A common mechanism of clinical HIV-1 resistance to the CCR5 antagonist maraviroc despite divergent resistance levels and lack of common gp120 resistance mutations
详细信息    查看全文
  • 作者：Michael Roche (1) (4)
    Hamid Salimi (1) (3)
    Renee Duncan (1)
    Brendan L Wilkinson (10)
    Kelechi Chikere (11)
    Miranda S Moore (1) (14)
    Nicholas E Webb (11)
    Helena Zappi (1) (8)
    Jasminka Sterjovski (1)
    Jacqueline K Flynn (1) (4)
    Anne Ellett (1)
    Lachlan R Gray (1) (5)
    Benhur Lee (11)
    Becky Jubb (12)
    Mike Westby (12)
    Paul A Ramsland (2) (7) (9)
    Sharon R Lewin (1) (13) (4)
    Richard J Payne (10)
    Melissa J Churchill (1) (3) (6)
    Paul R Gorry (1) (4) (8)
  • 关键词：HIV ; 1 ; Maraviroc ; Resistance ; Env ; gp120 ; V3 loop ; CCR5 N ; terminus ; CCR5 ECLs
  • 刊名：Retrovirology
  • 出版年：2013
  • 出版时间：December 2013
  • 年：2013
  • 卷：10
  • 期：1
  • 全文大小：1451KB
  • 参考文献：1. Wilen CB, Tilton JC, Doms RW: Molecular mechanisms of HIV entry. / Adv Exp Med Biol 2012, 726:223-42. CrossRef
    2. Gorry PR, Ancuta P: Coreceptors and HIV-1 pathogenesis. / Curr HIV/AIDS Rep 2011,8(1):45-3. CrossRef
    3. Cormier EG, Dragic T: 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 2002,76(17):8953-957. CrossRef
    4. Huang CC, Tang M, Zhang MY, Majeed S, Montabana E, Stanfield RL, Dimitrov DS, Korber B, Sodroski J, Wilson IA: Structure of a V3-containing HIV-1 gp120 core. / Science 2005,310(5750):1025-028. CrossRef
    5. Farzan M, Mirzabekov T, Kolchinsky P, Wyatt R, Cayabyab M, Gerard NP, Gerard C, Sodroski J, Choe H: Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. / Cell 1999,96(5):667-76. CrossRef
    6. Brelot A, Heveker N, Adema K, Hosie MJ, Willett B, Alizon M: Effect of mutations in the second extracellular loop of CXCR4 on its utilization by human and feline immunodeficiency viruses. / J Virol 1999,73(4):2576-586.
    7. Farzan M, Choe H, Vaca L, Martin K, Sun Y, Desjardins E, Ruffing N, Wu L, Wyatt R, Gerard N: A tyrosine-rich region in the N terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5. / J Virol 1998,72(2):1160-164.
    8. Cormier EG, Persuh M, Thompson DA, Lin SW, Sakmar TP, Olson WC, Dragic T: Specific interaction of CCR5 amino-terminal domain peptides containing sulfotyrosines with HIV-1 envelope glycoprotein gp120. / Proc Natl Acad Sci USA 2000,97(11):5762-767. CrossRef
    9. Kondru R, Zhang J, Ji C, Mirzadegan T, Rotstein D, Sankuratri S, Dioszegi M: Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists. / Mol Pharmacol 2008,73(3):789-00. CrossRef
    10. Dragic T, Trkola A, Thompson DA, Cormier EG, Kajumo FA, Maxwell E, Lin SW, Ying W, Smith SO, Sakmar TP: 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(10):5639-644. CrossRef
    11. Maeda K, Das D, Ogata-Aoki H, Nakata H, Miyakawa T, Tojo Y, Norman R, Takaoka Y, Ding J, Arnold GF: Structural and molecular interactions of CCR5 inhibitors with CCR5. / J Biol Chem 2006,281(18):12688-2698. CrossRef
    12. Seibert C, Ying W, Gavrilov S, Tsamis F, Kuhmann SE, Palani A, Tagat JR, Clader JW, McCombie SW, Baroudy BM: Interaction of small molecule inhibitors of HIV-1 entry with CCR5. / Virology 2006,349(1):41-4. CrossRef
    13. Tsamis F, Gavrilov S, Kajumo F, Seibert C, Kuhmann S, Ketas T, Trkola A, Palani A, Clader JW, Tagat JR: Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. / J Virol 2003,77(9):5201-208. CrossRef
    14. Watson C, Jenkinson S, Kazmierski W, Kenakin T: The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. / Mol Pharmacol 2005,67(4):1268-282. CrossRef
    15. Tilton JC, Wilen CB, Didigu CA, Sinha R, Harrison JE, Agrawal-Gamse C, Henning EA, Bushman FD, Martin JN, Deeks SG: A maraviroc-resistant HIV-1 with narrow cross-resistance to other CCR5 antagonists depends on both N-terminal and extracellular loop domains of drug-bound CCR5. / J Virol 2010, 84:10863-0876. CrossRef
    16. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C: Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. / Antimicrob Agents Chemother 2005,49(11):4721-732. CrossRef
    17. Wood A, Armour D: The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. / Prog Med Chem 2005, 43:239-71. CrossRef
    18. Gorry PR, Ellett A, Lewin SR: Maraviroc. In / Kucers-The Use of Antibiotics. 6th edition. Edited by: Grayson L, Crowe S, McCarthy J, Mills J, Mouton J, Norrby SR, Paterson D, Pfaller M. London: Hodder & Stoughton Ltd; 2010:2869-876.
    19. Strizki JM, Tremblay C, Xu S, Wojcik L, Wagner N, Gonsiorek W, Hipkin RW, Chou CC, Pugliese-Sivo C, Xiao Y: Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. / Antimicrob Agents Chemother 2005,49(12):4911-919. CrossRef
    20. Maeda K, Nakata H, Koh Y, Miyakawa T, Ogata H, Takaoka Y, Shibayama S, Sagawa K, Fukushima D, Moravek J: 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 2004,78(16):8654-662. CrossRef
    21. Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, Shiraishi M, Aramaki Y, Okonogi K, Ogawa Y: A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. / Proc Natl Acad Sci USA 1999,96(10):5698-703. CrossRef
    22. Westby M, Lewis M, Whitcomb J, Youle M, Pozniak AL, James IT, Jenkins TM, Perros M, van der Ryst E: 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 2006,80(10):4909-920. CrossRef
    23. Tsibris AM, Korber B, Arnaout R, Russ C, Lo CC, Leitner T, Gaschen B, Theiler J, Paredes R, Su Z: Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. / PLoS One 2009,4(5):e5683. CrossRef
    24. Fatkenheuer G, Nelson M, Lazzarin A, Konourina I, Hoepelman AI, Lampiris H, Hirschel B, Tebas P, Raffi F, Trottier B: Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. / N Engl J Med 2008,359(14):1442-455. CrossRef
    25. Cooper DA, Heera J, Goodrich J, Tawadrous M, Saag M, Dejesus E, Clumeck N, Walmsley S, Ting N, Coakley E: Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. / J Infect Dis 2010,201(6):803-13. CrossRef
    26. Gulick RM, Su Z, Flexner C, Hughes MD, Skolnik PR, Wilkin TJ, Gross R, Krambrink A, Coakley E, Greaves WL: Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS clinical trials group 5211. / J Infect Dis 2007,196(2):304-12. CrossRef
    27. Landovitz RJ, Angel JB, Hoffmann C, Horst H, Opravil M, Long J, Greaves W, Fatkenheuer G: Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. / J Infect Dis 2008,198(8):1113-122. CrossRef
    28. Kitrinos KM, Amrine-Madsen H, Irlbeck DM, Word JM, Demarest JF: Virologic failure in therapy-naive subjects on aplaviroc plus lopinavir-ritonavir: detection of aplaviroc resistance requires clonal analysis of envelope. / Antimicrob Agents Chemother 2009,53(3):1124-131. CrossRef
    29. Demarest JF, Amrine-Madsen H, Irlbeck DM, Kitrinos KM: Virologic failure in first-line human immunodeficiency virus therapy with a CCR5 entry inhibitor, aplaviroc, plus a fixed-dose combination of lamivudine-zidovudine: nucleoside reverse transcriptase inhibitor resistance regardless of envelope tropism. / Antimicrob Agents Chemother 2009,53(3):1116-123. CrossRef
    30. Putcharoen O, Lee SH, Henrich TJ, Hu Z, Vanichanan J, Coakley E, Greaves W, Gulick RM, Kuritzkes DR, Tsibris AM: HIV-1 clinical isolates resistant to CCR5 antagonists exhibit delayed entry kinetics that are corrected in the presence of drug. / J Virol 2012,86(2):1119-128. CrossRef
    31. McNicholas P, Wei Y, Whitcomb J, Greaves W, Black TA, Tremblay CL, Strizki JM: Characterization of emergent HIV resistance in treatment-naive subjects enrolled in a vicriviroc phase 2 trial. / J Infect Dis 2010,201(10):1470-480. CrossRef
    32. Ogert RA, Hou Y, Ba L, Wojcik L, Qiu P, Murgolo N, Duca J, Dunkle LM, Ralston R, Howe JA: Clinical resistance to vicriviroc through adaptive V3 loop mutations in HIV-1 subtype D gp120 that alter interactions with the N-terminus and ECL2 of CCR5. / Virology 2010,400(1):145-55. CrossRef
    33. Tsibris AM, Sagar M, Gulick RM, Su Z, Hughes M, Greaves W, Subramanian M, Flexner C, Giguel F, Leopold KE: In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject. / J Virol 2008,82(16):8210-214. CrossRef
    34. Westby M, Smith-Burchnell C, Mori J, Lewis M, Mosley M, Stockdale M, Dorr P, Ciaramella G, Perros M: 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 2007,81(5):2359-371. CrossRef
    35. Pugach P, Marozsan AJ, Ketas TJ, Landes EL, Moore JP, Kuhmann SE: HIV-1 clones resistant to a small molecule CCR5 inhibitor use the inhibitor-bound form of CCR5 for entry. / Virology 2007,361(1):212-28. CrossRef
    36. Pugach P, Ray N, Klasse PJ, Ketas TJ, Michael E, Doms RW, Lee B, Moore JP: Inefficient entry of vicriviroc-resistant HIV-1 via the inhibitor-CCR5 complex at low cell surface CCR5 densities. / Virology 2009,387(2):296-02. CrossRef
    37. Ogert RA, Wojcik L, Buontempo C, Ba L, Buontempo P, Ralston R, Strizki J, Howe JA: Mapping resistance to the CCR5 co-receptor antagonist vicriviroc using heterologous chimeric HIV-1 envelope genes reveals key determinants in the C2-V5 domain of gp120. / Virology 2008,373(2):387-99. CrossRef
    38. Henrich TJ, Lewine NR, Lee SH, Rao SS, Berro R, Gulick RM, Moore JP, Tsibris AM, Kuritzkes DR: Differential use of CCR5 by HIV-1 clinical isolates resistant to small-molecule CCR5 antagonists. / Antimicrob Agents Chemother 2012,56(4):1931-935. CrossRef
    39. Tilton JC, Amrine-Madsen H, Miamidian JL, Kitrinos KM, Pfaff J, Demarest JF, Ray N, Jeffrey JL, Labranche CC, Doms RW: HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry. / AIDS Res Hum Retroviruses 2010,26(1):13-4. CrossRef
    40. Kuhmann SE, Pugach P, Kunstman KJ, Taylor J, Stanfield RL, Snyder A, Strizki JM, Riley J, Baroudy BM, Wilson IA: Genetic and phenotypic analyses of human immunodeficiency virus type 1 escape from a small-molecule CCR5 inhibitor. / J Virol 2004,78(6):2790-807. CrossRef
    41. Henrich TJ, Tsibris AM, Lewine NR, Konstantinidis I, Leopold KE, Sagar M, Kuritzkes DR: Evolution of CCR5 antagonist resistance in an HIV-1 subtype C clinical isolate. / J Acquir Immune Defic Syndr 2010,55(4):420-27. CrossRef
    42. Pfaff JM, Wilen CB, Harrison JE, Demarest JF, Lee B, Doms RW, Tilton JC: HIV-1 resistance to CCR5 antagonists associated with highly efficient use of CCR5 and altered tropism on primary CD4+ T cells. / J Virol 2010,84(13):6505-514. CrossRef
    43. Anastassopoulou CG, Ketas TJ, Depetris RS, Thomas AM, Klasse PJ, Moore JP: Resistance of a human immunodeficiency virus type 1 isolate to a small molecule CCR5 inhibitor can involve sequence changes in both gp120 and gp41. / Virology 2011,413(1):47-9. CrossRef
    44. Anastassopoulou CG, Ketas TJ, Klasse PJ, Moore JP: Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41. / Proc Natl Acad Sci USA 2009,106(13):5318-323. CrossRef
    45. Anastassopoulou CG, Ketas TJ, Sanders RW, Klasse PJ, Moore JP: Effects of sequence changes in the HIV-1 gp41 fusion peptide on CCR5 inhibitor resistance. / Virology 2012,428(2):86-7. CrossRef
    46. McNicholas PM, Mann PA, Wojcik L, Phd PQ, Lee E, McCarthy M, Shen J, Black TA, Strizki JM: Mapping and characterization of vicriviroc resistance mutations from HIV-1 isolated from treatment-experienced subjects enrolled in a phase II study (VICTOR-E1). / J Acquir Immune Defic Syndr 2011,56(3):222-29. CrossRef
    47. Inc P: / Maraviroc Tablets NDA 22-28: Antiviral Drugs Advisory Committee (AVDAC) Briefing Document. New York, NY: Pfizer Inc; 2007.
    48. Berro R, Sanders RW, Lu M, Klasse PJ, Moore JP: Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry. / PLoS Pathog 2009,5(8):e1000548. CrossRef
    49. Laakso MM, Lee FH, Haggarty B, Agrawal C, Nolan KM, Biscone M, Romano J, Jordan AP, Leslie GJ, Meissner EG: V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies. / PLoS Pathog 2007,3(8):e117. CrossRef
    50. Ogert RA, Ba L, Hou Y, Buontempo C, Qiu P, Duca J, Murgolo N, Buontempo P, Ralston R, Howe JA: Structure-function analysis of human immunodeficiency virus type 1 gp120 amino acid mutations associated with resistance to the CCR5 coreceptor antagonist vicriviroc. / J Virol 2009,83(23):12151-2163. CrossRef
    51. Roche M, Jakobsen MR, Sterjovski J, Ellett A, Posta F, Lee B, Jubb B, Westby M, Lewin SR, Ramsland PA: HIV-1 escape from the CCR5 antagonist maraviroc associated with an altered and less efficient mechanism of gp120-CCR5 engagement that attenuates macrophage-tropism. / J Virol 2011, 85:4330-342. CrossRef
    52. Jubb B, Buttler S, Craig C, Westby M: Maraviroc-resistant viruses continue to use the extracellular loop and N-terminal regions of CCR5 for cell entry. In / Program and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections. Boston; 2011. February 27-March 2 Poster P590
    53. Marozsan AJ, Kuhmann SE, Morgan T, Herrera C, Rivera-Troche E, Xu S, Baroudy BM, Strizki J, Moore JP: Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D). / Virology 2005,338(1):182-99. CrossRef
    54. Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, Pugach P, Xu S, Wojcik L, Tagat J: HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. / Proc Natl Acad Sci USA 2002,99(1):395-00. CrossRef
    55. Delobel P, Raymond S, Mavigner M, Cazabat M, Alvarez M, Marchou B, Massip P, Izopet J: Shift in phenotypic susceptibility suggests a competition mechanism in a case of acquired resistance to maraviroc. / AIDS 2010,24(9):1382-384. CrossRef
    56. Mori J, Lewis M, Simpson P, Whitcomb J, Perros M, van der Ryst E, Westby M: Characterization of maraviroc resistance in patients failing treatment with CCR5-tropic virus in MOTIVATE 1 and MOTIVATE 2 (24 week analysis). / Program and abstracts of the 6th European Drug Resistance Workshop, Budapest, March 26-8 Poster 51 2008.
    57. Flynn JK, Paukovics G, Moore MS, Ellett A, Gray LR, Duncan R, Salimi H, Jubb B, Westby M, Purcell DFJ: The magnitude of HIV-1 resistance to the CCR5 antagonist maraviroc may impart a differential alteration in HIV-1 tropism for macrophages and T-cell subsets. / Virology 2013. doi:10.1016/j.virol.2013.03.026.
    58. Roche M, Jakobsen MR, Ellett A, Salimiseyedabad H, Jubb B, Westby M, Lee B, Lewin SR, Churchill MJ, Gorry PR: HIV-1 predisposed to acquiring resistance to maraviroc (MVC) and other CCR5 antagonists in vitro has an inherent, low-level ability to utilize MVC-bound CCR5 for entry. / Retrovirology 2011,8(1):89. CrossRef
    59. Johnston SH, Lobriz MA, Nguyen S, Lassen K, Delair S, Posta F, Bryson YJ, Arts EJ, Chou T, Lee B: A quantitative affinity-profiling system that reveals distinct CD4/CCR5 usage patterns among human immunodeficiency virus type 1 and simian immunodeficiency virus strains. / J Virol 2009, 83:11016-1026. CrossRef
    60. Chikere K, Chou T, Gorry PR, Lee B: Affinofile profiling: How efficiency of CD4/CCR5 usage impacts the biological and pathogenic phenotype of HIV. / Virology 2013, 435:81-1. CrossRef
    61. Sterjovski J, Churchill MJ, Ellett A, Gray LR, Roche MJ, Dunfee RL, Purcell DF, Saksena N, Wang B, Sonza S: Asn 362 in gp120 contributes to enhanced fusogenicity by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with AIDS. / Retrovirology 2007, 4:89. CrossRef
    62. Sterjovski J, Roche M, Churchill MJ, Ellett A, Farrugia W, Gray LR, Cowley D, Poumbourios P, Lee B, Wesselingh S: An altered and more efficient mechanism of CCR5 engagement contributes to macrophage tropism of CCR5-using HIV-1 envelopes. / Virology 2010, 404:269-78. CrossRef
    63. Ratcliff AN, Shi W, Arts EJ: HIV-1 resistance to maraviroc conferred by a Cd4 binding site mutation in the envelope glycoprotein Gp120. / J Virol 2012, 87:923-34. CrossRef
    64. Cashin K, Roche M, Sterjovski J, Ellett A, Gray LR, Cunningham AL, Ramsland PA, Churchill MJ, Gorry PR: Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages. / J Virol 2011, 85:10699-0709. CrossRef
    65. Salimi H, Roche M, Webb N, Gray LR, Chikere K, Sterjovski J, Ellett A, Wesselingh SL, Ramsland PA, Lee B: Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5. / J Leukoc Biol 2013, 93:113-26. CrossRef
    66. Etemad-Moghadam B, Sun Y, Nicholson EK, Fernandes M, Liou K, Gomila R, Lee J, Sodroski J: Envelope glycoprotein determinants of increased fusogenicity in a pathogenic simian-human immunodeficiency virus (SHIV-KB9) passaged in vivo. / J Virol 2000,74(9):4433-440. CrossRef
    67. Chiang JJ, Gardner MR, Quinlan BD, Dorfman T, Choe H, Farzan M: Enhanced Recognition and Neutralization of HIV-1 by Antibody-Derived CCR5-Mimetic Peptide Variants. / J Virol 2012,86(22):12417-2421. CrossRef
    68. Kwong JA, Dorfman T, Quinlan BD, Chiang JJ, Ahmed AA, Choe H, Farzan M: A tyrosine-sulfated CCR5-mimetic peptide promotes conformational transitions in the HIV-1 envelope glycoprotein. / J Virol 2011,85(15):7563-571. CrossRef
    69. Farzan M, Chung S, Li W, Vasilieva N, Wright PL, Schnitzler CE, Marchione RJ, Gerard C, Gerard NP, Sodroski J: Tyrosine-sulfated peptides functionally reconstitute a CCR5 variant lacking a critical amino-terminal region. / J Biol Chem 2002,277(43):40397-0402. CrossRef
    70. Taleski D, Butler SJ, Stone MJ, Payne RJ: Divergent and site-selective solid-phase synthesis of sulfopeptides. / Chem Asian J 2011, 6:1316-320. CrossRef
    71. Simpson LS, Zhu JZ, Widlanski TS, Stone MJ: Regulation of chemokine recognition by site-specific tyrosine sulfation of receptor peptides. / Chem Biol 2009,16(2):153-61. CrossRef
    72. Zhu JZ, Millard CJ, Ludeman JP, Simpson LS, Clayton DJ, Payne RJ, Widlanski TS, Stone MJ: Tyrosine sulfation influences the chemokine binding selectivity of peptides derived from chemokine receptor CCR3. / Biochemistry 2011,50(9):1524-534. CrossRef
    73. Huang CC, Lam SN, Acharya P, Tang M, Xiang SH, Hussan SS, Stanfield RL, Robinson J, Sodroski J, Wilson IA: Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. / Science 2007,317(5846):1930-934. CrossRef
    74. Berro R, Klasse PJ, Jakobsen MR, Gorry PR, Moore JP, Sanders RW: V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc. / Virology 2012,427(2):158-65. CrossRef
    75. Platt EJ, Wehrly K, Kuhmann SE, Chesebro B, Kabat D: Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. / J Virol 1998,72(4):2855-864.
    76. Soda Y, Shimizu N, Jinno A, Liu HY, Kanbe K, Kitamura T, Hoshino H: Establishment of a new system for determination of coreceptor usages of HIV based on the human glioma NP-2 cell line. / Biochem Biophys Res Commun 1999,258(2):313-21. CrossRef
    77. Gao F, Morrison SG, Robertson DL, Thornton CL, Craig S, Karlsson G, Sodroski J, Morgado M, Galvao-Castro B, von Briesen H: Molecular cloning and analysis of functional envelope genes from human immunodeficiency virus type 1 sequence subtypes A through G. / The WHO and NIAID Networks for HIV Isolation and Characterization. J Virol 1996,70(3):1651-667.
    78. Gray L, Roche M, Churchill MJ, Sterjovski J, Ellett A, Poumbourios P, Sherieff S, Wang B, Saksena N, Purcell DF: Tissue-specific sequence alterations in the human immunodeficiency virus type 1 envelope favoring CCR5 usage contribute to persistence of dual-tropic virus in the brain. / J Virol 2009,83(11):5430-441. CrossRef
    79. Gao F, Morrison SG, Robertson DL, Thornton CL, Craig S, Karlsson G, Sodroski J, Morgado M, Galvao-Castro B, von Briesen H: Molecular cloning and analysis of functional envelope genes from human immunodeficiency virus type 1 sequence subtypes A through G. The WHO and NIAID Networks for HIV Isolation and Characterization. / J Virol 1996,70(3):1651-667.
    80. Yang X, Wyatt R, Sodroski J: Improved elicitation of neutralizing antibodies against primary human immunodeficiency viruses by soluble stabilized envelope glycoprotein trimers. / J Virol 2001,75(3):1165-171. CrossRef
    81. Lee B, Sharron M, Montaner LJ, Weissman D, Doms RW: Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. / Proc Natl Acad Sci USA 1999,96(9):5215-220. CrossRef
    82. Sterjovski J, Churchill MJ, Roche M, Ellett A, Farrugia W, Wesselingh SL, Cunningham AL, Ramsland PA, Gorry PR: CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity. / Virology 2011, 410:418-28. CrossRef
    83. Sali A, Blundell TL: Comparative protein modelling by satisfaction of spatial restraints. / J Mol Biol 1993,234(3):779-15. CrossRef
  • 作者单位：Michael Roche (1) (4)
    Hamid Salimi (1) (3)
    Renee Duncan (1)
    Brendan L Wilkinson (10)
    Kelechi Chikere (11)
    Miranda S Moore (1) (14)
    Nicholas E Webb (11)
    Helena Zappi (1) (8)
    Jasminka Sterjovski (1)
    Jacqueline K Flynn (1) (4)
    Anne Ellett (1)
    Lachlan R Gray (1) (5)
    Benhur Lee (11)
    Becky Jubb (12)
    Mike Westby (12)
    Paul A Ramsland (2) (7) (9)
    Sharon R Lewin (1) (13) (4)
    Richard J Payne (10)
    Melissa J Churchill (1) (3) (6)
    Paul R Gorry (1) (4) (8)

    1. Center for Virology, Monash University, Melbourne, Victoria, Australia
    4. Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia
    3. Department of Microbiology, Monash University, Melbourne, Victoria, Australia
    10. School of Chemistry, The University of Sydney, New South Wales, Australia
    11. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
    14. Fred Hutchinson Cancer Research Center, Seattle, WA, USA
    8. Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia
    5. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia
    12. Pfizer Global Research and Development, Sandwich, UK
    2. Center for Immunology, Monash University, Melbourne, Victoria, Australia
    7. Department of Immunology, Monash University, Melbourne, Victoria, Australia
    9. Department of Surgery (Austin Health), University of Melbourne, Kragujevac, Victoria, Australia
    13. Infectious Diseases Unit, The Alfred Hospital, Melbourne, Victoria, Australia
    6. Department of Medicine, Monash University, Melbourne, Victoria, Australia
  • ISSN：1742-4690
文摘
Background The CCR5 antagonist maraviroc (MVC) inhibits human immunodeficiency virus type 1 (HIV-1) entry by altering the CCR5 extracellular loops (ECL), such that the gp120 envelope glycoproteins (Env) no longer recognize CCR5. The mechanisms of HIV-1 resistance to MVC, the only CCR5 antagonist licensed for clinical use are poorly understood, with insights into MVC resistance almost exclusively limited to knowledge obtained from in vitro studies or from studies of resistance to other CCR5 antagonists. To more precisely understand mechanisms of resistance to MVC in vivo, we characterized Envs isolated from 2 subjects who experienced virologic failure on MVC. Results Envs were cloned from subjects 17 and 24 before commencement of MVC (17-Sens and 24-Sens) and after virologic failure (17-Res and 24-Res). The Envs cloned during virologic failure showed broad divergence in resistance levels, with 17-Res Env exhibiting a relatively high maximal percent inhibition (MPI) of ~90% in NP2-CD4/CCR5 cells and peripheral blood mononuclear cells (PBMC), and 24-Res Env exhibiting a very low MPI of ~0 to 12% in both cell types, indicating relatively “weak-and “strong-resistance, respectively. Resistance mutations were strain-specific and mapped to the gp120 V3 loop. Affinity profiling by the 293-Affinofile assay and mathematical modeling using VERSA (Viral Entry Receptor Sensitivity Analysis) metrics revealed that 17-Res and 24-Res Envs engaged MVC-bound CCR5 inefficiently or very efficiently, respectively. Despite highly divergent phenotypes, and a lack of common gp120 resistance mutations, both resistant Envs exhibited an almost superimposable pattern of dramatically increased reliance on sulfated tyrosine residues in the CCR5 N-terminus, and on histidine residues in the CCR5 ECLs. This altered mechanism of CCR5 engagement rendered both the resistant Envs susceptible to neutralization by a sulfated peptide fragment of the CCR5 N-terminus. Conclusions Clinical resistance to MVC may involve divergent Env phenotypes and different genetic alterations in gp120, but the molecular mechanism of resistance of the Envs studied here appears to be related. The increased reliance on sulfated CCR5 N-terminus residues suggests a new avenue to block HIV-1 entry by CCR5 N-terminus sulfopeptidomimetic drugs.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址：北京市海淀区学院路29号 邮编：100083

电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700