title: 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.
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 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.
authors.affiliation: Laboratory of Molecular Retrovirology, Clinical Services Program, Science Applications International Corporation-Frederick Inc., National Cancer Institute-Frederick, Maryland 21702, USA. timamichi@nih.gov
authors.forename: Tomozumi
authors.initials: T
authors.lastname: Imamichi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Murphy
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Adelsberger
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Watkins
authors.forename: Steve C
authors.initials: SC
authors.lastname: Berg
authors.forename: Michael W
authors.initials: MW
authors.lastname: Baseler
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lempicki
authors.forename: Jianhui
authors.initials: J
authors.lastname: Guo
authors.forename: Judith G
authors.initials: JG
authors.lastname: Levin
authors.forename: H Clifford
authors.initials: HC
authors.lastname: Lane
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D003609:Dactinomycin / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D013936:Thymidine / Q000031:analogs & derivatives*; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D017931:DNA Primers; D003609:Dactinomycin; D013937:Thymidine Kinase; D013936:Thymidine