Actinomycin D:
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.
J Virol
2003 Jan;77(2):1011-20
Imamichi T, Murphy MA, Adelsberger JW, Yang J, Watkins CM, Berg SC, Baseler
MW, Lempicki RA, Guo J, Levin JG, Lane HC.
Laboratory of Molecular Retrovirology, Clinical Services Program, Science
Applications International Corporation-Frederick Inc., National Cancer
Institute-Frederick, Maryland 21702, USA. timamichi@nih.gov
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.
