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.
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.
Loftin
Lamorris M
LM
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Kienzle
Martha F
MF
Yi
Yanjie
Y
Lee
Benhur
B
Lee
Fang-Hua
FH
Gray
Lachlan
L
Gorry
Paul R
PR
Collman
Ronald G
RG
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*
D019713:Receptors, CCR5; D015728:Receptors, HIV; D054299:env Gene Products, Human Immunodeficiency Virus
J Virol. 1992 Dec;66(12):7517-21
1433527
J Virol. 2004 Jul;78(14):7565-74
15220431
J Virol. 2003 Nov;77(22):12057-66
14581542
J Biol Chem. 1999 Apr 2;274(14):9617-26
10092648
Nat Med. 1997 Nov;3(11):1259-65
9359702
Virology. 2004 Oct 10;328(1):74-88
15380360
J Virol. 2005 Feb;79(3):1480-6
15650174
Science. 1991 Jul 5;253(5015):71-4
1905842
Virology. 1998 Jan 5;240(1):83-92
9448692
J Virol. 1989 May;63(5):2118-25
2564898
J Virol. 2009 Nov;83(21):11016-26
19692480
Gene. 1991 Dec 15;108(2):193-9
1660837
Ann Intern Med. 1993 May 1;118(9):681-8
8096374
Virology. 2001 Mar 15;281(2):239-47
11277696
Cytometry. 1998 Oct 1;33(2):197-205
9773880
J Virol. 2006 Jan;80(2):750-8
16378977
J Virol. 1990 May;64(5):2416-20
2325207
J Virol. 1998 Dec;72(12):9763-70
9811711
J Virol. 1995 Mar;69(3):1810-8
7853521
J Neurovirol. 2003 Aug;9(4):432-41
12907388
J Immunol. 1998 Sep 15;161(6):3195-201
9743388
Mol Biol Cell. 2002 Feb;13(2):723-37
11854425
J Infect Dis. 1998 Aug;178(2):388-96
9697718
J Virol. 2000 Dec;74(24):11858-72
11090186
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5215-20
10220446
J Virol. 1995 Jul;69(7):4453-62
7769705
J Virol. 1992 Mar;66(3):1354-60
1738194
J Virol. 2008 Jan;82(2):664-73
17977968
J Virol. 2007 Aug;81(15):7885-93
17507467
Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6426-31
9177234
PLoS Pathog. 2009 Apr;5(4):e1000377
19360131
J Virol. 2001 Jun;75(12):5541-9
11356961
Virology. 2001 Feb 15;280(2):253-61
11162839
J Clin Invest. 1994 Nov;94(5):2060-7
7962552
J Virol. 2006 Apr;80(7):3684-91
16537640
J Virol. 1999 Sep;73(9):7117-25
10438797
Gene Ther. 1999 May;6(5):715-28
10505094
Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12324-9
15297611
Antimicrob Agents Chemother. 2005 Nov;49(11):4721-32
16251317
Science. 1986 Sep 5;233(4768):1089-93
3016903
Science. 1986 Jul 11;233(4760):215-9
3014648
J Virol. 2001 Aug;75(15):6776-85
11435556
Cell. 1996 Aug 9;86(3):367-77
8756719
Nature. 1996 Nov 14;384(6605):179-83
8906795
J Clin Immunol. 2001 Mar;21(2):116-25
11332650
J Exp Med. 1997 Feb 17;185(4):621-8
9034141
Antiviral Res. 2008 Feb;77(2):128-35
18160142
AIDS Res Hum Retroviruses. 2009 Mar;25(3):237-48
19327047
Virology. 1996 Aug 15;222(2):415-22
8806525
J Virol. 2007 Apr;81(7):3240-50
17251281
Immunol Rev. 2000 Oct;177:112-26
11138769
J Virol. 1997 Oct;71(10):7478-87
9311827
J Virol. 1999 Nov;73(11):9337-47
10516042
J Virol. 2000 Nov;74(21):10074-80
11024136
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7552-7
18490657
J Virol. 2003 Dec;77(24):13376-88
14645592
J Virol. 2004 Dec;78(23):12975-86
15542649
Retrovirology. 2007 Dec 12;4:89
18076768
J Infect Dis. 2000 Mar;181(3):927-32
10720514
J Exp Med. 1997 May 5;185(9):1681-91
9151905
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):658-63
11136236
J Clin Invest. 1999 Sep;104(5):R7-R11
10487781
J Virol. 2008 Dec;82(23):11758-66
18815295
J Virol. 2009 Aug;83(16):8208-20
19515785
Proc Natl Acad Sci U S A. 2000 May 23;97(11):5762-7
10823934
AIDS Res Hum Retroviruses. 2007 Mar;23(3):415-26
17411375
J Exp Med. 2009 Jun 8;206(6):1273-89
19487424
J Clin Invest. 2000 Oct;106(8):1039-52
11032864
AIDS Res Hum Retroviruses. 2001 Dec 10;17(18):1715-24
11788023
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15590-5
12434015
Science. 1993 Aug 27;261(5125):1179-81
8356453
Lancet. 2002 May 25;359(9320):1832-4
12044382
J Virol. 2001 Dec;75(24):12266-78
11711617
J Virol. 2009 Jun;83(11):5430-41
19321618
Science. 1987 May 15;236(4803):819-22
3646751
J Virol. 1997 Sep;71(9):6305-14
9261347