Induction of G 1 cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1
| Autor: | Davide Zella, Nhut Le, Robert R. Redfield, Elise Reardon, Alonso Heredia, Erin Klingebiel, Anthony Amoroso, Charles B. Davis, Joyelle K. Dominique |
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| Rok vydání: | 2003 |
| Předmět: |
Chemokine
T-Lymphocytes T cell Lymphocyte Biology Lymphocyte Activation Virus Replication Peripheral blood mononuclear cell medicine Extracellular Humans Hydroxyurea Cells Cultured Multidisciplinary Cell Cycle G1 Phase Biological Sciences Cell cycle Molecular biology medicine.anatomical_structure Viral replication Chemokines CC HIV-1 biology.protein Tetradecanoylphorbol Acetate Intracellular |
| Zdroj: | Proceedings of the National Academy of Sciences. 100:4179-4184 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0630584100 |
| Popis: | The β-chemokines RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-1α (MIP-1α), and MIP-1β are the natural ligands of the HIV-1 coreceptor CCR5 and compete with the virus for receptor binding. We show that secretion of the β-chemokines by activated lymphocytes starts before cellular DNA synthesis is detected and demonstrate that transient prolongation of the G 1 phase of the cell cycle by treatment with cytostatic drugs results in increased levels of the three chemokines in culture supernatants. Supernatants collected from peripheral blood mononuclear cells exposed to hydroxyurea, which arrests the cell cycle in late G 1 , contained high levels of β-chemokines. These supernatants were able to inhibit HIV-1 replication when added to cultures of infected lymphocytes. The observed antiviral effect likely was due to the increased levels of β-chemokines RANTES, MIP-1α, and MIP-1β because ( i ) supernatants greatly inhibited the replication of HIV-1 BaL, whereas they affected HIV-1 IIIb replication only slightly; ( ii ) neutralizing antibodies against the chemokines abrogated the antiviral effect of the supernatants; and ( iii ) the hydroxyurea concentrations shown to up-regulate chemokine levels were not sufficient to inhibit virus replication by depletion of intracellular nucleotide pools. Although antiviral properties have been reported previously for the cytostatic agents shown here to up-regulate β-chemokine levels, our results provide an additional mechanism by which these drugs may exert antiviral activity. In summary, increased extracellular levels of anti-HIV-1 β-chemokines resulting from transient prolongation of the G 1 phase of the lymphocyte cell cycle by treatment with cytostatic drugs may help to control the replication of CCR5-using strains of HIV-1. |
| Databáze: | OpenAIRE |
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