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Hemofiltrate CC chemokine 1[9-74] causes effective internalization of CCR5 and is a potent inhibitor of R5-tropic human immunodeficiency virus type 1 strains in primary T cells and macrophages.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2002 Apr; Vol. 46 (4), pp. 982-90. - Publication Year :
- 2002
-
Abstract
- Proteolytic processing of the abundant plasmatic human CC chemokine 1 (HCC-1) generates a truncated form, HCC-1[9-74], which is a potent agonist of CCR1, CCR3, and CCR5; promotes calcium influx and chemotaxis of T lymphoblasts, monocytes, and eosinophils; and inhibits infection by CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates. In the present study we demonstrate that HCC-1[9-74] interacts with the second external loop of CCR5 and inhibits replication of CCR5-tropic HIV-1 strains in both primary T cells and monocyte-derived macrophages. Low concentrations of the chemokine, however, frequently enhanced the replication of CCR5-tropic HIV-1 isolates but not the replication of X4-tropic HIV-1 isolates. Only HCC-1[9-74] and HCC-1[10-74], but not other HCC-1 length variants, displayed potent anti-HIV-1 activities. Fluorescence-activated cell sorter analysis revealed that HCC-1[9-74] caused up to 75% down-regulation of CCR5 cell surface expression, whereas RANTES (regulated on activation, normal T-cell expressed and secreted) achieved a reduction of only about 40%. Studies performed with green fluorescent protein-tagged CCR5 confirmed that both HCC-1[9-74] and RANTES, but not full-length HCC-1, mediated specific internalization of the CCR5 HIV-1 entry cofactor. Our results demonstrate that the interaction with HCC-1[9-74] causes effective intracellular sequestration of CCR5, but they also indicate that the effect of HCC-1[9-74] on viral replication is subject to marked cell donor- and HIV-1 isolate-dependent variations.
- Subjects :
- Antigens, Surface biosynthesis
Cells, Cultured
Chemokine CCL1
Chemokine CCL5 pharmacology
Dose-Response Relationship, Drug
Down-Regulation drug effects
Flow Cytometry
HIV-1 genetics
Humans
Microscopy, Fluorescence
Protein Binding
Structure-Activity Relationship
Subcellular Fractions metabolism
Subcellular Fractions virology
Virus Replication drug effects
Anti-HIV Agents pharmacology
CCR5 Receptor Antagonists
Chemokines, CC pharmacology
HIV-1 drug effects
Macrophages virology
Peptide Fragments pharmacology
T-Lymphocytes virology
Subjects
Details
- Language :
- English
- ISSN :
- 0066-4804
- Volume :
- 46
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 11897579
- Full Text :
- https://doi.org/10.1128/AAC.46.4.982-990.2002