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Actinomycin D induces high-level resistance to thymidine analogs in replication of human immunodeficiency virus type 1 by interfering with host cell thymidine kinase expression

  1. Author:
    Imamichi, T.
    Murphy, M. A.
    Adelsberger, J. W.
    Yang, J.
    Watkins, C. M.
    Berg, S. C.
    Baseler, M. W.
    Lempicki, R. A.
    Guo, J. H.
    Levin, J. G.
    Lane, H. C.

  2. Author Address

    NCI, Lab Mol Retrovirol, Clin Serv Program, SAIC Frederick Inc, POB B,Bldg 550,Room 126, Frederick, MD 21702 USA NCI, Lab Mol Retrovirol, Clin Serv Program, SAIC Frederick Inc, Frederick, MD 21702 USA NCI, AIDS Monitoring Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA NCI, Lab Immunopathogenesis & Bioinformat, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA NCI, Clin Serv Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA Imamichi T NCI, Lab Mol Retrovirol, Clin Serv Program, SAIC Frederick Inc, POB B,Bldg 550,Room 126, Frederick, MD 21702 USA
    1. Year: 2003
  2. Journal: Journal of Virology
    1. 77
    2. 2
    3. Pages: 1011-1020
  4. Type of Article: Article
  1. Abstract:

    Actinomycin D (ActD) is a transcription inhibitor and has been used in the treatment of certain forms of cancer. ActD has been reported to be a potential inhibitor of human immunodeficiency virus type I (HIV-1) replication due to its ability to inhibit reverse transcription. In contrast to what was expected, low concentrations of ActD (I to 10 nM) upregulated HIV-1 replication 8- to 10-fold in MT-2 cells and had no effect on HIV-2 replication or on HIV-1 replication in MT-4, Jurkat, or peripheral blood mononuclear cells. The upregulation of HIV-1 replication was associated with an increase in HIV-1 transcription and a decrease in CD4 and CXCR4 expression. To further evaluate the effects of ActD on emergence of drug resistance in HIV-1 replication, a series of drug resistance assays were performed. Of interest, treatment of MT-2 cells with ActD also led to a high level of resistance to thymidine analogs (>1,000-fold increase in resistance to zidovudine and >250-fold to stavudine) but not to other nucleoside reverse transcriptases (RT), nonnucleoside RT, or protease inhibitors. This resistance appeared to be due to a suppression of host cell thymidine kinase-1 (TK-1) expression. These results indicate that ActD leads to a novel form of thymidine analog resistance by suppressing host cell TK-1 expression. These results suggest that administration of combination drugs to HIV-1-infected patients may induce resistance to antiretroviral compounds via a modification of cellular factors.

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