HIV entry inhibitors: Mechanisms of action and resistance pathways

Journal of Antimicrobial Chemotherapy

Volumn 57, Issue 4, 2006, Pages 619-627

  Briz, Verónica ^a   Poveda, Eva ^a   Soriano, Vincent ^a  

^a HOSPITAL UNIVERSITARIO LA PAZ   (Spain)

Author keywords

Antivirals; CCR5; CXCR4; gp120

Indexed keywords

1 ACETYL N [3 [4 (4 CARBAMOYLBENZYL) 1 PIPERIDINYL]PROPYL] N (3 CHLORO 4 METHYLPHENYL) 4 PIPERIDINECARBOXAMIDE; 1,1' [1,4 PHENYLENEBIS(METHYLENE)]BIS(1,4,8,11 TETRAAZACYCLOTETRADECANE); 4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; AMD 070; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; ANTIVIRUS AGENT; APLAVIROC; BMS 806; CD4 ANTIGEN; CD4 IMMUNOGLOBULIN G2; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; CHEMOKINE RECEPTOR CXCR4; CHEMOKINE RECEPTOR CXCR4 ANTAGONIST; ENFUVIRTIDE; GLYCOPROTEIN GP 120; KRH 1636; KRH 2731; MARAVIROC; MOZOBIL; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; PRO 140; PROTEINASE INHIBITOR; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; SCH 350581; T LYMPHOCYTE RECEPTOR; TAK 652; TNX 355; UNCLASSIFIED DRUG; UNINDEXED DRUG; VICRIVIROC;

AMINO ACID SEQUENCE; ANTIBIOTIC RESISTANCE; ANTIBIOTIC SENSITIVITY; ANTIVIRAL ACTIVITY; CLINICAL TRIAL; CROSS RESISTANCE; DRUG APPROVAL; DRUG MECHANISM; DRUG USE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IN VITRO STUDY; INHIBITION KINETICS; LIVER TOXICITY; NONHUMAN; PROTEIN DOMAIN; QT PROLONGATION; RAT; RECEPTOR BINDING; REVIEW; TREATMENT OUTCOME; VIRUS TRANSMISSION;

DRUG RESISTANCE, VIRAL; HIV ENVELOPE PROTEIN GP120; HIV ENVELOPE PROTEIN GP41; HIV FUSION INHIBITORS; HIV INFECTIONS; HIV-1; HUMANS; PEPTIDE FRAGMENTS; RECEPTORS, CCR5; RECEPTORS, CXCR4;

EID: 33645116573     PISSN: 03057453     EISSN: 14602091     Source Type: Journal    
DOI: 10.1093/jac/dkl027     Document Type: Review

References (90)

1. Poveda E, Briz V, Soriano V. Enfuvirtide, the first fusion inhibitor to treat HIV infection. AIDS Rev 2005; 7: 139-47.
2. Dalgleish A, Beverley P, Clapham P et al. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 1984; 312: 763-7.
3. Klatzmann D, Champagne E, Chamaret S et al. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature 1984; 312: 767-8.
4. Sattentau Q, Weiss R. The CD4 antigen: Physiological ligand and HIV receptor. Cell 1988; 52, 631-3.
5. Hoxie J. Hypothetical assignment of intrachain disulfide bonds for HIV-2 and SIV envelope glycoproteins. AIDS Res Hum Retroviruses 1991; 7: 495-9.
6. Leonard C, Spellman M, Riddle L et al. Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant HIV envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J Biol Chem 1990; 265: 10373-82.
7. Madani N, Perdigoto A, Srinivasan K et al. Localized changes in the gp120 envelope glycoprotein confer resistance to HIV entry inhibitors BMS-806 and #155. J Virol 2004; 78: 3742-52.
8. Kwong P, Wyatt R, Robinson J et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998; 393: 648-59.
9. Myszka D, Sweet R, Hensley P et al. Energetics of the HIV gp120-CD4 binding reaction. Proc Natl Acad Sci USA 2000; 97: 9026-31.
10. Kwong P, Wyatt R, Majeed S et al. Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates. Structure 2000; 8: 1329-39.
11. Wyatt R, Kwong P, Desjardins E et al. The antigenic structure of the HIV gp 120 envelope glycoprotein. Nature 1998; 393: 705-11.
12. Allaway G, Davis-Bruno K, Beaudry G et al. Expression and characterization of CD4-Ig2, a novel heterotetramer that neutralizes primary HIV type 1 isolates. AIDS Res Hum Retroviruses 1995; 11: 533-9.
13. Jacobson J, Lowy I, Fletcher C et al. Single-dose safety, pharmacology and antiviral activity of the HIV type 1 entry inhibitor PRO 542 in HIV-infected adults. J Infect Dis 2000; 182: 326-9.
14. Nagashima K, Thompson D, Rosenfield S et al. HIV type 1 entry inhibitors PRO 542 and T-20 are potently synergistic in blocking virus-cell and cell fusion. J Infect Dis 2001; 183: 1121-5.
15. Moore J, Sattentau Q, Klasse P et al. A monoclonal antibody to CD4 domain 2 blocks soluble CD4-induced conformational changes in the envelope glycoproteins of HIV-1 and HIV infection of CD4+ cells. J Virol 1992; 66: 4784-93.
16. Kuritzkes D, Jacobson J, Powderly W et al. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 2004; 189: 286-91.
17. Reeves J, Piefer A. Emerging drug targets for antiretroviral therapy. Drugs 2005; 65: 1747-66.
18. Vermeire K, Bell T, Chi H et al. The anti-HIV potency of cyclotriazadisulfonamide analogs is directly correlated with their ability to down-modulate the CD4 receptor. Mol Pharmacol 2003; 63: 203-10.
19. Vermeire K, Zhang Y, Princen K et al. CADA inhibits HIV and human herpesvirus 7 replication by down-modulation of the cellular CD4 receptor. Virology 2002; 302: 342-53.
20. Lin P-F, Blair W, Wang T et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc Natl Acad Sci USA 2003; 100: 11013-8.
21. Guo Q, Ho H-T, Dicker I et al. Biochemical and genetic characterizations of a novel HIV type 1 inhibitor that blocks gp120-CD4 interactions. J Virol 2003; 77: 10528-36.
22. Lin P-H, Robinson B, Gong Y et al. Identification and characterization of a novel inhibitor of HIV-1 entry-I: Virology and resistance. In: Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 24 February 2002. Abstract 9. USA.
23. Lin P, Guo K, Fridell R et al. Identification and characterization of a novel inhibitor of HIV-1 entry-II: Mechanism of action. In: Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 24 February 2002. Abstract 10. USA.
24. Wang J, Williams R, Lin P. A novel class of HIV-1 inhibitors that targets the viral envelope and inhibits CD4 receptor binding. Curr Pharm Des 2004; 10: 1785-93.
25. Veazey R, Klasse P, Schader S et al. Protection of macaques from vaginal SHIV challenges by vaginally delivered inhibitors of virus-cell fusion. Nature 2005; 438: 99-102.
26. Moore P, Cilliers T, Mornis L. Predicted genotypic resistance to the novel entry inhibitor, BMS378806, among HIV-1 isolates of subtypes A to G. AIDS 2004; 18: 2327-30.
27. Comier E, Dragic T. The crown and stem of the V3 loop play distinct roles in HIV type 1 envelope glycoprotein interactions with the CCR5 coreceptor. J Virol 2002; 76: 8953-7.
28. Berger E, Doms R, Fenyö E et al. A new classification for HIV-1. Nature 1998; 391: 240.
29. Dragic T, Trkola A, Lin S et al. Amino-terminal substitutions in the CCR5 coreceptor impair gp120 binding and HIV type 1 entry. J Virol 1998; 72: 279-85.
30. Wu L, LaRosa G, Kassam N et al. 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 1997; 186: 1373-81.
31. Picard L, Wilkinson D, McKnight A et al. Role of the amino-terminal extracellular domain of CXCR4 in HIV type 1 entry. Virology 1997; 231: 105-11.
32. Baba M, Nishimura O, Kanzaki N et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 1999; 96: 5698-703.
33. Dragic T, Trkola A, Thompson D et al. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci USA 2000; 97: 5639-44.
34. Lizawa Y, Kanzaki N, Takashima K et al. Anti-HIV-1 activity of TAK-220, a small molecule CCR5 antagonist. In: Tenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 10-14 February 2003. Abstract 11. USA.
35. Baba M, Kanzaki N, Miyake H et al. RAK-652, a novel small molecule inhibitor of CCR5 antagonist with potent anti-HIV-1 activity. In: Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 22-25 February 2005. Abstract 541. USA.
36. Trkola A, Ketas T, Nagashima K et al. Potent, broad-spectrum inhibition of HIV type 1 by the CCR5 monoclonal antibody PRO 140. J Virol 2001; 75: 579-88.
37. Reynes J, Rouzier R, Kanouni T et al. SCH C: Safety and antiviral effects of a CCR5 receptor antagonist in HIV-1 infected subjects. In: Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 24-28 February 2002. Abstract 1. USA.
38. Strizki J, Tremblay C, Xu S et al. Discovery and characterization of vicriviroc (SCH 417690), a novel CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob Agents and Chemother 2005; 49: 4991-9.
39. Tsamis F, Gavrilov S, Kajumo F et al. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-31125 and SCH-350581 inhibit HIV type 1 entry. J Virol 2003; 77: 5201-8.
40. Dunkle L, Keung A, Sansone A et al. Vicriviroc is a novel, potent CCR5 inhibitor with pharmaceutic, pharmacokinetic and pharmacodynamic (PK/PD) properties that support once daily dosing. In: First International Workshop on Targeting HIV Entry, Bethesda MD, 2-3 December 2005. Abstract 13. USA.
41. Hitchcock C. The discovery and exploratory development of UK-427,857: A novel CCR5 antagonist for the treatment of HIV. In: Thirteenth International Symposium on HIV and Emerging Infectious Diseases, Toulon, France, 3-5 June 2004, Abstract OP 4.5.
42. De Clercq E. New approaches toward anti-HIV chemotherapy. J Med Chem 2005; 10; 241-74.
43. Fätkenheuer G, Pozniak A, Johnson M et al. Evaluation of dosing frequency and food effect on viral load reduction during short-term monotherapy with UK-427,857, a novel CCR5 antagonist. In: Fifteenth International AIDS Conference, Bangkok, Thailand, 11-16 July 2004. Abstract B4489.
44. Castonguay L, Weng Y, Adolfsen W et al. Binding of 2-aryl-4(piperidin-1yl)butanmines and 1, 3, 4-trisubstituted pyrrolidines to human CCR5: A molecular modeling-guide mutagenesis study of the binding pocket. Biochemistry 2003; 42: 1544-50.
45. Maeda K, Nakata H, Miyakawa T et al. Spirodiketopiperazine-based CCR5 inhibitor, which preserves CC chemokine/CCR5 interactions and exerts potent activity against R5 HIV type 1 in vitro. J Virol 2004; 78: 8654-62.
46. Nakata H, Maeda K, Kawano Y et al. Potent in vivo anti-R5HIV effects of AK602, a novel spirodiketopiperazine (SPD)-containing HIV-specific CCR5 inhibitor, in hu-PBMC-NOD-mice. In: Tenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 10-14 February 2003. Abstract 564a. USA.
47. Maeda K, Ogata H, Harada S et al. Determination of binding sites of a unique CCR5 inhibitor AK602/ONO-4128/ GW873140 on human CCR5. In: Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 8-11 February 2004. Abstract 540. USA.
48. Watson C, Jenkinson S, Kazmierski W et al. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric non-competitive HIV entry inhibitor. Mol Pharmacol 2003; 67: 1268-82.
49. Donzella G, Schols D, Lin S et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 1998; 4: 72-7.
50. Schols D, Claes S, De Clercq E et al. AMD-3100, a CXCR4 antagonist, reduced HIV viral load and X4 virus levels in humans. In: Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 24-28 February 2002. Abstract 2. USA
51. Schols D, Claes S, Hatse S et al. Anti-HIV activity profile of AMD070, an orally bioavailable CXCR4 antagonist. In: Sixteenth International Conference on Antiviral Research, Savannah, GA, 27 April to 1 May 2003. Abstract A39. USA.
52. Ichiyama K, Yokoyama-Kumakura S, Tanaka Y et al. A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 2003; 100: 4185-90.
53. Murakami E, Yoshida A, Kumakura S et al. KRH-2731: An orally bioavailable CXCR4 antagonist in vivo. In: Fifteenth International AIDS Conference, Bangkok, Thailand, 11-16 July 2004. Abstract LbA01.
54. Murakami T, Nakajima T, Koyanagi Y et al. A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection. J Exp Med 1997; 186: 1389-93.
55. Labrosse B, Brelot N, Heveker N et al. Determinants for sensitivity of HIV coreceptor CXCR4 to the bicyclam AMD3100. J Virol 1998; 72: 6381-8.
56. Brelot A, Heveker N, Pleskoff O et al. Role of the first and third extracellular domains of CXCR4 in HIV coreceptor activity. J Virol 1997; 71: 4744-51.
57. Trkola A, Kuhmann S, Strizki J et al. HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci USA 2002; 99: 395-400.
58. Kuhmann S, Pugach P, Kunstman K et al. Genetic and phenotypic analyses of HIV type 1 escape from a small-molecule CCR5 inhibitor. J Virol 2004; 78: 2790-807.
59. Marozsan A, Kuhmann S, Morgan T et al. Generation and properties of a HIV type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D). Virology 2005; 338: 182-99.
60. Westby M, Mori J, Smith-Burchnell D et al. Maraviroc (UK-427,857)-resistant HIV-1 variants, selected by serial passage, are sensitive to CCR5 antagonists and T-20. Antivir Ther 2005; 10: S72.
61. De Vreese K, Kofler-Mongold V, Leutgeb C et al. The molecular target of bicyclams, potent inhibitors of HIV replication. J Virol 1996; 70: 689-96.
62. Schols D, Este J, Cabrera C et al. T-cell-line tropic HIV type 1 that is made resistant to stromal cell-derived factor 1α contains mutations in the envelope gp120 but does not show a switch in coreceptor use. J Virol 1998; 72: 4032-7.
63. Westby M, Whitcomb J, Huang W et al. Reversible predominance of CXCR4 using variants in a non-responsive dual tropic patient receiving the CCR5 antagonist UK-427,857. In: Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 8-11 February 2004. Abstract 538. USA.
64. Kitrinos K, LaBranche C, Stanhope M et al. Clonal analysis detects pre-existing R5X4-tropic virus in patient demonstrating populations-level tropism shift on 873140 monotherapy. Antivir Ther 2005; 10: S68.
65. Este J, Cabrera C, Blanco J et al. Shift of clinical human immunodeficiency virus type 1 isolates from X4 to R5 and prevention of emergence of the syncytium-inducing phenotype by blockade of CXCR4. J Virol 1999; 73: 5577-85.
66. Weiss C. HIV-1 gp41: Mediator of fusion and target for inhibition. AIDS Rev 2003; 5: 214-21.
67. Wild C, Oas T, McDanal D et al. A synthetic peptide inhibitor of HIV replication: Correlation between solution structure and viral inhibition. Proc Natl Acad Sci USA 1992; 89: 10537-41.
68. Wild C, Shugars D, Greenwell T et al. Peptides corresponding to a predictive alpha-helical domain of HIV type 1 are potent inhibitors of virus infection. Proc Natl Acad Sci USA 1994; 91: 9770-4.
69. Jiang S, Li K, Strik N et al. A. HIV-1 inhibition by a peptide. Nature 1993; 365: 113.
70. Wild C, Greenwell T, Matthews T. A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus mediated cell-cell fusion. AIDS Res Hum Retroviruses 1993; 9: 1051-3.
71. Lazzarin A, Clotet B, Cooper D et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003; 348: 2186-95.
72. Lalezari J, Henry M, O'Hearn M et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003; 348: 2175-85.
73. Robertson D. US FDA approves new class of HIV therapeutics. Nat Biotechnol 2003; 21: 470-1.
74. Kilby J, Eron J. Novel therapies based on mechanisms of HIV-1 cell entry. N Engl J Med 2003; 348: 2228-38.
75. Miralles G, Lalezari J, Bellos N et al. T-1249 demonstrates potent antiviral activity over 10-day dosing in most patients who have failed a regimen containing enfuvirtide: Planned interim analysis of T1249-102, a phase I/II study. In: Tenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 10-14 February 2003. Abstract 14Ib.
76. Melby T, Zhang Y, Cammack N et al. Genotypic and phenotypic evolution of virus envelope through 48 weeks of T-1249 treatment in the T1249-105 study. Antivir Ther 2005; 10: S76.
77. Rimsky L, Shugars D, Matthews T. Determinants of HIV type 1 resistance to gp41-derived inhibitors peptides. J Virol 1998; 78: 986-93.
78. Wei X, DeckerJ, Liu H et al. Emergence of resistant HIV-1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 2002; 46: 1896-905.
79. Sista P, Melby T, Davison D et al. Characterization of determinants of genotypic and phenotypic resistance to enfuvirtide in baseline and on-treatment HIV-1 isolates. AIDS 2004; 18: 1787-94.
80. Poveda E, Rodés B, Labernardière JL et al. Evolution of genotypic and phenotypic resistance to enfuvirtide in HIV-infected patients experiencing prolonged virologic failure. J Med Virol 2004; 74: 21-8.
81. Poveda E, Rodés B, Lebel-Binay S et al. Dynamics of enfuvirtide resistance in HIV-infected patients during and after long-term enfuvirtide salvage therapy. J Clin Virol 2005; 34: 295-301.
82. Labrosse B, Labernardière J, Dam E et al. Baseline susceptibility of primary HIV-1 to entry inhibitors. J Virol 2003; 77: 1610-3.
83. Stanfield-Oakley S, Jefrey J, McDanal C et al. Determinants of susceptibility to enfuvirtide map to gp41 in enfuvirtide-naive HIV-1. Antivir Ther 2003; 8: S22.
84. Xu L, Pozniak A, Wildfire A et al. Evolution of HR1 and HR2 mutations in HIV-1 gp41 associated with long-term enfuvirtide therapy. In: Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 8-11 February 2004. Abstract 659. USA.
85. Cabrera C, García E, Marfil S et al. Resistance to enfuvirtide (ENF) proceeds through selection of mutations in gp41 and gp120. In: Fourteenth International HIV Drug Resistance Workshop, Quebec, Canada, 7-11 June 2005. Abstract 167.
86. Xu L, Pozniak A, Wildfire A et al. Emergence and evolution of enfuvirtide following long-term therapy involves heptad repeat 2 mutations within gp41. Antimicrob Agents Chemother 2005; 49: 1113-9.
87. Derdeyn C, Decker J, Sfakianos J et al. Sensitivity of HIV 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 2001; 75: 8605-14.
88. Reeves J, Gallo S, Ahmad N et al. Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA 2002; 99: 16249-54.
89. Whitcomb J, Huang W, Fransen S et al. Analysis of baseline enfuvirtide (T-20) susceptibility and co-receptor tropism in two phase III study populations. In: Tenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 10-14 February 2003. Abstract 557. USA.
90. Su C, Heilek-Snyder G, Fenger D et al. The relationship between susceptibility to enfuvirtide of baseline viral recombinants and polymorphisms in the env region of R5-tropic HIV-1. Antivir Ther 2003; 8: S59.