: 7293–7305PubMedCrossRefGoogle Scholar
  60. 60.
    Scanlan CN, Pantophlet R, Wormald MR, Ollmann Saphire E, Stanfield R, Wilson IA, Katinger H, Dwek RA, Rudd PM, Burton DR (2002) The broadly neutralizing anti-human immunodeficiency virus type 1 antibody 2G12 recognizes a cluster of alpha12 mannose residues on the outer face of gp120. J Virol 76: 7306–7321PubMedCrossRefGoogle Scholar
  61. 61.
    Parren PW, Burton DR (2001) The antiviral activity of antibodies in vitro and in vivo. Adv Immunol 77: 195–262PubMedGoogle Scholar
  62. 62.
    Zwick MB, Wang M, Poignard P, Stiegler G, Katinger H, Burton DR, Parren PW (2001) Neutralization synergy of human immunodeficiency virus type 1 primary isolates by cocktails of broadly neutralizing antibodies. J Virol 75: 12198–12208PubMedCrossRefGoogle Scholar
  63. 63.
    Veazey RS, Shattock RJ, Pope M, Kirijan JC, Jones J, Hu Q, Ketas T, Marx PA, Klasse PJ, Burton DR et al. (2003) Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med 9: 343–346PubMedCrossRefGoogle Scholar
  64. 64.
    Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, Hanson CE, Beary H, Hayes D, Frankel SS, Birx DL et al. (2000) Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med 6: 207–210PubMedCrossRefGoogle Scholar
  65. 65.
    Frank I, Pope M (2002) The enigma of dendritic cell-immunodeficiency virus interplay. Curr Mol Med 2: 229–248PubMedCrossRefGoogle Scholar
  66. 66.
    Huskens D, Van Laethem K, Vermeire K, Balzarini J, Schols D (2007) Resistance of HIV-1 to the broadly HIV-1-neutralizing, anti-carbohydrate antibody 2G12. Virology 360: 294–304PubMedCrossRefGoogle Scholar
  67. 67.
    Shattock RJ, Griffin GE, Gorodeski GI (2000) In vitro models of mucosal HIV transmission. Nat Med 6: 607–608PubMedCrossRefGoogle Scholar
  68. 68.
    Li M, Salazar-Gonzalez JF, Derdeyn CA, Morris L, Williamson C, Robinson JE, Decker JM, Li Y, Salazar MG, Polonis VR et al. (2006) Genetic and neutralization properties of subtype C human immunodeficiency virus type 1 molecular env clones from acute and early heterosexually acquired infections in Southern Africa. J Virol 80: 11776–11790PubMedCrossRefGoogle Scholar
  69. 69.
    Zhang MY, Xiao X, Sidorov IA, Choudhry V, Cham F, Zhang PF, Bouma P, Zwick M, Choudhary A, Montefiori DC et al. (2004) Identification and characterization of a new cross-reactive human immunodeficiency virus type 1-neutralizing human monoclonal antibody. J Virol 78: 9233–9242PubMedCrossRefGoogle Scholar
  70. 70.
    Dove A (2002) Uncorking the biomanufacturing bottleneck. Nat Biotechnol 20: 777–779PubMedCrossRefGoogle Scholar
  71. 71.
    Lederman MM, Offord RE, Hartley O (2006) Microbicides and other topical strategies to prevent vaginal transmission of HIV. Nat Rev Immunol 6: 371–382PubMedCrossRefGoogle Scholar
  72. 72.
    Gallaher WR, Ball JM, Garry RF, Martin-Amedee AM, Montelaro RC (1995) A general model for the surface glycoproteins of HIV and other retroviruses. AIDS Res Hum Retroviruses 11: 191–202PubMedCrossRefGoogle Scholar
  73. 73.
    Leonard CK, Spellman MW, Riddle L, Harris RJ, Thomas JN, Gregory TJ (1990) Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J Biol Chem 265: 10373–10382PubMedGoogle Scholar
  74. 74.
    Balzarini J (2006) Inhibition of HIV entry by carbohydrate-binding proteins. Antiviral Res 71: 237–247PubMedCrossRefGoogle Scholar
  75. 75.
    Balzarini J, Van Laethem K, Hatse S, Froeyen M, Peumans W, Van Damme E, Schols D (2005) Carbohydrate-binding agents cause deletions of highly conserved glycosylation sites in HIV GP120: a new therapeutic concept to hit the achilles heel of HIV. J Biol Chem 280: 41005–41014PubMedCrossRefGoogle Scholar
  76. 76.
    Dey B, Lerner DL, Lusso P, Boyd MR, Elder JH, Berger EA (2000) Multiple antiviral activities of cyanovirin-N: blocking of human immunodeficiency virus type 1 gp120 interaction with CD4 and coreceptor and inhibition of diverse enveloped viruses. J Virol 74: 4562–4569PubMedCrossRefGoogle Scholar
  77. 77.
    Tsai CC, Emau P, Jiang Y, Agy MB, Shattock RJ, Schmidt A, Morton WR, Gustafson KR, Boyd MR (2004) Cyanovirin-N inhibits AIDS virus infections in vaginal transmission models. AIDS Res Hum Retroviruses 20: 11–18PubMedCrossRefGoogle Scholar
  78. 78.
    Balzarini J, Van Laethem K, Peumans WJ, Van Damme EJ, Bolmstedt A, Gago F, Schols D (2006) Mutational pathways, resistance profile, and side effects of cyanovirin relative to human immunodeficiency virus type 1 strains with N-glycan deletions in their gp120 envelopes. J Virol 80: 8411–8421PubMedCrossRefGoogle Scholar
  79. 79.
    Kwong PD, Doyle ML, Casper DJ, Cicala C, Leavitt SA, Majeed S, Steenbeke TD, Venturi M, Chaiken I, Fung M et al. (2002) HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420: 678–682PubMedCrossRefGoogle Scholar
  80. 80.
    Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR et al. (2000) DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100: 587–597PubMedCrossRefGoogle Scholar
  81. 81.
    Curtis BM, Scharnowske S, Watson AJ (1992) Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Proc Natl Acad Sci USA 89: 8356–8360PubMedCrossRefGoogle Scholar
  82. 82.
    Hong PW, Flummerfelt KB, de Parseval A, Gurney K, Elder JH, Lee B (2002) Human immunodeficiency virus envelope (gp120) binding to DC-SIGN and primary dendritic cells is carbohydrate dependent but does not involve 2G12 or cyanovirin binding sites: implications for structural analyses of gp120-DC-SIGN binding. J Virol 76: 12855–12865PubMedCrossRefGoogle Scholar
  83. 83.
    Balzarini J, Van Herrewege Y, Vermeire K, Vanham G, Schols D (2007) Carbohydrate-binding agents efficiently prevent dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-directed HIV-1 transmission to T lymphocytes. Mol Pharmacol 71: 3–11PubMedCrossRefGoogle Scholar
  84. 84.
    Snyder GA, Ford J, Torabi-Parizi P, Arthos JA, Schuck P, Colonna M, Sun PD (2005) Characterization of DC-SIGN/R interaction with human immunodeficiency virus type 1 gp120 and ICAM molecules favors the receptor’s role as an antigen-capturing rather than an adhesion receptor. J Virol 79: 4589–4598PubMedCrossRefGoogle Scholar
  85. 85.
    Liu H, Hladik F, Andrus T, Sakchalathorn P, Lentz GM, Fialkow MF, Corey L, McElrath MJ, Zhu T (2005) Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms. Eur J Hum Genet 13: 707–715PubMedCrossRefGoogle Scholar
  86. 86.
    Liu H, Carrington M, Wang C, Holte S, Lee J, Greene B, Hladik F, Koelle DM, Wald A, Kurosawa K et al. (2006) Repeat-region polymorphisms in the gene for the dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin-related molecule: effects on HIV-1 susceptibility. J Infect Dis 193: 698–702PubMedCrossRefGoogle Scholar
  87. 87.
    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
  88. 88.
    Wang HG, Williams RE, Lin PF (2004) A novel class of HIV-1 inhibitors that targets the viral envelope and inhibits CD4 receptor binding. Curr Pharm Des 10: 1785–1793PubMedCrossRefGoogle Scholar
  89. 89.
    Si Z, Madani N, Cox JM, Chruma JJ, Klein JC, Schon A, Phan N, Wang L, Biorn AC, Cocklin S et al. (2004) Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proc Natl Acad Sci USA 101: 5036–5041PubMedCrossRefGoogle Scholar
  90. 90.
    Ji H, Bracken C, Lu M (2000) Buried polar interactions and conformational stability in the simian immunodeficiency virus (SIV) gp41 core. Biochemistry 39: 676–685PubMedCrossRefGoogle Scholar
  91. 91.
    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
  92. 92.
    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
  93. 93.
    Hu Q, Frank I, Williams V, Santos JJ, Watts P, Griffin GE, Moore JP, Pope M, Shattock RJ (2004) Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J Exp Med 199: 1065–1075PubMedCrossRefGoogle Scholar
  94. 94.
    Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ et al. (2005) Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 438: 99–102PubMedCrossRefGoogle Scholar
  95. 95.
    Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA (1996) CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272: 1955–1958PubMedCrossRefGoogle Scholar
  96. 96.
    Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA (1996) The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382: 829–833PubMedCrossRefGoogle Scholar
  97. 97.
    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
  98. 98.
    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
  99. 99.
    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
  100. 100.
    Berger EA, Murphy PM, Farber JM (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17: 657–700PubMedCrossRefGoogle Scholar
  101. 101.
    Clapham PR, McKnight A (2002) Cell surface receptors, virus entry and tropism of primate lentiviruses. J Gen Virol 83: 1809–1829PubMedGoogle Scholar
  102. 102.
    Hartley O, Gaertner H, Wilken J, Thompson D, Fish R, Ramos A, Pastore C, Dufour B, Cerini F, Melotti A et al. (2004) Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors. Proc Natl Acad Sci USA 101: 16460–16465PubMedCrossRefGoogle Scholar
  103. 103.
    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
  104. 104.
    Lederman MM, Veazey RS, Offord R, Mosier DE, Dufour J, Mefford M, Piatak M, Jr, Lifson JD, Salkowitz JR, Rodriguez B et al. (2004) Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 306: 485–487PubMedCrossRefGoogle Scholar
  105. 105.
    Shen DM, Shu M, Willoughby CA, Shah S, Lynch CL, Hale JJ, Mills SG, Chapman KT, Malkowitz L, Springer MS et al. (2004) Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds. Bioorg Med Chem Lett 14: 941–945Google Scholar
  106. 106.
    International AIDS Society (2007) International AIDS Society Statement on Announcement that Two Phase III Trials of HIV Microbiocide Candidate Ushercell Have Benn Halted. [accessed 2007 Mar 2]; available from Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2007

Authors and Affiliations

  • Clyde E. Hart
    • 1
  • Tammy Evans-Strickfaden
    • 1
  1. 1.Division of HIV/AIDS Prevention, Center for HIV, Viral Hepatitis, STD & TB PreventionCenters for Disease Control and PreventionAtlantaUSA

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