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Journal of Virology, September 2001, p. 8203-8215, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8203-8215.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Vanessa B. Soros,1 Héctor Valderrama Carvajal,2,3 Stéphane Richard,2,3 and Alan W. Cochrane1,*

Department of Medical and Molecular Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8,1 and Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research,2 and McGill University,3 Montreal, Quebec H3T 1E2, Canada

Received 20 December 2000/Accepted 4 June 2001

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 (Sam68Delta C) 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. Sam68Delta C does not inhibit Rev activity by inhibiting Rev from shuttling between the nucleus and cytoplasm. Inhibition by Sam68Delta C is a consequence of its mislocalization to the cytoplasm, as evidenced by the fact that addition of an exogenous nuclear localization signal to Sam68Delta C restores nuclear localization and stimulation of Rev activity. We demonstrate that Sam68Delta C causes perinuclear accumulation of unspliced HIV env RNA and propose that Sam68Delta C inhibits Rev activity by sequestering Rev-responsive RNA away from the translation apparatus.

* Corresponding author. Mailing address: Department of Medical and Molecular Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Phone: (416) 978-2500. Fax: (416) 978-6885. E-mail: alan.cochrane{at}utoronto.ca.

Journal of Virology, September 2001, p. 8203-8215, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8203-8215.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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