LEPTOMYCIN-B IS AN INHIBITOR OF NUCLEAR EXPORT - INHIBITION OF NUCLEOCYTOPLASMIC TRANSLOCATION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) REV PROTEIN AND REV-DEPENDENT MESSENGER-RNA

Background: The human immunodeficiency virus type 1 (HIV-1) regulatory protein Rev is required for unspliced and incompletely spliced viral mRNAs to appear in the cytoplasm and thus for viral replication. Trans location of Rev from the nucleus to the cytoplasm is essential if Rev is to function. We wanted to identify inhibitors of this transport pro cess because they would be potential antiviral agents. Results: The St reptomyces metabolite, leptomycin B, and other antibiotics of the lept omycin/kazusamycin family were identified as inhibitors of the nucleo- cytoplasmic translocation of Rev at nanomolar concentrations. Rev-depe ndent export of mRNA into the cytoplasm is also blocked by leptomycin B, which inhibits Rev-dependent, but not Rev-independent gene expressi on in a short-term transfection assay, In primary human monocytes, lep tomycin B suppresses HIV-1 replication. Conclusions: Leptomycin B is t he first low molecular weight inhibitor of nuclear export to be identi fied. Although it cannot be used therapeutically, it should serve as a valuable tool for dissecting nuclear export pathways.