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Inhibition of Human Immunodeficiency Virus Type 1 Rev Function by a Dominant-Negative Mutant of Sam68 through Sequestration of Unspliced RNA at Perinuclear Bundles

By Vanessa B. Soros, Héctor Valderrama Carvajal, Stéphane Richard and Alan W. Cochrane


Human immunodeficiency virus (HIV) type 1 encodes an essential protein, Rev, which functions to transport unspliced and singly spliced viral transcripts from the nucleus to the cytoplasm to allow expression of the viral structural proteins. It has previously been reported that Sam68 synergistically stimulates Rev activity (T. Reddy et al., Nat. Med. 5:635–642, 1999). Here we report that the Sam68-like mammalian proteins SLM1 and SLM2 also stimulate Rev activity. Their stimulation ability cannot be attributed to a shuttling property, since Sam68, SLM1, and SLM2 do not display significant shuttling activity alone or in the presence of Rev. In addition, Sam68, SLM1, and SLM2 do not affect the equilibrium between unspliced and completely spliced HIV RNA. The C-terminally truncated Sam68 mutant (Sam68ΔC) previously observed to inhibit the Sam68-mediated stimulation of Rev activity (Reddy et al., 1999) also inhibits SLM1- and SLM2-mediated stimulation of Rev activity. This suggests that the mechanism by which Sam68, SLM1, and SLM2 stimulate Rev activity may be common. Sam68ΔC does not inhibit Rev activity by inhibiting Rev from shuttling between the nucleus and cytoplasm. Inhibition by Sam68ΔC is a consequence of its mislocalization to the cytoplasm, as evidenced by the fact that addition of an exogenous nuclear localization signal to Sam68ΔC restores nuclear localization and stimulation of Rev activity. We demonstrate that Sam68ΔC causes perinuclear accumulation of unspliced HIV env RNA and propose that Sam68ΔC inhibits Rev activity by sequestering Rev-responsive RNA away from the translation apparatus

Topics: Virus-Cell Interactions
Publisher: American Society for Microbiology
Year: 2001
DOI identifier: 10.1128/JVI.75.17.8203-8215.2001
OAI identifier:
Provided by: PubMed Central
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