Targeting chemokine receptors in HIV: A status report

Annual Review of Pharmacology and Toxicology

Volumn 48, Issue , 2008, Pages 425-461

  Kuhmann, Shawn E ^a   Hartley, Oliver ^b  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

^b UNIVERSITY OF GENEVA MEDICAL SCHOOL   (Switzerland)

Author keywords

CCR5; Coreceptor; Microbicide; Prevention; Resistance; Therapy

Indexed keywords

1 ACETYL N [3 [4 (4 CARBAMOYLBENZYL) 1 PIPERIDINYL]PROPYL] N (3 CHLORO 4 METHYLPHENYL) 4 PIPERIDINECARBOXAMIDE; 4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; 4 [1 [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4 METHYL 4 PIPERIDINYL] 2 METHYL 1 [1 [4 (TRIFLUOOROMETHYL)PHENYL]ETHYL]PIPERAZINE; 8 [(4 AMINOBUTYL)(2 BENZIMIDAZOLYLMETHYL)AMINO] 1,2,3,4 TETRAHYDROQUINOLINE; 8 [4 (2 BUTOXYETHOXY)PHENYL] 1,2,3,4 TETRAHYDRO 1 ISOBUTYL N [4 (1 PROPYL 1H IMIDAZOL 5 YLMETHYLSULFINYL)PHENYL] 1 BENZAZOCINE 5 CARBOXAMIDE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; APLAVIROC; CHEMOKINE RECEPTOR; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; CHEMOKINE RECEPTOR CXCR4; MARAVIROC; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY 004; N [3 [4 (3 BENZYL 1 ETHYL 5 PYRAZOLYL) 1 PIPERIDINYLMETHYL] 4 (3 FLUOROPHENYL)CYCLOPENTYL] N METHYLVALINE; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; NONOXINOL 9; PLERIXAFOR; PRO 140; VICRIVIROC;

BINDING SITE; CLINICAL TRIAL; DEVELOPING COUNTRY; DRUG BIOAVAILABILITY; DRUG COST; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG STABILITY; DRUG USE; DRUG WITHDRAWAL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IN VITRO STUDY; LIVER TOXICITY; MUTANT; NONHUMAN; PHYSIOLOGY; PRIORITY JOURNAL; REVIEW; RNA INTERFERENCE; UNITED STATES; VIRUS CELL INTERACTION; VIRUS TRANSMISSION; ANTIVIRAL RESISTANCE; DRUG ANTAGONISM; DRUG EFFECT; HUMAN IMMUNODEFICIENCY VIRUS 1; METABOLISM;

ANTI-HIV AGENTS; DRUG DELIVERY SYSTEMS; DRUG RESISTANCE, VIRAL; HIV INFECTIONS; HIV-1; HUMANS; RECEPTORS, CCR5; RECEPTORS, CXCR4;

EID: 41149178257     PISSN: 03621642     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.48.113006.094847     Document Type: Review

References (159)

1. UNAIDS/WHO. 2006. AIDS Epidemic Update. Geneva, Switz.: UNAIDS/WHO
2. Hammer SM, Saag MS, Schechter M, Montaner JS, Schooley RT, et al. 2006. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA 296:827-43
3. Stephenson J. 2007. Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus. JAMA 297:1535-36
4. Food Drug Adm. (FDA), Center Drug Eval. Res. 2007. Summary Minutes of the Antiviral Drugs Advisory Comm. Meet.
5. Quinn TC, Overbaugh J. 2005. HIV/AIDS in women: an expanding epidemic. Science 308:1582-83
6. Ruxin J, Paluzzi JE, Wilson PA, Tozan Y, Kruk M, Teklehaimanot A. 2005. Emerging consensus in HIV/AIDS, malaria, tuberculosis, and access to essential medicines. Lancet 365:618-21
7. 2007. Newer approaches to HIV prevention. Lancet 369:615
8. Shattock RJ, Moore JP. 2003. Inhibiting sexual transmission of HIV-1 infection. Nat. Rev. Microbiol. 1:25-34
9. Grant RM, Buchbinder S, Cates W Jr, Clarke E, Coates T, et al. 2005. AIDS. Promote HIV chemoprophylaxis research, don't prevent it. Science 309:2170-71
10. Lederman MM, Penn-Nicholson A, Cho M, Mosier D. 2006. Biology of CCR5 and its role in HIV infection and treatment. JAMA 296:815-26
11. O'Hara BM, Olson WC. 2002. HIV entry inhibitors in clinical development. Curr. Opin. Pharmacol. 2:523-28
12. Gallo SA, Finnegan CM, Viard M, Raviv Y, Dimitrov A, et al. 2003. The HIV env-mediated fusion reaction. Biochim. Biophys. Acta 1614:36-50
13. Huang CC, Tang M, Zhang MY, Majeed S, Montabana E, et al. 2005. Structure of a V3-containing HIV-1 gp120 core. Science 310:1025-28
14. Chen B, Vogan EM, Gong H, Skehel JJ, Wiley DC, Harrison SC. 2005. Structure of an unliganded simian immunodeficiency virus gp120 core. Nature 433:834-41
15. Cocchi F, DeVico AL, Garzino-Demo A, Cara A, Gallo RC, Lusso P. 1996. The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nat. Med. 2:1244-47
16. Rizzuto CD, Wyatt R, Hernandez-Ramos N, Sun Y, Kwong PD, et al. 1998. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 280:1949-53
17. Weiss CD. 2003. HIV-1 gp41: mediator of fusion and target for inhibition. AIDS Rev. 5:214-21
18. + T cells [see comments]. Science 270:1811-15
19. 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 272:872-77
20. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, 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 382:833-35
21. Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, et al. 1996. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382:829-33
22. Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, et al. 1996. CC CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272:1955-58
23. Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, et al. 1996. The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85:1135-48
24. Deng FI, Liu R, Ellmeier W, Choe S, Unutmaz D, et al. 1996. Identification of a major coreceptor for primary isolates of HIV-1. Nature 381:661-66
25. + cells is mediated by the chemokine receptor CC-CKR-5. Nature 381:667-73
26. Berger EA, Murphy PM, Farber JM. 1999. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 17:657-700
27. Moore JP, Kitchen SG, Pugach P, Zack JA. 2004. The CCR5 and CXCR4 coreceptors-central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res. Hum. Retrovir. 20:111-26
28. Berger EA, Doms RW, Fenyo EM, Korber BT, Littman DR, et al. 1998. A new classification for HIV-1. Nature 391:240
29. Whitcomb JM, Fluang W, Fransen S, Limoli K, Toma J, et al. 2007. Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism. Antimicrob. Agents Chemother. 51:566-75
30. Spudich SS, Huang W, Nilsson AC, Petropoulos CJ, Liegler TJ, et al. 2005. HIV-1 chemokine coreceptor utilization in paired cerebrospinal fluid and plasma samples: a survey of subjects with viremia. J Infect. Dis. 191:890-98
31. Hartley O, Klasse PJ, Sattentau OJ, Moore JP. 2005. V3: HIV's Switch-Hitter. AIDS Res. Hum. Retrovir. 21:171-89
32. Zhang Y, Moore JP. 1999. Will multiple coreceptors need to be targeted by inhibitors of human immunodeficiency virus type 1 entry? J. Virol. 73:3443-48
33. Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. 1997. Change in coreceptor use correlates with disease progression in HIV-1-infected individuals. J. Exp. Med. 185:621-28
34. Margolis L, Shattock R. 2006. Selective transmission of CCR5-utilizing HIV-1: the 'gatekeeper' problem resolved? Nat. Rev. Microbiol. 4:312-17
35. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, et al. 1996. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86:367-77
36. Martinson JJ, Chapman NH, Rees DC, Liu YT, Clegg JB. 1997. Global distribution of the CCR5 gene 32-basepair deletion. Nat. Genet. 16:100-3
37. Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, et al. 1996. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat. Med. 2:1240-43
38. Dean M, Carrington M, Winkler C, Hutdey GA, Smith MW, et al. 1996. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemoph. Growth Dev. Study, Multicent. AIDS Cohort Study, Multicent. Hemoph. Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:1856-62. Erratum. 1996. Science 274(5290):1069
39. Zimmerman PA, Buckler-White A, Alkhatib G, Spalding T, Kubofcik J, et al. 1997. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol. Med. 3:23-36
40. Salkowitz JR, Purvis SF, Meyerson H, Zimmerman P, O'Brien TR, et al. 2001. Characterization of high-risk HIV-1 seronegative hemophiliacs. Clin. Immunol. 98:200-11
41. Michael NL, Chang G, Louie LG, Mascola JR, Dondero D, et al. 1997. The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat. Med. 3:338-40
42. Gorry PR, Zhang C, Wu S, Kunstman K, Trachtenberg E, et al. 2002. Persistence of dual-tropic HIV-1 in an individual homozygous for the CCR5Δ32 allele. Lancet 359:1832-34
43. Michael NL, Nelson JA, KewalRamani VN, Chang G, O'Brien SJ, et al. 1998. Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5δ32. J. Virol. 72:6040-47
44. Naif HM, Cunningham AL, Alali M, Li S, Nasr N, et al. 2002. A human immunodeficiency virus type 1 isolate from an infected person homozygous for CCR5Δ32 exhibits dual tropism by infecting macrophages and MT2 cells via CXCR4. J. Virol. 76:3114-24
45. Sheppard HW, Celum C, Michael NL, O'Brien S, Dean M, et al. 2002. HIV-1 infection in individuals with the CCR5-Δ32/Δ32 genotype: acquisition of syncytium-inducing virus at seroconversion. J. Acquired Immune Defic. Syndr. 29:307-13
46. Shankarappa R, Margolick JB, Gange SJ, Rodrigo AG, Upchurch D, et al. 1999. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J. Virol. 73:10489-502
47. Brumme ZL, Brumme CJ, Henrick BM, et al. 2005. Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral- naïve individuals. J. Infect. Dis. 192:466-74
48. Moyle GJ, Wildfire A, Mandalia S, Mayer H, Goodrich J, et al. 2005. Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection. J. Infect. Dis. 191:866-72
49. Coakley E, Benhamida J, Chappey C, Whitcomb J, Goodrich J, et al. 2006. An evaluation of tropism profiles and other characteristics among 3988 individuals screened for the A4001026, A4001027 (motivate 1) and A4001028 (motivate 2) studies for maraviroc. Presented at Int. Worksh. Target. HIV Entry, 2nd, Boston, MA
50. Gulick RM, Su Z, Flexner C, Hughes MD, Skolnik PR, et al. 2007. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS clinical trial group 5211. J. Infect. Dis. 196:304-12
51. Melby T, Despirito M, Demasi R, Greenberg M, Heilek-Snyder G, Graham N. 2006. HIV-1 coreceptor tropism in triple-class-expe?ienced patients: baseline correlates and relationship to enfuvirtide response. Presented at 13 th Conf. Retrovir. Oppor. Infect., Denver, CO
52. Wilkin T, Su Z, Kuritzkes D, Hughes M, Flexner C, et al. 2006. Co-receptor tropism in patients screening for ACTG 5211, a phase 2 study of vicriviroc, a CCR5 inhibitor. Presented at 13th Conf. Retrovir. Oppor. Infect., Denver, CO
53. Ioannidis JP, Rosenberg PS, Goedert JJ, Ashton LJ, Benfield TL, et al. 2001. Effects of CCR5-Δ32, CCR2-641, and SDF-1 3′A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data. Ann. Intern. Med. 135:782-95
54. + T cell depletion in HIV-1-infected human lymphoid tissue. Proc. Natl. Acad. Sci. USA 96:663-68
55. Arthos J, Cicala C, Selig SM, White AA, Ravindranath HM, et al. 2002. The role of the CD4 receptor vs HIV coreceptors in envelope-mediated apoptosis in peripheral blood mononuclear cells. Virology 292:98-106
56. Kwa D, Vingerhoed J, Boeser-Nunnink B, Broersen S, Schuitemaker H. 2001. Cytopathic effects of nonsyncytium-inducing and syncytium-inducing human immunodeficiency virus type 1 variants on different CD4(+)-T-cell subsets are determined only by coreceptor expression. J. Virol. 75:10455-59
57. + T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques. Proc. Natl. Acad. Sci. USA 102:8000-5
58. + T cell subsets in rhesus monkeys, explaining their divergent clinical courses. Proc. Natl. Acad. Sci. USA 101:12324-29
59. Douek DC. 2003. Disrupting T-cell homeostasis: how HIV-1 infection causes disease. AIDS Rev. 5:172-77
60. Murphy PM. 2002. International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol. Rev. 54:227-29
61. 2003. Chemokine/chemokine receptor nomenclature. Cytokine 21:48-49
62. de Silva E, Stumpf MP. 2004. HIV and the CCR5-Δ32 resistance allele. FEMS Microbiol. Lett. 241:1-12
63. Fry J, Bogulavsky Grossman J. 2007. Collaborative Approaches to HIV Drug Development: Planning for Long-Term Monitoring of Safety in CCR5 Antagonist Development, ed. V Miller. Rep. FDA/FCHR Jt. Public Meet. Washington, DC: Forum Collab. HIV Res.
64. Murdoch C. 2000. CXCR4: chemokine receptor extraordinaire. Immunol. Rev. 177:175-84
65. Baggiolini M, Moser B. 1997. Blocking chemokine receptors. J. Exp. Med. 186:1189-91
66. Endres MJ, Clapham PR, Marsh M, Ahuja M, Turner JD, et al. 1996. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell 87:745-56
67. Hendrix CW, Collier AC, Lederman MM, Schols D, Pollard RB, et al. 2004. Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J. Acquired Immune Defic. Syndr. 37:1253-62
68. Stone ND, Dunaway SB, Flexner CW, Tierney C, Calandra GB, et al. 2007. Multiple dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects (ACTG A5191). Antimicrob. Agents Chemother. 51:2351-58
69. Klasse PJ, Shattock RJ, Moore JP. 2006. Which topical microbicides for blocking HIV-1 transmission will work in the real world? PLoS Med. 3:e351
70. Lederman MM, Offord RE, Hartley O. 2006. Microbicides and other topical strategies to prevent vaginal transmission of HIV. Nat. Rev. Immunol. 6:371-82
71. Weber J, Desai K, Darbyshire J. 2005. The development of vaginal microbicides for the prevention of HIV transmission. PLoS Med. 2:e142
72. Hillier SL, Moench T, Shattock R, Black R, Reichelderfer P, Veronese F. 2005. In vitro and in vivo: the story of nonoxynol 9. J. Acquired Immune Defic. Syndr. 39:1-8
73. Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, et al. 2005. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307:1434-40
74. Nardese V, Longhi R, Polo S, Sironi F, Arcelloni C, et al. 2001. Structural determinants of CCR5 recognition and HIV-1 blockade in RANTES. Nat. Struct. Biol. 8:611-15
75. Schmidtmayerova H, Sherry B, Bukrinsky M. 1996. Chemokines and HIV replication. Nature 382:767
76. Hartley O, Offord RE. 2005. Engineering chemokines to develop optimized HIV inhibitors. Curr. Protein Pept. Sci. 6:207-19
77. Arenzana-Seisdedos F, Virelizier JL, Rousset D, Clark-Lewis I, Loetscher P, et al. 1996. HIV blocked by chemokine antagonist. Nature 383:400
78. Gong JH, Uguccioni M, Dewald B, Baggiolini M, Clark-Lewis I. 1996. RANTES and MCP-3 antagonists bind multiple chemokine receptors. J. Biol. Chem. 271:10521-27
79. Simmons G, Clapham PR, Picard L, Offord RE, Rosenkilde MM, et al. 1997. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276:276-79
80. Trkola A, Paxton WA, Monard SP, Hoxie JA, Siani MA, et al. 1998. Genetic subtype-independent inhibition of human immunodeficiency virus type 1 replication by CC and CXC chemokines. J. Virol. 72:396-404
81. Amara A, Gall SL, Schwartz O, Salamero J, Montes M, et al. 1997. HIV coreceptor downregulation as antiviral principle: SDF-1alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. J. Exp. Med. 186:139-46
82. Alkhatib G, Locati M, Kennedy PE, Murphy PM, Berger EA. 1997. HIV-1 coreceptor activity of CCR5 and its inhibition by chemokines: independence from G protein signaling and importance of coreceptor downmodulation. Virology 234:340-48
83. Ferguson SS. 2001. Evolving concepts in G protein-coupled receptor endocytosis: The role in receptor desensitization and signaling. Pharmacol. Rev. 53:1-24
84. Hartley O, Gaertner H, Wilken J, Thompson D, Fish R, et al. 2004. Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors. Proc. Natl. Acad. Sci. USA 101:16460-65
85. Sabbe R, Picchio GR, Pastore C, Chaloin O, Hartley O, et al. 2001. Donor-and ligand-dependent differences in C-C chemokine receptor 5 reexpression. J. Virol. 75:661-71
86. Mack M, Luckow B, Nelson PJ, Cihak J, Simmons G, et al. 1998. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J. Exp. Med. 187:1215-24
87. Oppermann M, Mack M, Proudfoot AE, Olbrich H. 1999. Differential effects of CC chemokines on CC chemokine receptor 5 (CCR5) phosphorylation and identification of phosphorylation sites on the CCR5 carboxyl terminus. J. Biol. Chem. 274:8875-85
88. Proudfoot AE, Handel TM, Johnson Z, Lau EK, LiWang P, et al. 2003. Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc. Natl. Acad. Sci. USA 100:1885-90
89. Moore JP. 2005. Topical microbicides become topical. N. Engl. J. Med. 352:298-300
90. Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, et al. 1999. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA 96:5698-703
91. Castonguay LA, Weng Y, Adolfsen W, Di Salvo J, Kilburn R, et al. 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 42:1544-50
92. Dragic T, Trkola A, Thompson DA, Cormier EG, Kajumo FA, et al. 2000. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc. Natl. Acad. Sci. USA 97:5639-44
93. Nishikawa M, Takashima K, Nishi T, Furuta RA, Kanzaki N, et al. 2005. Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5. Antimicrob. Agents Chemother. 49:4708-15
94. Tsamis F, Gavrilov S, Kajumo F, Seibert C, Kuhmann S, et al. 2003. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-3,51,125 and SCH-3,50,581 inhibit human immunodeficiency virus type 1 entry. J. Virol. 77:5201-8
95. Seibert C, Ying W, Gavrilov S, Tsamis F, Kuhmann SE, et al. 2006. Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Virology 349:41-54
96. Maeda K, Das D, Ogata-Aoki H, Nakata H, Miyakawa T, et al. 2 006. Structural and molecular interactions of CCR5 inhibitors with CCR5. J. Biol. Chem. 281:12688-98
97. Watson C, Jenkinson S, Kazmierski W, Kenakin T. 2005.The CCR5 receptor-based mechanism of action of 8,73,140, a potent allosteric noncompetitive HIV entry inhibitor. Mol. Pharmacol. 67:1268-82
98. May LT, Leach K, Sexton PM, Christopoulos A. 2007. Mlosteric modulation of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 47:1-51
99. Billick E, Seibert C, Pugach P, Ketas T, Trkola A, 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. 78:4134-44
100. Maeda K, Nakata H, Koh Y, Miyakawa T, Ogata H, et al. 2004. 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. 78:8654-62
101. Mascelli MA, Zhou H, Sweet R, Getsy J, Davis HM, et al. 2007. Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: impact of these parameters on early clinical development. J. Clin. Pharmacol. 47:553-65
102. Olson WC, Rabut GE, Nagashima KA, Tran DN, Anselma DJ, et al. 1999. Differential inhibition of human immunodeficiency virus type 1 fusion, gp120 binding, and CC-chemokine activity by monoclonal antibodies to CCR5. J. Virol. 73:4145-55
103. Lee B, Sharron M, Blanpain C, Doranz BJ, Vakili J, 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. 274:9617-26
104. Wu L, LaRosa G, Kassam N, Gordon CJ, Heath H, et al. 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. 186:1373-81
105. Ji C, Brandt M, Dioszegi M, Jekle A, Schwoerer S, et al. 2007. Novel CCR5 monoclonal antibodies with potent and broad-spectrum anti-HIV activities. Antiviral Res. 74:125-37
106. Safarian D, Carnec X, Tsamis F, Kajumo F, Dragic T. 2006. An anti-CCR5 monoclonal antibody and small molecule CCR5 antagonists synergize by inhibiting different stages of human immunodeficiency virus type 1 entry. Virology 352:477-84
107. Zhang J, Rao E, Dioszegi M, Kondru R, DeRosier A, et al. 2007. The second extracellular loop of CCR5 contains the dominant epitopes for highly potent antihuman immunodeficiency virus monoclonal antibodies. Antimicrob. Agents Chemother. 51:1386-97
108. Roschke V, Clark S, Branco L, Kanakaraj P, Kaufman T, et al. 2004. Characterization of a panel of novel human monoclonal antibodies that specifically antagonize CCR5 and block HIV entry. Presented at 44th Annu. Intersci. Conf. Antimicrob. Agents Chemother., Washington, DC
109. Olson WC, Tsurushita N, Hinton PR, Xiong J, Ketas TJ, et al. 2002. Potent, broad-spectrum inhibition of HIV-1 entry with the humanized monoclonal antibody PRO 140. Presented at XIV Int. AIDS Conf., Barcelona, Spain
110. Stoger E, Sack M, Nicholson L, Fischer R, Christou P. 2005 Recent progress in plantibody technology. Curr Pharm Des 11:2439-57
111. van de Laar T, Visser C, Holster M, Lopez CG, Kreuning D, et al. 2007. Increased heterologous protein production by Saccharomyces cerevisiae growing on ethanol as sole carbon source. Biotechnol. Bioeng. 96:483-94
112. Hannon GJ. 2002. RNA interference. Nature 418:244-51
113. Dykxhoorn DM, Lieberman J. 2005. The silent revolution: RNA interference as basic biology, research tool, and therapeutic. Annu. Rev. Med. 56:401-23
114. Kitabwalla M, Ruprecht RM. 2002. RNA interference-a new weapon against HIV and beyond. N. Engl. J. Med. 347:1364-67
115. Song E, Lee SK, Dykxhoorn DM, Novina C, Zhang D, et al. 2003. Sustained small interfering RNA-mediated human immunodeficiency virus type 1 inhibition in primary macrophages. J. Virol. 77:7174-81
116. Qin XF, An DS, Chen IS, Baltimore D. 2003. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc. Natl. Acad. Sci. USA 100:183-88
117. Richman DD. 2 006. Antiviral drug resistance. Antiviral Res. 71:117-21
118. Pantophlet R, Burton DR. 2006. GP120: target for neutralizing HIV-1 anti-bodies. Annu. Rev. Immunol. 24:739-69
119. Frost SD, Wrin T, Smith DM, Kosakovsky Pond SL, et al. 2005. Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection. Proc. Natl. Acad. Sci. USA 102:18514-19
120. Wei X, Decker JM, Wang S, Hui H, Kappes JC, et al. 2003. Antibody neutralization and escape by HIV-1. Nature 422:307-12
121. Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, et al. 2002. HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc. Natl. Acad. Sci. USA 99:395-400
122. Marozsan AJ, Kuhmann SE, Morgan T, Herrera C, Rivera-Troche E, et al. 2005. Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-4,17,690 (SCH-D). Virology 338:182-99
123. Westby M, Smith-Burchnell C, Mori J, Lewis M, Mosley M, et al. 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. 81:2359-71
124. Baba M, Miyake H, Wang X, Okamoto M, Takashima K. 2007. Isolation and characterization of human immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652. Antimicrob. Agents Chemother. 51:707-15
125. Pastore C, Nedellec R, Ramos A, Hartley O, Miamidian JL, et al. 2007. Conserved changes in envelope function during human immunodeficiency virus type 1 coreceptor switching. J. Virol. 81:8165-79
126. Pastore C, Ramos A, Mosier DE. 2004. Intrinsic obstacles to human immunodeficiency virus type 1 coreceptor switching. J. Virol. 78:7565-74
127. Mosier DE, Picchio GR, Gulizia RJ, Sabbe R, Poignard P, et al. 1999. Highly potent RANTES analogues either prevent CCR5-using human immunodeficiency virus type 1 infection in vivo or rapidly select for CXCR4-using variants. J. Virol. 73:3544-50
128. Speck RF, Wehrly K, Platt EJ, Atchison RE, Charo IF, et al. 1997. Selective employment of chemokine receptors as human immunodeficiency virus type 1 coreceptors determined by individual amino acids within the envelope V3 loop. J. Virol. 71:7136-39
129. Wolinsky SM, Veazey RS, Kunstman KJ, Klasse PJ, Dufour J, et al. 2004. Effect of a CCR5 inhibitor on viral loads in macaques dual-infected with R5 and X4 primate immunodeficiency viruses. Virology 328:19-29
130. 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 361:212-28
131. Pastore C, Picchio GR, Galimi F, Fish R, Hartley O, et al. 2003. Two mechanisms for human immunodeficiency virus type 1 inhibition by N-terminal modifications of RANTES. Antimicrob. Agents Chemother. 47:509-17
132. Ramjee G, Shattock R, Delany S, McGowan I, Morar N, Gottemoeller M. 2006. Microbicides 2006 conference. AIDS Res. Ther. 3:25
133. Johnson VA, Brun-Vezinet F, Clotet B, Conway B, Kuritzkes DR, et al. 2005. Update of the drug resistance mutations in HIV-1: 2005. Top. HIV Med. 13:51-57
134. Fatkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, et al. 2005. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat. Med. 11:1170-72
135. Lalezari J, Thompson M, Kumar P, Piliero P, Davey R, et al. 2005. Antiviral activity and safety of 8,73,140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults. AIDS 19:1443-48
136. Schuermann D, Pechardscheck C, Rouzier R, Nougarede R, Faetkenheuer G, et al. 2005. SCH 4,17,690: antiviral activity of a potent new CCR5 receptor antagonist. Presented at 3rd Int. AIDS Soc. Conf. HIV Pathog. Treatm., Rio de Janeiro, Brazil
137. Crabb C. 2006. GlaxoSmithKline ends aplaviroc trials. AIDS 20:641
138. Greaves W, Landovitz R, Fatkenheuer G, Hoffmann C, Antunes F, et al. 2006. Late virologic breakthrough in treatment-naïve patients on a regimen of Combivir + vicriviroc. Presented at 13th Conf. Retrovir. Oppor. Infect., Denver, CO
139. Mayer H. 2005. A case of severe hepatotoxicity. Presented at 1st Int. Workshop Target. HIV Entry, Bethesda, MD
140. Pfizer Inc. 2007. Maraviroc tablets NDA 22-128. Antiviral Drugs Advisory Committee (AVDAC) Brief. Doc., April 24
141. 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. 50:3289-96
142. Ji C, Zhang J, Dioszegi M, Chiu S, Rao E, et al. 2007. CCR5 small molecule antagonists and monoclonal antibodies exert potent synergistic antiviral effects by co-binding to the receptor. Mol. Pharmacol. 72:18-28
143. Roche. 2007. Fuzeon prescribing information. http://www.rocheusa.com/ products/fuzeon
144. Veazey RS, Klasse PJ, Ketas TJ, Reeves JD, Piatak M Jr, et al. 2003. Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian-human immunodeficiency virus infection. J. Exp. Med. 198:1551-62
145. Davis CW, Doms RW. 2004. HIV Transmission: Closing all the doors. J. Exp. Med. 199:1037-40
146. Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, et al. 2005. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 438:99-102
147. Lederman MM, Veazey RS, Offord R, Mosier DE, Dufour J, et al. 2004. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 306:485-87
148. 2006. Int. Meet. Inst. Hum. Virol., Baltimore, Md., 17-21 Nov. Retrovirology 3(Suppl. 1):S1-109, P1-79 (Abstr.)
149. Veazey RS, Springer MS, Marx PA, Dufour J, Klasse PJ, Moore JP. 2005. Protection of macaques from vaginal SHIV challenge by an orally delivered CCR5 inhibitor. Nat. Med. 11:1293-94
150. Turner D, Weinberg MA. 2006. HIV transmission and primary drug resistance. AIDS Rev. 8:17-23
151. 2005. Merck and Bristol-Myers Squibb License New AIDS Drugs to IPM for Development as Microbicides to Protect Women from HIV. http://www.ipm- microbicides.org/news_room/english/press_releases/2005/2005_1031_bms.htm
152. Takashima K, Miyake H, Kanzaki N, Tagawa Y, Wang X, et al. 2005. Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonist. Antimicrob. Agents Chemother. 49:3474-82
153. Baba M, Takashima K, Miyake H, Kanzaki N, Teshima K, et al. 2005. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob. Agents Chemother. 49:4584-91
154. Strizki JM, Xu S, Wagner NE, Wojcik L, Liu J, et al. 2001. SCH-C (SCH 3,51,125), 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 98:12718-23
155. Strizki JM, Tremblay C, Xu S, Wojcik L, Wagner N, et al. 2005. Discovery and characterization of vicriviroc (SCH 4,17,690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 49-4911-19
156. Kuhmann SE, Pugach P, Kunstman KJ, Taylor J, Stanfield RL, et al. 2004. Genetic and phenotypic analyses of human immunodeficiency virus type 1 escape from a small-molecule CCR5 inhibitor. J. Virol. 78:2790-807
157. Westby M, Mori J, Smith-Burchnell C, Lewis M, Mosley M, et al. 2005. Maraviroc (MVC, UK-4,27,857)-resistant HIV-1 variants, selected by serial passage, are sensitive to CCR5 antagonists (GW873140, Schering-C, Schering-D) and T-20 (enfuvirtide). Presented at XIV Int. Drug Resist. Workshop, Québec City, Can.
158. Progenies. 2007. Progenies announces positive results in clinical trial of novel HIV therapy. Press release, May 1
159. Lalezari J, Lederman M, Yadavalli G, Para M, DeJesus E, et al. 2006. A phase 1, dose-escalation, placebo controlled study of a fully human monoclonal antibody (CCR5m.Ab004) against CCR5 in patients with CCR5 tropic HIV-1 infection. Presented at 46th Int. Conf. Antimicrob. Agents Chemother., San Francisco, CA