title: Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry.
abstract: HIV-1 variants resistant to small molecule CCR5 inhibitors recognize the inhibitor-CCR5 complex, while also interacting with free CCR5. The most common genetic route to resistance involves sequence changes in the gp120 V3 region, a pathway followed when the primary isolate CC1/85 was cultured with the AD101 inhibitor in vitro, creating the CC101.19 resistant variant. However, the D1/86.16 escape mutant contains no V3 changes but has three substitutions in the gp41 fusion peptide. By using CCR5 point-mutants and gp120-targeting agents, we have investigated how infectious clonal viruses derived from the parental and both resistant isolates interact with CCR5. We conclude that the V3 sequence changes in CC101.19 cl.7 create a virus with an increased dependency on interactions with the CCR5 N-terminus. Elements of the CCR5 binding site associated with the V3 region and the CD4-induced (CD4i) epitope cluster in the gp120 bridging sheet are more exposed on the native Env complex of CC101.19 cl.7, which is sensitive to neutralization via these epitopes. However, D1/86.16 cl.23 does not have an increased dependency on the CCR5 N-terminus, and its CCR5 binding site has not become more exposed. How this virus interacts with the inhibitor-CCR5 complex remains to be understood.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Reem
authors.initials: R
authors.lastname: Berro
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Per J
authors.initials: PJ
authors.lastname: Klasse
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D008969:Molecular Sequence Data; D011817:Rabbits; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D016415:Sequence Alignment; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D065100:CCR5 Receptor Antagonists; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5
references.citation: J Virol. 2008 Jun;82(11):5460-71
references.pmid: 18353949
references.citation: J Mol Biol. 2008 Jan 25;375(4):969-78
references.pmid: 18068724
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5639-44
references.pmid: 10779565
references.citation: J Virol Methods. 2003 Aug;111(2):111-20
references.pmid: 12880926
references.citation: Cell. 1999 Mar 5;96(5):667-76
references.pmid: 10089882
references.citation: Mol Biol Cell. 2008 Nov;19(11):4707-16
references.pmid: 18753405
references.citation: Antimicrob Agents Chemother. 1993 May;37(5):1095-101
references.pmid: 8517697
references.citation: J Virol. 2000 Jan;74(2):627-43
references.pmid: 10623724
references.citation: AIDS Res Hum Retroviruses. 1997 Aug 10;13(12):1007-15
references.pmid: 9264287
references.citation: J Virol. 2006 Jun;80(12):6093-105
references.pmid: 16731948
references.citation: J Biol Chem. 2002 Oct 25;277(43):40397-402
references.pmid: 12183462
references.citation: J Virol. 1995 Jan;69(1):101-9
references.pmid: 7527081
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11013-8
references.pmid: 12930892
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5318-23
references.pmid: 19289833
references.citation: Curr Top Microbiol Immunol. 2006;303:97-120
references.pmid: 16570858
references.citation: J Gen Virol. 2001 Aug;82(Pt 8):1807-1814
references.pmid: 11457985
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: J Virol. 1998 Feb;72(2):1160-4
references.pmid: 9445013
references.citation: Retrovirology. 2008 Jan 18;5:5
references.pmid: 18205925
references.citation: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6574-8
references.pmid: 2395859
references.citation: Virology. 2006 May 25;349(1):41-54
references.pmid: 16494916
references.citation: AIDS Res Hum Retroviruses. 2007 Jan;23(1):28-32
references.pmid: 17263629
references.citation: J Virol. 1993 Apr;67(4):1772-7
references.pmid: 8095306
references.citation: PLoS One. 2009 May 25;4(5):e5683
references.pmid: 19479085
references.citation: J Virol. 2009 Apr;83(8):3798-809
references.pmid: 19193800
references.citation: Antimicrob Agents Chemother. 2009 Mar;53(3):1124-31
references.pmid: 19075068
references.citation: J Virol. 1995 Jan;69(1):122-30
references.pmid: 7527082
references.citation: J Exp Med. 1995 Jul 1;182(1):185-96
references.pmid: 7540648
references.citation: J Virol. 2004 Mar;78(6):2790-807
references.pmid: 14990699
references.citation: J Virol. 1999 Feb;73(2):1645-8
references.pmid: 9882373
references.citation: Antimicrob Agents Chemother. 2007 Feb;51(2):707-15
references.pmid: 17116673
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: J Virol. 2005 Jul;79(14):8812-27
references.pmid: 15994775
references.citation: J Med Chem. 2004 May 6;47(10):2405-8
references.pmid: 15115380
references.citation: J Virol. 1998 May;72(5):3512-9
references.pmid: 9557629
references.citation: Virology. 2008 Apr 10;373(2):387-99
references.pmid: 18190945
references.citation: Virology. 2008 Aug 1;377(2):401-7
references.pmid: 18519143
references.citation: J Virol. 1995 Nov;69(11):6609-17
references.pmid: 7474069
references.citation: Annu Rev Pharmacol Toxicol. 2008;48:425-61
references.pmid: 17937593
references.citation: J Virol. 2008 Jan;82(2):903-16
references.pmid: 18003735
references.citation: J Exp Med. 1997 Feb 17;185(4):621-8
references.pmid: 9034141
references.citation: PLoS Pathog. 2007 Aug 24;3(8):e117
references.pmid: 17722977
references.citation: Structure. 2004 Feb;12(2):193-204
references.pmid: 14962380
references.citation: J Virol. 2004 Apr;78(7):3742-52
references.pmid: 15016894
references.citation: Biochemistry. 2009 Feb 3;48(4):779-85
references.pmid: 19170639
references.citation: J Virol. 1992 Jan;66(1):235-43
references.pmid: 1727487
references.citation: J Virol. 1997 Oct;71(10):7478-87
references.pmid: 9311827
references.citation: Nat Med. 1996 Nov;2(11):1244-7
references.pmid: 8898753
references.citation: J Immunol. 1990 Jun 1;144(11):4183-8
references.pmid: 2341717
references.citation: Mol Pharmacol. 2008 Mar;73(3):789-800
references.pmid: 18096812
references.citation: Virology. 2004 Jul 1;324(2):525-30
references.pmid: 15207637
references.citation: Science. 2005 Nov 11;310(5750):1025-8
references.pmid: 16284180
references.citation: J Virol. 2003 May;77(9):5201-8
references.pmid: 12692222
references.citation: Biochemistry. 2006 Sep 12;45(36):10973-80
references.pmid: 16953583
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: J Virol. 1992 Dec;66(12):7538-42
references.pmid: 1433529
references.citation: Virology. 2004 Mar 30;321(1):8-22
references.pmid: 15033560
references.citation: Antimicrob Agents Chemother. 2008 Jan;52(1):128-36
references.pmid: 17954689
references.citation: Virology. 2008 Nov 25;381(2):251-60
references.pmid: 18822440
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. 2004 Apr 6;101(14):5036-41
references.pmid: 15051887
references.citation: J Virol. 2007 Mar;81(5):2359-71
references.pmid: 17182681
references.citation: J Virol. 1998 Jan;72(1):279-85
references.pmid: 9420225
references.citation: Virology. 2007 Apr 25;361(1):212-28
references.pmid: 17166540
references.citation: J Virol. 2001 Dec;75(24):12266-78
references.pmid: 11711617