Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry.
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.
Berro
Reem
R
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
Sanders
Rogier W
RW
Lu
Min
M
Klasse
Per J
PJ
Moore
John P
JP
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
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D065100:CCR5 Receptor Antagonists; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5
J Virol. 2008 Jun;82(11):5460-71
18353949
J Mol Biol. 2008 Jan 25;375(4):969-78
18068724
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5639-44
10779565
J Virol Methods. 2003 Aug;111(2):111-20
12880926
Cell. 1999 Mar 5;96(5):667-76
10089882
Mol Biol Cell. 2008 Nov;19(11):4707-16
18753405
Antimicrob Agents Chemother. 1993 May;37(5):1095-101
8517697
J Virol. 2000 Jan;74(2):627-43
10623724
AIDS Res Hum Retroviruses. 1997 Aug 10;13(12):1007-15
9264287
J Virol. 2006 Jun;80(12):6093-105
16731948
J Biol Chem. 2002 Oct 25;277(43):40397-402
12183462
J Virol. 1995 Jan;69(1):101-9
7527081
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11013-8
12930892
Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5318-23
19289833
Curr Top Microbiol Immunol. 2006;303:97-120
16570858
J Gen Virol. 2001 Aug;82(Pt 8):1807-1814
11457985
J Virol. 1998 Apr;72(4):3464-8
9525683
J Virol. 2008 Aug;82(16):8210-4
18495779
J Virol. 1998 Feb;72(2):1160-4
9445013
Retrovirology. 2008 Jan 18;5:5
18205925
Proc Natl Acad Sci U S A. 1990 Sep;87(17):6574-8
2395859
Virology. 2006 May 25;349(1):41-54
16494916
AIDS Res Hum Retroviruses. 2007 Jan;23(1):28-32
17263629
J Virol. 1993 Apr;67(4):1772-7
8095306
PLoS One. 2009 May 25;4(5):e5683
19479085
J Virol. 2009 Apr;83(8):3798-809
19193800
Antimicrob Agents Chemother. 2009 Mar;53(3):1124-31
19075068
J Virol. 1995 Jan;69(1):122-30
7527082
J Exp Med. 1995 Jul 1;182(1):185-96
7540648
J Virol. 2004 Mar;78(6):2790-807
14990699
J Virol. 1999 Feb;73(2):1645-8
9882373
Antimicrob Agents Chemother. 2007 Feb;51(2):707-15
17116673
Mol Pharmacol. 2005 Apr;67(4):1268-82
15644495
Science. 1998 Jun 19;280(5371):1949-53
9632396
J Virol. 2005 Jul;79(14):8812-27
15994775
J Med Chem. 2004 May 6;47(10):2405-8
15115380
J Virol. 1998 May;72(5):3512-9
9557629
Virology. 2008 Apr 10;373(2):387-99
18190945
Virology. 2008 Aug 1;377(2):401-7
18519143
J Virol. 1995 Nov;69(11):6609-17
7474069
Annu Rev Pharmacol Toxicol. 2008;48:425-61
17937593
J Virol. 2008 Jan;82(2):903-16
18003735
J Exp Med. 1997 Feb 17;185(4):621-8
9034141
PLoS Pathog. 2007 Aug 24;3(8):e117
17722977
Structure. 2004 Feb;12(2):193-204
14962380
J Virol. 2004 Apr;78(7):3742-52
15016894
Biochemistry. 2009 Feb 3;48(4):779-85
19170639
J Virol. 1992 Jan;66(1):235-43
1727487
J Virol. 1997 Oct;71(10):7478-87
9311827
Nat Med. 1996 Nov;2(11):1244-7
8898753
J Immunol. 1990 Jun 1;144(11):4183-8
2341717
Mol Pharmacol. 2008 Mar;73(3):789-800
18096812
Virology. 2004 Jul 1;324(2):525-30
15207637
Science. 2005 Nov 11;310(5750):1025-8
16284180
J Virol. 2003 May;77(9):5201-8
12692222
Biochemistry. 2006 Sep 12;45(36):10973-80
16953583
J Virol. 2002 Sep;76(17):8953-7
12163614
Science. 2007 Sep 28;317(5846):1930-4
17901336
Virology. 2005 Jul 20;338(1):182-99
15935415
J Virol. 1992 Dec;66(12):7538-42
1433529
Virology. 2004 Mar 30;321(1):8-22
15033560
Antimicrob Agents Chemother. 2008 Jan;52(1):128-36
17954689
Virology. 2008 Nov 25;381(2):251-60
18822440
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):395-400
11782552
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5036-41
15051887
J Virol. 2007 Mar;81(5):2359-71
17182681
J Virol. 1998 Jan;72(1):279-85
9420225
Virology. 2007 Apr 25;361(1):212-28
17166540
J Virol. 2001 Dec;75(24):12266-78
11711617