期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：7
页码：4179-4184
DOI：10.1073/pnas.0630584100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The {beta}-chemokines RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-1 (MIP-1), and MIP-1{beta} are the natural ligands of the HIV-1 coreceptor CCR5 and compete with the virus for receptor binding. We show that secretion of the {beta}-chemokines by activated lymphocytes starts before cellular DNA synthesis is detected and demonstrate that transient prolongation of the G1 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 G1, contained high levels of {beta}-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 {beta}-chemokines RANTES, MIP-1, and MIP-1{beta} 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 {beta}-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 {beta}-chemokines resulting from transient prolongation of the G1 phase of the lymphocyte cell cycle by treatment with cytostatic drugs may help to control the replication of CCR5-using strains of HIV-1.
