title: Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev.
abstract: The HIV-1 Rev protein facilitates the nuclear export of mRNA containing the Rev response element (RRE) through binding to the export receptor CRM-1. Here we show that a cellular nuclear protein, Sam68 (Src-associated protein in mitosis), specifically interacts with RRE and can partially substitute for as well as synergize with Rev in RRE-mediated gene expression and virus replication. Differential sensitivity to leptomycin B, an inhibitor of CRM-1, indicates that the export pathways mediated by Rev and Sam68 are distinct. C-terminally deleted mutants of Sam68 inhibited the transactivation of RRE-mediated expression by both wild-type Sam68 and Rev. They were retained in the cytoplasm and impeded the nuclear localization of Rev in co-expressed cells. These mutants also inhibited wild-type HIV-1 replication to the same extent as the RevM10 mutant, and may be useful as anti-viral agents in the treatment of AIDS.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla 92093, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Reddy
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: J K
authors.initials: JK
authors.lastname: Mau
authors.forename: C D
authors.initials: CD
authors.lastname: Goodwin
authors.forename: M
authors.initials: M
authors.lastname: Suhasini
authors.forename: H
authors.initials: H
authors.lastname: Tang
authors.forename: K
authors.initials: K
authors.lastname: Frimpong
authors.forename: D W
authors.initials: DW
authors.lastname: Rose
authors.forename: F
authors.initials: F
authors.lastname: Wong-Staal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured / Q000821:virology; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D015694:Gene Products, rev; D005799:Genes, Dominant; D017930:Genes, Reporter; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells / Q000821:virology; D006801:Humans; D028884:Karyopherins; D007701:Kinetin; D009154:Mutation; D011687:Purines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D020218:Response Elements; D014779:Virus Replication / Q000235:genetics*; D054321:rev Gene Products, Human Immunodeficiency Virus; D000097606:Exportin 1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002352:Carrier Proteins; D015500:Chloramphenicol O-Acetyltransferase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D015694:Gene Products, rev; D028884:Karyopherins; D007701:Kinetin; D011687:Purines; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D054321:rev Gene Products, Human Immunodeficiency Virus; D000097606:Exportin 1 Protein; C489559:KHDRBS1 protein, human; C090046:olomoucine; C038753:leptomycin B