Inhibition of multidrug-resistant HIV-1 by interference with cellular S-adenosylmethionine decarboxylase activity.
S-adenosylmethionine decarboxylase (SAMDC), a key enzyme in polyamine biosynthesis, can be specifically inhibited by the experimental drug SAM486A. The pharmaceutical interference with SAMDC activity results in the depletion of the intracellular pool of spermidine and spermine. In particular, low spermidine levels compromise hypusine modification and, thereby, activation of eukaryotic initiation factor 5A (eIF-5A), which is a cellular cofactor of the essential human immunodeficiency virus type 1 (HIV-1) regulatory protein Rev. In the present study, we show that SAM486A efficiently suppresses HIV-1 replication, including the replication of viruses that are resistant to multiple reverse transcriptase and protease inhibitors. At drug concentrations that efficiently inhibit the formation of progeny viruses, no toxic effects of SAM486A on cellular metabolism are observed. It is demonstrated that the antiretroviral effect of SAM486A is based on the fact that Rev activity is severely compromised in drug-treated cells. Thus, inhibition of cellular SAMDC activity may provide a novel strategy to achieve suppression of otherwise drug-resistant viruses.
Schäfer
Birgit
B
Heinrich-Pette-Institute for Experimental Virology and Immunology, Martinistrasse, Hamburg, Germany.
Hauber
Ilona
I
Bunk
Andrea
A
Heukeshoven
Jochen
J
Düsedau
Arne
A
Bevec
Dorian
D
Hauber
Joachim
J
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D000578:Amidines / Q000494:pharmacology* / Q000633:toxicity; D000914:Antibodies, Viral / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D024882:Drug Resistance, Viral / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D015757:Genes, rev / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000633:toxicity; D010448:Peptide Initiation Factors / Q000187:drug effects; D016133:Polymerase Chain Reaction / Q000379:methods; D016601:RNA-Binding Proteins / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D000097574:Eukaryotic Translation Initiation Factor 5A
D012437:Adenosylmethionine Decarboxylase; D000578:Amidines; D000914:Antibodies, Viral; D017931:DNA Primers; D004791:Enzyme Inhibitors; D007189:Indans; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C082408:4-amidinoindan-1-one 2'-amidinohydrazone