PMID- 12502817
OWN - NLM
STAT- MEDLINE
DCOM- 20030122
LR  - 20190508
IS  - 0022-538X (Print)
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 77
IP  - 2
DP  - 2003 Jan
TI  - 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.
PG  - 1011-20
AB  - 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.
FAU - Imamichi, Tomozumi
AU  - Imamichi T
AD  - Laboratory of Molecular Retrovirology, Clinical Services Program, Science 
      Applications International Corporation-Frederick Inc., National Cancer 
      Institute-Frederick, Maryland 21702, USA. timamichi@nih.gov
FAU - Murphy, Michael A
AU  - Murphy MA
FAU - Adelsberger, Joseph W
AU  - Adelsberger JW
FAU - Yang, Jun
AU  - Yang J
FAU - Watkins, Catherine M
AU  - Watkins CM
FAU - Berg, Steve C
AU  - Berg SC
FAU - Baseler, Michael W
AU  - Baseler MW
FAU - Lempicki, Richard A
AU  - Lempicki RA
FAU - Guo, Jianhui
AU  - Guo J
FAU - Levin, Judith G
AU  - Levin JG
FAU - Lane, H Clifford
AU  - Lane HC
LA  - eng
GR  - N01CO12400/CA/NCI NIH HHS/United States
GR  - N01-CO-12400/CO/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Anti-HIV Agents)
RN  - 0 (DNA Primers)
RN  - 1CC1JFE158 (Dactinomycin)
RN  - EC 2.7.1.21 (Thymidine Kinase)
RN  - VC2W18DGKR (Thymidine)
SB  - IM
MH  - Anti-HIV Agents/*pharmacology
MH  - Base Sequence
MH  - Cell Line
MH  - DNA Primers
MH  - Dactinomycin/*pharmacology
MH  - *Drug Resistance, Viral
MH  - HIV-1/*physiology
MH  - Humans
MH  - Thymidine/*analogs & derivatives
MH  - Thymidine Kinase/*antagonists & inhibitors/metabolism
MH  - Virus Replication/*drug effects
PMC - PMC140776
EDAT- 2002/12/28 04:00
MHDA- 2003/01/23 04:00
PMCR- 2003/01/01
CRDT- 2002/12/28 04:00
PHST- 2002/12/28 04:00 [pubmed]
PHST- 2003/01/23 04:00 [medline]
PHST- 2002/12/28 04:00 [entrez]
PHST- 2003/01/01 00:00 [pmc-release]
AID - 1027 [pii]
AID - 10.1128/jvi.77.2.1011-1020.2003 [doi]
PST - ppublish
SO  - J Virol. 2003 Jan;77(2):1011-20. doi: 10.1128/jvi.77.2.1011-1020.2003.