title: HIV-1 resistance to CCR5 antagonists associated with highly efficient use of CCR5 and altered tropism on primary CD4+ T cells.
abstract: We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4(+) T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N' terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a tropism shift toward effector memory cells upon infection of primary CD4(+) T cells in the presence of APL, with relative sparing of the central memory CD4(+) T cell subset. If such a tropism shift proves to be a common feature of CCR5-antagonist-resistant viruses, then continued use of CCR5 antagonists even in the face of virologic failure could provide a relative degree of protection to the T(CM) subset of CD4(+) T cells and result in improved T cell homeostasis and immune function.
authors.affiliation: Department of Microbiology, University of Pennsylvania, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pfaff
authors.forename: Craig B
authors.initials: CB
authors.lastname: Wilen
authors.forename: Jessamina E
authors.initials: JE
authors.lastname: Harrison
authors.forename: James F
authors.initials: JF
authors.lastname: Demarest
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
authors.forename: John C
authors.initials: JC
authors.lastname: Tilton
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D054659:Diketopiperazines; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000502:physiology*; D015728:Receptors, HIV / Q000037:antagonists & inhibitors / Q000502:physiology*; D013141:Spiro Compounds / Q000494:pharmacology; D056189:Viral Tropism; D053585:Virus Attachment
chemical_list: D019380:Anti-HIV Agents; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D010879:Piperazines; D019713:Receptors, CCR5; D015728:Receptors, HIV; D013141:Spiro Compounds; C514793:gp120 protein, Human immunodeficiency virus 1; C499671:aplaviroc
references.citation: J Biol Chem. 2006 May 5;281(18):12688-98
references.pmid: 16476734
references.citation: J Virol. 2009 Nov;83(21):11016-26
references.pmid: 19692480
references.citation: J Virol. 2002 Nov;76(21):10791-800
references.pmid: 12368322
references.citation: Antimicrob Agents Chemother. 2000 Jan;44(1):51-6
references.pmid: 10602722
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5215-20
references.pmid: 10220446
references.citation: J Virol. 2001 Jun;75(12):5541-9
references.pmid: 11356961
references.citation: AIDS. 2005 Sep 23;19(14):1443-8
references.pmid: 16135896
references.citation: PLoS Pathog. 2009 Aug;5(8):e1000548
references.pmid: 19680536
references.citation: Cell. 1998 May 29;93(5):681-4
references.pmid: 9630213
references.citation: J Virol. 2006 May;80(10):4909-20
references.pmid: 16641282
references.citation: Cell. 1996 Nov 1;87(3):437-46
references.pmid: 8898197
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):395-400
references.pmid: 11782552
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5318-23
references.pmid: 19289833
references.citation: J Virol. 1998 Apr;72(4):3464-8
references.pmid: 9525683
references.citation: J Virol. 2008 Aug;82(16):8210-4
references.pmid: 18495779
references.citation: Nature. 1996 Nov 14;384(6605):184-7
references.pmid: 8906796
references.citation: J Virol. 1998 Feb;72(2):1160-4
references.pmid: 9445013
references.citation: Curr Opin HIV AIDS. 2009 Mar;4(2):82-7
references.pmid: 19339945
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10598-602
references.pmid: 12960367
references.citation: Virology. 2006 May 25;349(1):41-54
references.pmid: 16494916
references.citation: J Infect Dis. 2007 Jul 15;196(2):304-12
references.pmid: 17570119
references.citation: AIDS Res Hum Retroviruses. 1998 May 1;14(7):607-17
references.pmid: 9591715
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5639-44
references.pmid: 10779565
references.citation: Nature. 1999 Oct 14;401(6754):708-12
references.pmid: 10537110
references.citation: Antimicrob Agents Chemother. 2009 Mar;53(3):1124-31
references.pmid: 19075068
references.citation: J Virol. 2009 Dec;83(23):12151-63
references.pmid: 19776131
references.citation: Antiviral Res. 2010 Jan;85(1):91-100
references.pmid: 19683546
references.citation: J Virol. 2004 Mar;78(6):2790-807
references.pmid: 14990699
references.citation: Antimicrob Agents Chemother. 2007 Feb;51(2):707-15
references.pmid: 17116673
references.citation: Virology. 2009 May 10;387(2):296-302
references.pmid: 19303620
references.citation: Mol Pharmacol. 2005 Apr;67(4):1268-82
references.pmid: 15644495
references.citation: Science. 1998 Jun 19;280(5371):1949-53
references.pmid: 9632396
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12718-23
references.pmid: 11606733
references.citation: Nature. 1998 Jun 18;393(6686):648-59
references.pmid: 9641677
references.citation: J Exp Med. 2007 Sep 3;204(9):2171-85
references.pmid: 17724130
references.citation: AIDS Res Hum Retroviruses. 2000 May 20;16(8):741-9
references.pmid: 10826481
references.citation: Virology. 2008 Apr 10;373(2):387-99
references.pmid: 18190945
references.citation: J Biol Chem. 1999 Apr 2;274(14):9617-26
references.pmid: 10092648
references.citation: PLoS Pathog. 2007 Aug 24;3(8):e117
references.pmid: 17722977
references.citation: AIDS. 2004 Apr 9;18(6):837-48
references.pmid: 15060431
references.citation: Virology. 2000 Jun 5;271(2):240-7
references.pmid: 10860877
references.citation: AIDS Res Hum Retroviruses. 2010 Jan;26(1):13-24
references.pmid: 20055594
references.citation: J Virol. 2003 May;77(9):5201-8
references.pmid: 12692222
references.citation: Science. 2006 Jun 9;312(5779):1530-3
references.pmid: 16763152
references.citation: J Virol. 2002 Sep;76(17):8953-7
references.pmid: 12163614
references.citation: Science. 2007 Sep 28;317(5846):1930-4
references.pmid: 17901336
references.citation: Virology. 2005 Jul 20;338(1):182-99
references.pmid: 15935415
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1925-30
references.pmid: 9050881
references.citation: Nature. 2005 Feb 24;433(7028):834-41
references.pmid: 15729334
references.citation: Biochim Biophys Acta. 2003 Jul 11;1614(1):36-50
references.pmid: 12873764
references.citation: Antiviral Res. 2001 May;50(2):95-115
references.pmid: 11369431
references.citation: J Virol. 2007 Mar;81(5):2359-71
references.pmid: 17182681
references.citation: Virology. 2007 Apr 25;361(1):212-28
references.pmid: 17166540
references.citation: Retrovirology. 2006 Aug 17;3:52
references.pmid: 16916447
references.citation: J Mol Biol. 2008 Sep 12;381(4):956-74
references.pmid: 18590744
references.citation: J Virol. 1997 Sep;71(9):6305-14
references.pmid: 9261347