Advertisement

Introduction to entry inhibitors in the management of HIV infection

  • John C. Tilton
  • Robert W. Doms
Part of the Milestones in Drug Therapy book series (MDT)

Abstract

The introduction of highly active antiretroviral therapy (HAART) has dramatically improved the survival of patients infected with human immunodeficiency virus (HIV). However, HAART is complicated by the continuing emergence of drug-resistant strains of HIV and toxicities associated with the antiretroviral agents [1, 2]. Furthermore, since the combination HAART regimens are incapable of eradicating HIV infection, lifelong therapy is required to avoid disease progression [3, 4]. Together, these factors necessitate the continual development of new antiretroviral agents that can be utilized against resistant viruses or that in combination with other agents can provide superior viral suppression with less toxicity.

Keywords

Fusion Peptide Entry Inhibitor Coreceptor Usage 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lucas GM, Chaisson RE, Moore RD (1999) Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med 131: 81–87PubMedGoogle Scholar
  2. 2.
    Yerly S, Kaiser L, Race E, Bru JP, Clavel F, Perrin L (1999) Transmission of antiretroviral-drugresistant HIV-1 variants. Lancet 354: 729–733PubMedCrossRefGoogle Scholar
  3. 3.
    Chun TW, Davey RT Jr, Engel D, Lane HC, Fauci AS (1999) Re-emergence of HIV after stopping therapy. Nature 401: 874–875PubMedCrossRefGoogle Scholar
  4. 4.
    Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R et al. (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278: 1295–1300PubMedCrossRefGoogle Scholar
  5. 5.
    Starcich BR, Hahn BH, Shaw GM, McNeely PD, Modrow S, Wolf H, Parks ES, Parks WP, Josephs SF, Gallo RC, Wong-Staal F (1986) Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS. Cell 45: 637–648PubMedCrossRefGoogle Scholar
  6. 6.
    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
  7. 7.
    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: 648–659PubMedCrossRefGoogle Scholar
  8. 8.
    Huang CC, Tang M, Zhang MY, Majeed S, Montabana E, Stanfield RL, Dimitrov DS, Korber B, Sodroski J, Wilson IA et al. (2005) Structure of a V3-containing HIV-1 gp120 core. Science 310: 1025–1028PubMedCrossRefGoogle Scholar
  9. 9.
    Chen B, Vogan EM, Gong H, Skehel JJ, Wiley DC, Harrison SC (2005) Structure of an unliganded simian immunodeficiency virus gp120 core. Nature 433: 834–841PubMedCrossRefGoogle Scholar
  10. 10.
    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: 1949–1953PubMedCrossRefGoogle Scholar
  11. 11.
    Dubay JW, Roberts SJ, Brody B, Hunter E (1992) Mutations in the leucine zipper of the human immunodeficiency virus type 1 transmembrane glycoprotein affect fusion and infectivity. J Virol 66: 4748–4756PubMedGoogle Scholar
  12. 12.
    Wild C, Dubay JW, Greenwell T, Baird T Jr, Oas TG, McDanal C, Hunter E, Matthews T (1994) Propensity for a leucine zipper-like domain of human immunodeficiency virus type 1 gp41 to form oligomers correlates with a role in virus-induced fusion rather than assembly of the glycoprotein complex. Proc Natl Acad Sci USA 91: 12676–12680PubMedCrossRefGoogle Scholar
  13. 13.
    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 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci USA 91: 9770–9774PubMedCrossRefGoogle Scholar
  14. 14.
    Zhu P, Chertova E, Bess J Jr, Lifson JD, Arthur LO, Liu J, Taylor KA, Roux KH (2003) Electron tomography analysis of envelope glycoprotein trimers on HIV and simian immunodeficiency virus virions. Proc Natl Acad Sci USA 100: 15812–15817PubMedCrossRefGoogle Scholar
  15. 15.
    Zhu P, Liu J, Bess J Jr, Chertova E, Lifson JD, Grise H, Ofek GA, Taylor KA, Roux KH (2006) Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature 441: 847–852PubMedCrossRefGoogle Scholar
  16. 16.
    Trkola A, Dragic T, Arthos J, Binlay JM, Olson WC, Allaway GP, Cheng-Meyer 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
  17. 17.
    Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, Gerard C, Sodroski J (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384: 179–183PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang YJ, Dragic T, Cao Y, Kostrikis L, Kwon DS, Littman DR, KewalRamani VN, Moore JP (1998) Use of coreceptors other than CCR5 by non-syncytium-inducing adult and pediatric isolates of human immunodeficiency virus type 1 is rare in vitro. J Virol 72: 9337–9344PubMedGoogle Scholar
  19. 19.
    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: 667–673PubMedCrossRefGoogle Scholar
  20. 20.
    Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Peiper SC, Parmentier M, Collman RG, Doms RW (1996) A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 85: 1149–1158PubMedCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    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
  23. 23.
    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
  24. 24.
    Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF et al. (1996) The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382: 833–835PubMedCrossRefGoogle Scholar
  25. 25.
    Feng Y, Broder CC, Kennedy PE, Berger EA (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272: 872–877PubMedCrossRefGoogle Scholar
  26. 26.
    Basmaciogullari S, Babcock GJ, Van Ryk D, Wojtowicz W, Sodroski J (2002) Identification of conserved and variable structures in the human immunodeficiency virus gp120 glycoprotein of importance for CXCR4 binding. J Virol 76: 10791–10800PubMedCrossRefGoogle Scholar
  27. 27.
    Hoffman TL, LaBranche CC, Zhang W, Canziani G, Robinson J, Chaiken I, Hoxie JA, Doms RW (1999) Stable exposure of the coreceptor-binding site in a CD4-independent HIV-1 envelope protein. Proc Natl Acad Sci USA 96: 6359–6364PubMedCrossRefGoogle Scholar
  28. 28.
    Cormier EG, Tran DN, Yukhayeva L, Olson WC, Dragic T (2001) Mapping the determinants of the CCR5 amino-terminal sulfopeptide interaction with soluble human immunodeficiency virus type 1 gp120-CD4 complexes. J Virol 75: 5541–5549PubMedCrossRefGoogle Scholar
  29. 29.
    Cormier EG, Dragic T (2002) The crown and stem of the V3 loop play distinct roles in human immunodeficiency virus type 1 envelope glycoprotein interactions with the CCR5 coreceptor. J Virol 76: 8953–8957PubMedCrossRefGoogle Scholar
  30. 30.
    Rizzuto C, Sodroski J (2000) Fine definition of a conserved CCR5-binding region on the human immunodeficiency virus type 1 glycoprotein 120. AIDS Res Hum Retroviruses 16: 741–749PubMedCrossRefGoogle Scholar
  31. 31.
    Wu L, LaRosa G, Kassam N, Gordon CJ, Heath H, Ruffing N, Chen H, Humblias J, Samson M, Parmentier M, Moore JP, Mackay CR (1997) Interaction of chemokine receptor CCR5 with its ligands: multiple domains for HIV-1 gp120 binding and a single domain for chemokine binding. J Exp Med 186: 1373–1381PubMedCrossRefGoogle Scholar
  32. 32.
    Lee B, Sharron M, Blanpain C, Doranz BJ, Vakili J, Setoh P, Berg E, Liu G, Guy HR, Durell SR et al. (1999) Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function. J Biol Chem 274: 9617–9626PubMedCrossRefGoogle Scholar
  33. 33.
    Samson M, LaRosa G, Libert F, Paindavoine P, Detheux M, Vassart G, Parmentier M (1997) The second extracellular loop of CCR5 is the major determinant of ligand specificity. J Biol Chem 272: 24934–24941PubMedCrossRefGoogle Scholar
  34. 34.
    Platt EJ, Kuhmann SE, Rose PP, Kabat D (2001) Adaptive mutations in the V3 loop of gp120 enhance fusogenicity of human immunodeficiency virus type 1 and enable use of a CCR5 coreceptor that lacks the amino-terminal sulfated region. J Virol 75: 12266–12278PubMedCrossRefGoogle Scholar
  35. 35.
    Farzan M, Mirzabekov T, Kolchinksy P, Wyatt R, Cayabyab M, Gerard NP, Gerard C, Sodroski J, Choe H (1999) Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 96: 667–676PubMedCrossRefGoogle Scholar
  36. 36.
    Farzan M, Vasilieva N, Schnitzler CE, Chung S, Robinson J, Gerard NP, Gerard C, Choe H, Sodroski J (2000) A tyrosine-sulfated peptide based on the N terminus of CCR5 interacts with a CD4-enhanced epitope of the HIV-1 gp120 envelope glycoprotein and inhibits HIV-1 entry. J Biol Chem 275: 33516–33521PubMedCrossRefGoogle Scholar
  37. 37.
    Cormier EG, Persuh M, Thompson DA, Lin SW, Sakmar TP, Olson WC, Dragic T (2000) Specific interaction of CCR5 amino-terminal domain peptides containing sulfotyrosines with HIV-1 envelope glycoprotein gp120. Proc Natl Acad Sci USA 97: 5762–5767PubMedCrossRefGoogle Scholar
  38. 38.
    Lin G, Baribaud F, Romano J, Doms RW, Hoxie JA (2003) Identification of gp120 binding sites on CXCR4 by using CD4-independent human immunodeficiency virus type 2 Env proteins. J Virol 77: 931–942PubMedCrossRefGoogle Scholar
  39. 39.
    Lu Z, Berson JF, Chen Y, Turner JD, Zhang T, Sharron M, Jenks MH, Wang Z, Kim J, Rucker J, Hoxie JA, Peiper SC, Doms RW (1997) Evolution of HIV-1 coreceptor usage through interactions with distinct CCR5 and CXCR4 domains. Proc Natl Acad Sci USA 94: 6426–6431PubMedCrossRefGoogle Scholar
  40. 40.
    Chabot DJ, Zhang PF, Quinnan GV, Broder CC (1999) Mutagenesis of CXCR4 identifies important domains for human immunodeficiency virus type 1 X4 isolate envelope-mediated membrane fusion and virus entry and reveals cryptic coreceptor activity for R5 isolates. J Virol 73: 6598–6609PubMedGoogle Scholar
  41. 41.
    Doranz BJ, Orsini MJ, Turner JD, Hoffman TL, Berson JF, Hoxie JA, Peiper SC, Brass LF, Doms RW (1999) Identification of CXCR4 domains that support coreceptor and chemokine receptor functions. J Virol 73: 2752–2761PubMedGoogle Scholar
  42. 42.
    Abrahamyan LG, Markosyan RM, Moore JP, Cohen FS, Melikyan GB (2003) Human immunodeficiency virus type 1 Env with an intersubunit disulfide bond engages coreceptors but requires bond reduction after engagement to induce fusion. J Virol 77: 5829–5836PubMedCrossRefGoogle Scholar
  43. 43.
    Chan DC, Fass D, Berger JM, Kim PS (1997) Core structure of gp41 from the HIV envelope glycoprotein. Cell 89: 263–273PubMedCrossRefGoogle Scholar
  44. 44.
    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
  45. 45.
    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
  46. 46.
    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
  47. 47.
    Madani N, Perdigoto AL, Srinivasan K, Cox JM, Chruma JJ, LaLonde J, Head M, Smith AB 3rd, Sodroski JG (2004) Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155. J Virol 78: 3742–3752PubMedCrossRefGoogle Scholar
  48. 48.
    Balotta C, Vigano A, Riva C, Colombo MC, Salvaggio A, de Pasquale MP, Crupi L, Papagno L, Galli M, Moroni M, Principi N (1996) HIV type 1 phenotype correlates with the stage of infection in vertically infected children. AIDS Res Hum Retroviruses 12: 1247–1253PubMedCrossRefGoogle Scholar
  49. 49.
    Schuitemaker H, Koot M, Kootstra NA, Dercksen MW, de Goede RE, van Steenwijk RP, Lange JM, Schattenkerk JK, Miedema F, Tersmette M (1992) Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol 66: 1354–1360PubMedGoogle Scholar
  50. 50.
    Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR (1997) Change in coreceptor use coreceptor use correlates with disease progression in HIV-1 infected individuals. J Exp Med 185: 621–628PubMedCrossRefGoogle Scholar
  51. 51.
    Salvatori F, Scarlatti G (2001) HIV type 1 chemokine receptor usage in mother-to-child transmission. AIDS Res Hum Retroviruses 17: 925–935PubMedCrossRefGoogle Scholar
  52. 52.
    Long EM, Rainwater SM, Lavreys L, Mandaliya K, Overbaugh J (2002) HIV type 1 variants transmitted to women in Kenya require the CCR5 coreceptor for entry, regardless of the genetic complexity of the infecting virus. AIDS Res Hum Retroviruses 18: 567–576PubMedCrossRefGoogle Scholar
  53. 53.
    Casper CH, Clevestig P, Carlenor E, Leitner T, Anzen B, Lidman K, Belfrage E, Albert J, Bohlin AB, Naver L et al. (2002) Link between the X4 phenotype in human immunodeficiency virus type 1-infected mothers and their children, despite the early presence of R5 in the child. J Infect Dis 186: 914–921PubMedCrossRefGoogle Scholar
  54. 54.
    Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86: 367–377PubMedCrossRefGoogle Scholar
  55. 55.
    Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E et al. (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273: 1856–1862PubMedCrossRefGoogle Scholar
  56. 56.
    Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C et al. (1996) Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382: 722–725PubMedCrossRefGoogle Scholar
  57. 57.
    Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, Kang S, Ceradini D, Jin Z, Yazdanbakhsh K et al. (1996) The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 2: 1240–1243PubMedCrossRefGoogle Scholar
  58. 58.
    Rappaport J, Cho YY, Hendel H, Schwartz EJ, Schachter F, Zagury JF (1997) 32 bp CCR-5 gene deletion and resistance to fast progression in HIV-1 infected heterozygotes. Lancet 349: 922–923PubMedCrossRefGoogle Scholar
  59. 59.
    Michael NL, Chang G, Louie LG, Mascola JR, Dondero D, Birx DL, Sheppard HW (1997) The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat Med 3: 338–340PubMedCrossRefGoogle Scholar
  60. 60.
    Reynes J, Rouzie R, Kanouni T, Baillat V, Baroudy B, Keung A, Hogan C, Markowitz M, Laughlin M (2002) SCH C: Safety and antiviral effects of a CCR5 receptor antagonist in HIV-1 infected subjects. In: 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA. Abstract no. 1Google Scholar
  61. 61.
    Pozniak AL, Fätkenheuer G, Johnson M, Hoepelman IM, Rockstroh J, Goebel F, Abel S, James I, Rosario M, Medhurst C et al. (2003) Effect of short-term monotherapy with UK-427,857 on viral load in HIV-infected patients. In: 43rd Interscience conference on Antimicrobial Agents and Chemotherapy, Chicago, IL. Abstract no. H-443Google Scholar
  62. 62.
    Schurmann D, Rouzier R, Nougarede R, Reynes J, Fatkenheuer G, Raffi F, Michelet C, Tarral A, Hoffmann C, Kiunke J, Sprenger H, vanLier J, Sansone A, Jackson M, Lauglin M (2004) Antiviral activity of a CCR5 receptor antagonist. In: 11th Conference on Retroviruses and Opportunistic Infections. Abstract no. 140LBGoogle Scholar
  63. 63.
    Westby M, Lewis M, Whitcomb J, Youle M, Pozniak AL, James IT, Jenkins TM, Perros M., van der Ryst E (2006) Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 80: 4909–4920PubMedCrossRefGoogle Scholar
  64. 64.
    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: 182–199PubMedCrossRefGoogle Scholar
  65. 65.
    Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, Pugach P, Xu S, Wojcik L, Tagat J et al. (2002) HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci USA 99: 395–400PubMedCrossRefGoogle Scholar
  66. 66.
    Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, Alldredge L, Hunter E, Lambert D, Bolognesi D et al. (1998) Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4: 1302–1307PubMedCrossRefGoogle Scholar
  67. 67.
    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
  68. 68.
    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
  69. 69.
    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 long-term enfuvirtide treatment. New Microbiol 27: 51–61PubMedGoogle Scholar
  70. 70.
    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
  71. 71.
    Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M, Pohlmann S, Sfakianos JN, Derdeyn CA, Blumenthal R et al. (2002) Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA 99: 16249–16254PubMedCrossRefGoogle Scholar
  72. 72.
    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
  73. 73.
    Melby T, Despirito M, Demasi R, Heilek-Snyder G, Greenberg ML, Graham N (2006) HIV-1 coreceptor use in triple-class treatment-experienced patients: Baseline prevalence, correlates, and relationship to enfuvirtide response. J Infect Dis 194: 238–246PubMedCrossRefGoogle Scholar
  74. 74.
    Bleul CC, Wu L, Hoxie JA, Springer TA, Mackay CR (1997) The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci USA 94: 1925–1930PubMedCrossRefGoogle Scholar
  75. 75.
    Blaak H, van’t Wout AB, Brouwer M, Hooibrink B, Hovenkamp E, Schuitemaker H (2000) In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4(+) T cell decline. Proc Natl Acad Sci USA 97: 1269–1274PubMedCrossRefGoogle Scholar
  76. 76.
    Jamieson BD, Pang S, Aldrovandi GM, Zha J, Zack JA (1995) In vivo pathogenic properties of two clonal human immunodeficiency virus type 1 isolates. J Virol 69: 6259–6264PubMedGoogle Scholar
  77. 77.
    Berkowitz RD, Alexander S, McCune JM (2000) Causal relationships between HIV-1 coreceptor utilization, tropism, and pathogenesis in human thymus. AIDS Res Hum Retroviruses 16: 1039–1045PubMedCrossRefGoogle Scholar
  78. 78.
    Berkowitz RD, Alexander S, Bare C, Linquist-Stepps V, Bogan M, Moreno ME, Gibson L, Wieder ED, Kosek J, Stoddart CA, McCune JM (1998) CCR5-and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo. J Virol 72: 10108–10117PubMedGoogle Scholar
  79. 79.
    Berkowitz RD, van’t Wout AB, Kootstra NA, Moreno ME, Linquist-Stepps VD, Bare C, Stoddart CA, Schuitemaker H, McCune JM (1999) R5 strains of human immunodeficiency virus type 1 from rapid progressors lacking X4 strains do not possess X4-type pathogenicity in human thymus. J Virol 73: 7817–7822PubMedGoogle Scholar
  80. 80.
    Correa R, Munoz-Fernandez MA (2001) Viral phenotype affects the thymic production of new T cells in HIV-1-infected children. AIDS 15: 1959–1963PubMedCrossRefGoogle Scholar
  81. 81.
    Kaneshima H, Su L, Bonyhadi ML, Connor RI, Ho DD, McCune JM (1994) Rapid-high, syncytium-inducing isolates of human immunodeficiency virus type 1 induce cytopathicity in the human thymus of the SCID-hu mouse. J Virol 68: 8188–8192PubMedGoogle Scholar
  82. 82.
    Roos MT, Lange JM, de Goede RE, Coutinho RA, Schellekens PT, Miedema F, Tersmette M (1992) Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection. J Infect Dis 165: 427–432PubMedGoogle Scholar
  83. 83.
    van’t Wout AB, Kootstra NA, Mulder-Kampinga GA, Albrecht-van Lent N, Scherpbier HJ, Veenstra J, Boer K, Coutinho RA, Miedema F, Schuitemaker H (1994) Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J Clin Invest 94: 2060–2067CrossRefGoogle Scholar
  84. 84.
    Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, Ho DD (1993) Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261: 1179–1181PubMedCrossRefGoogle Scholar
  85. 85.
    Zhang LQ, MacKenzie P, Cleland A, Holmes EC, Brown AJ, Simmonds P (1993) Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol 67: 3345–3356PubMedGoogle Scholar
  86. 86.
    Cornelissen M, Mulder-Kampinga G, Veenstra J, Zorgdrager F, Kuiken C, Hartman S, Dekker J, van der Hoek L, Sol C, Coutinho R (1995) Syncytium-inducing (SI) phenotype suppression at seroconversion after intramuscular inoculation of a non-syncytium-inducing/SI phenotypically mixed human immunodeficiency virus population. J Virol 69: 1810–1818PubMedGoogle Scholar
  87. 87.
    Pratt RD, Shapiro JF, McKinney N, Kwok S, Spector SA (1995) Virologic characterization of primary human immunodeficiency virus type 1 infection in a health care worker following needle-stick injury. J Infect Dis 172: 851–854PubMedGoogle Scholar
  88. 88.
    Fouchier RA, Groenink M, Kootstra 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
  89. 89.
    De Jong JJ, De Ronde A, Keulen W, Tersmette M, Goudsmit J (1992) Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution. J Virol 66: 6777–6780PubMedGoogle Scholar
  90. 90.
    Shioda T, Levy JA, Cheng-Mayer C (1992) Small amino acid changes in the V3 hypervariable region of gp120 can affect the T-cell-line and macrophage tropism of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 89: 9434–9438PubMedCrossRefGoogle Scholar
  91. 91.
    de Roda Husman AM, Koot M, Cornelissen M, Keet IP, Brouwer M, Broersen SM, Bakker M, Roos MT, Prins M, de Wolf F et al. (1997) Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann Intern Med 127: 882–890Google Scholar
  92. 92.
    Karlsson A, Parsmyr K, Sandstrom E, Fenyo EM, Albert J (1994) MT-2 cell tropism as prognostic marker for disease progression in human immunodeficiency virus type 1 infection. J Clin Microbiol 32: 364–370PubMedGoogle Scholar
  93. 93.
    Maas JJ, Gange SJ, Schuitemaker H, Coutinho RA, van Leeuwen R, Margolick JB (2000) Strong association between failure of T cell homeostasis and the syncytium-inducing phenotype among HIV-1-infected men in the Amsterdam Cohort Study. AIDS 14: 1155–1161PubMedCrossRefGoogle Scholar
  94. 94.
    Richman DD, Bozzette SA (1994) The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis 169: 968–974PubMedGoogle Scholar
  95. 95.
    Scarlatti G, Tresoldi E, Bjorndal A, Fredriksson R, Colognesi C, Deng HK, Malnati MS, Plebani A, Siccardi AG, Littman DR et al. (1997) In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nat Med 3: 1259–1265PubMedCrossRefGoogle Scholar
  96. 96.
    Billick E, Seibert C, Pugach P, Ketas T, Trkola A, Endres MJ, Murgolo NJ, Coates E, Reyes GR, Baroudy BM et al. (2004) The differential sensitivity of human and rhesus macaque CCR5 to small-molecule inhibitors of human immunodeficiency virus type 1 entry is explained by a single amino acid difference and suggests a mechanism of action for these inhibitors. J Virol 78: 4134–4144PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2007

Authors and Affiliations

  • John C. Tilton
    • 1
  • Robert W. Doms
    • 1
  1. 1.Department of MicrobiologyUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations