title: Constrained use of CCR5 on CD4+ lymphocytes by R5X4 HIV-1: efficiency of Env-CCR5 interactions and low CCR5 expression determine a range of restricted CCR5-mediated entry.
abstract: R5X4 HIV-1 has impaired utilization of CCR5 on primary CD4+ lymphocytes but the mechanisms responsible are not well defined. Using a panel of diverse R5X4 Envs we identified a spectrum of CCR5 use on CD4+ lymphocytes. Greater lymphocyte CCR5 use correlated with relative resistance to CCR5 mAbs and small molecule antagonists. Increasing CCR5 expression on lymphocytes increased the proportion of entry mediated by CCR5 for all R5X4 isolates except 89.6. In cell lines with regulated CCR5 expression, strains with greater lymphocyte CCR5 use better exploited limiting levels of CCR5. Introduction of an R306S mutation in the 89.6 V3 domain enhanced its utilization of CCR5 at low levels and switched its preference to CCR5 for lymphocyte entry. Thus, the degree to which R5X4 HIV-1 use primary lymphocyte CCR5 is determined by low CCR5 expression coupled with variations in the efficiency of Env-CCR5 interactions, which is in part governed by V3 sequences.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Lamorris M
authors.initials: LM
authors.lastname: Loftin
authors.forename: Martha F
authors.initials: MF
authors.lastname: Kienzle
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Yi
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.forename: Fang-Hua
authors.initials: FH
authors.lastname: Lee
authors.forename: Lachlan
authors.initials: L
authors.lastname: Gray
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D015870:Gene Expression; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*; D053586:Virus Internalization; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D019713:Receptors, CCR5; D015728:Receptors, HIV; D054299:env Gene Products, Human Immunodeficiency Virus
references.citation: J Virol. 1992 Dec;66(12):7517-21
references.pmid: 1433527
references.citation: J Virol. 2004 Jul;78(14):7565-74
references.pmid: 15220431
references.citation: J Virol. 2003 Nov;77(22):12057-66
references.pmid: 14581542
references.citation: J Biol Chem. 1999 Apr 2;274(14):9617-26
references.pmid: 10092648
references.citation: Nat Med. 1997 Nov;3(11):1259-65
references.pmid: 9359702
references.citation: Virology. 2004 Oct 10;328(1):74-88
references.pmid: 15380360
references.citation: J Virol. 2005 Feb;79(3):1480-6
references.pmid: 15650174
references.citation: Science. 1991 Jul 5;253(5015):71-4
references.pmid: 1905842
references.citation: Virology. 1998 Jan 5;240(1):83-92
references.pmid: 9448692
references.citation: J Virol. 1989 May;63(5):2118-25
references.pmid: 2564898
references.citation: J Virol. 2009 Nov;83(21):11016-26
references.pmid: 19692480
references.citation: Gene. 1991 Dec 15;108(2):193-9
references.pmid: 1660837
references.citation: Ann Intern Med. 1993 May 1;118(9):681-8
references.pmid: 8096374
references.citation: Virology. 2001 Mar 15;281(2):239-47
references.pmid: 11277696
references.citation: Cytometry. 1998 Oct 1;33(2):197-205
references.pmid: 9773880
references.citation: J Virol. 2006 Jan;80(2):750-8
references.pmid: 16378977
references.citation: J Virol. 1990 May;64(5):2416-20
references.pmid: 2325207
references.citation: J Virol. 1998 Dec;72(12):9763-70
references.pmid: 9811711
references.citation: J Virol. 1995 Mar;69(3):1810-8
references.pmid: 7853521
references.citation: J Neurovirol. 2003 Aug;9(4):432-41
references.pmid: 12907388
references.citation: J Immunol. 1998 Sep 15;161(6):3195-201
references.pmid: 9743388
references.citation: Mol Biol Cell. 2002 Feb;13(2):723-37
references.pmid: 11854425
references.citation: J Infect Dis. 1998 Aug;178(2):388-96
references.pmid: 9697718
references.citation: J Virol. 2000 Dec;74(24):11858-72
references.pmid: 11090186
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5215-20
references.pmid: 10220446
references.citation: J Virol. 1995 Jul;69(7):4453-62
references.pmid: 7769705
references.citation: J Virol. 1992 Mar;66(3):1354-60
references.pmid: 1738194
references.citation: J Virol. 2008 Jan;82(2):664-73
references.pmid: 17977968
references.citation: J Virol. 2007 Aug;81(15):7885-93
references.pmid: 17507467
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6426-31
references.pmid: 9177234
references.citation: PLoS Pathog. 2009 Apr;5(4):e1000377
references.pmid: 19360131
references.citation: J Virol. 2001 Jun;75(12):5541-9
references.pmid: 11356961
references.citation: Virology. 2001 Feb 15;280(2):253-61
references.pmid: 11162839
references.citation: J Clin Invest. 1994 Nov;94(5):2060-7
references.pmid: 7962552
references.citation: J Virol. 2006 Apr;80(7):3684-91
references.pmid: 16537640
references.citation: J Virol. 1999 Sep;73(9):7117-25
references.pmid: 10438797
references.citation: Gene Ther. 1999 May;6(5):715-28
references.pmid: 10505094
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12324-9
references.pmid: 15297611
references.citation: Antimicrob Agents Chemother. 2005 Nov;49(11):4721-32
references.pmid: 16251317
references.citation: Science. 1986 Sep 5;233(4768):1089-93
references.pmid: 3016903
references.citation: Science. 1986 Jul 11;233(4760):215-9
references.pmid: 3014648
references.citation: J Virol. 2001 Aug;75(15):6776-85
references.pmid: 11435556
references.citation: Cell. 1996 Aug 9;86(3):367-77
references.pmid: 8756719
references.citation: Nature. 1996 Nov 14;384(6605):179-83
references.pmid: 8906795
references.citation: J Clin Immunol. 2001 Mar;21(2):116-25
references.pmid: 11332650
references.citation: J Exp Med. 1997 Feb 17;185(4):621-8
references.pmid: 9034141
references.citation: Antiviral Res. 2008 Feb;77(2):128-35
references.pmid: 18160142
references.citation: AIDS Res Hum Retroviruses. 2009 Mar;25(3):237-48
references.pmid: 19327047
references.citation: Virology. 1996 Aug 15;222(2):415-22
references.pmid: 8806525
references.citation: J Virol. 2007 Apr;81(7):3240-50
references.pmid: 17251281
references.citation: Immunol Rev. 2000 Oct;177:112-26
references.pmid: 11138769
references.citation: J Virol. 1997 Oct;71(10):7478-87
references.pmid: 9311827
references.citation: J Virol. 1999 Nov;73(11):9337-47
references.pmid: 10516042
references.citation: J Virol. 2000 Nov;74(21):10074-80
references.pmid: 11024136
references.citation: Proc Natl Acad Sci U S A. 2008 May 27;105(21):7552-7
references.pmid: 18490657
references.citation: J Virol. 2003 Dec;77(24):13376-88
references.pmid: 14645592
references.citation: J Virol. 2004 Dec;78(23):12975-86
references.pmid: 15542649
references.citation: Retrovirology. 2007 Dec 12;4:89
references.pmid: 18076768
references.citation: J Infect Dis. 2000 Mar;181(3):927-32
references.pmid: 10720514
references.citation: J Exp Med. 1997 May 5;185(9):1681-91
references.pmid: 9151905
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):658-63
references.pmid: 11136236
references.citation: J Clin Invest. 1999 Sep;104(5):R7-R11
references.pmid: 10487781
references.citation: J Virol. 2008 Dec;82(23):11758-66
references.pmid: 18815295
references.citation: J Virol. 2009 Aug;83(16):8208-20
references.pmid: 19515785
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5762-7
references.pmid: 10823934
references.citation: AIDS Res Hum Retroviruses. 2007 Mar;23(3):415-26
references.pmid: 17411375
references.citation: J Exp Med. 2009 Jun 8;206(6):1273-89
references.pmid: 19487424
references.citation: J Clin Invest. 2000 Oct;106(8):1039-52
references.pmid: 11032864
references.citation: AIDS Res Hum Retroviruses. 2001 Dec 10;17(18):1715-24
references.pmid: 11788023
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15590-5
references.pmid: 12434015
references.citation: Science. 1993 Aug 27;261(5125):1179-81
references.pmid: 8356453
references.citation: Lancet. 2002 May 25;359(9320):1832-4
references.pmid: 12044382
references.citation: J Virol. 2001 Dec;75(24):12266-78
references.pmid: 11711617
references.citation: J Virol. 2009 Jun;83(11):5430-41
references.pmid: 19321618
references.citation: Science. 1987 May 15;236(4803):819-22
references.pmid: 3646751
references.citation: J Virol. 1997 Sep;71(9):6305-14
references.pmid: 9261347