Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev.
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.
Reddy
T R
TR
Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Xu
W
W
Mau
J K
JK
Goodwin
C D
CD
Suhasini
M
M
Tang
H
H
Frimpong
K
K
Rose
D W
DW
Wong-Staal
F
F
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
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