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Journal of Virology, January 2003, p. 1011-1020, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1011-1020.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Laboratory of Molecular Retrovirology,¹ AIDS Monitoring Laboratory,² Laboratory of Immunopathogenesis and Bioinformatics, Clinical Services Program, Science Applications International Corporation-Frederick Inc., National Cancer Institute-Frederick, Frederick, Maryland,³ Laboratory of Molecular Genetics, National Institute of Child Health and Human Development,⁴ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland⁵

Received 21 May 2002/ Accepted 8 October 2002

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 1 (HIV-1) replication due to its ability to inhibit reverse transcription. In contrast to what was expected, low concentrations of ActD (1 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.