Cell surface expression of CCR5 and other host factors influence the inhibition of HIV-1 infection of human lymphocytes by CCR5 ligands

被引:46
作者
Ketas, Thomas J.
Kuhmann, Shawn E.
Palmer, Ashley
Zurita, Juan
He, Weijing
Ahuja, Sunil K.
Klasse, Per Johan
Moore, John P.
机构
[1] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA
[2] Univ Texas, Hlth Sci Ctr San Antonio, Vet Adm Res Ctr AIDS & HIV I Infect, S Texas Vet Hlth Care Syst, San Antonio, TX 78285 USA
[3] Univ Texas, Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78285 USA
关键词
CCR5; inhibitor; viral entry; IC50; receptor density;
D O I
10.1016/j.virol.2007.02.022
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Several CCR5 ligands, including small molecules and monoclonal antibodies (MAbs), are being developed as therapies for infection with strains of human immunodeficiency virus type I (HIV-1) that use CCR5 for entry (R5 viruses). The efficacy of such therapies could be influenced by inter-individual differences in host factors, such as CCR5 expression levels. To study this, we used peripheral blood mononuclear cells (PBMCs) from humans and rhesus macaques. The half-maximal inhibitory concentrations (IC50) of the small-molecule CCR5 ligands CMPD 167, UK427,857 and SCH-D, and of the PRO 140 MAb, differ by > 2 logs in a donor-dependent manner. We studied this variation by using flow cytometry to measure CCR5 expression on PBMCs from six of the human donors: the IC50 values of both SCH-D and PRO 140 correlated with CCR5 expression (R-2=0.64 and 0.99, respectively). We also determined the efficacy of the CCR5 ligands against HIV-1 infection of HeLa-derived cell lines that express CD4 at the same level but vary 2-fold in CCR5 expression (JC.48 and JC.53 cells). The moderately greater CCR5 expression on the JC.53 than the JC.48 cells was associated with proportionately higher median IC50 values for a] I four CCR5 ligands but not for a soluble CD4-based inhibitor or a non-nucleoside reverse transcriptase inhibitor. We conclude that differences in CCR5 expression on human PBMCs, which can be affected by CCL3L1 gene dose, may influence the antiviral potency of CCR5 ligands in vitro, but other host factors are also likely to be involved. These host factors may affect the clinical activity of CCR5 inhibitors, including their use as topical microbicides to prevent HIV-1 transmission. (c) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:281 / 290
页数:10
相关论文
共 55 条
  • [1] ANTI-BACTEROIDES LIPOPOLYSACCHARIDE IGG LEVELS IN HEALTHY-ADULTS AND SEPSIS PATIENTS
    ALLAN, E
    POXTON, IR
    BARCLAY, GR
    [J]. FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY, 1995, 11 (01): : 5 - 12
  • [2] Anonymous, 2005, Antiviral Chemistry & Chemotherapy, V16, P339
  • [3] Evaluating the immunogenicity of a disulfide-stabilized, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1
    Beddows, S
    Schülke, N
    Kirschner, M
    Barnes, K
    Franti, M
    Michael, E
    Ketas, T
    Sanders, RW
    Maddon, PJ
    Olson, WC
    Moore, JP
    [J]. JOURNAL OF VIROLOGY, 2005, 79 (14) : 8812 - 8827
  • [4] The differential sensitivity of human and rhesus macaque CCR5 to small-molecule inhibitors of human immunodeficiency virus type 1 entry is explained by a single amino acid difference and suggests a mechanism of action for these inhibitors
    Billick, E
    Seibert, C
    Pugach, P
    Ketas, T
    Trkola, A
    Endres, MJ
    Murgolo, NJ
    Coates, E
    Reyes, GR
    Baroudy, BM
    Sakmar, TP
    Moore, JP
    Kuhmann, SE
    [J]. JOURNAL OF VIROLOGY, 2004, 78 (08) : 4134 - 4144
  • [5] Butticaz C, 2003, ANTIVIR THER, V8, P373
  • [6] Change in coreceptor use correlates with disease progression in HIV-1-infected individuals
    Connor, RI
    Sheridan, KE
    Ceradini, D
    Choe, S
    Landau, NR
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 185 (04) : 621 - 628
  • [7] A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5
    Dragic, T
    Trkola, A
    Thompson, DAD
    Cormier, EG
    Kajumo, FA
    Maxwell, E
    Lin, SW
    Ying, WW
    Smith, SO
    Sakmar, TP
    Moore, JP
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (10) : 5639 - 5644
  • [8] Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1
    Fätkenheuer, G
    Pozniak, AL
    Johnson, MA
    Plettenberg, A
    Staszewski, S
    Hoepelman, AIM
    Saag, MS
    Goebel, FD
    Rockstroh, JK
    Dezube, BJ
    Jenkins, TM
    Medhurst, C
    Sullivan, JF
    Ridgway, C
    Abel, S
    James, IT
    Youle, M
    van der Ryst, E
    [J]. NATURE MEDICINE, 2005, 11 (11) : 1170 - 1172
  • [9] Gold S, 2000, DANCE MAG, V74, P20
  • [10] The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility
    Gonzalez, E
    Kulkarni, H
    Bolivar, H
    Mangano, A
    Sanchez, R
    Catano, G
    Nibbs, RJ
    Freedman, BI
    Quinones, MP
    Bamshad, MJ
    Murthy, KK
    Rovin, BH
    Bradley, W
    Clark, RA
    Anderson, SA
    O'Connell, RJ
    Agan, BK
    Ahuja, SS
    Bologna, R
    Sen, L
    Dolan, MJ
    Ahuja, SK
    [J]. SCIENCE, 2005, 307 (5714) : 1434 - 1440