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.
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.
Münch
Jan
J
Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
Ständker
Ludger
L
Pöhlmann
Stefan
S
Baribaud
Frédéric
F
Papkalla
Armin
A
Rosorius
Olaf
O
Stauber
Roland
R
Sass
Gabriele
G
Heveker
Nikolaus
N
Adermann
Knut
K
Escher
Sylvia
S
Klüver
Enno
E
Doms
Robert W
RW
Forssmann
Wolf-Georg
WG
Kirchhoff
Frank
F
D019380:Anti-HIV Agents / Q000494:pharmacology*; D000954:Antigens, Surface / Q000096:biosynthesis; D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D054402:Chemokine CCL1; D018946:Chemokine CCL5 / Q000494:pharmacology; D019742:Chemokines, CC / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000821:virology*; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism / Q000821:virology; D013601:T-Lymphocytes / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000954:Antigens, Surface; D065100:CCR5 Receptor Antagonists; D054402:Chemokine CCL1; D018946:Chemokine CCL5; D019742:Chemokines, CC; C462200:HCC-1(9-74); D010446:Peptide Fragments