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Journal of Virology, January 2009, p. 940-952, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01520-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Trafficking through the Rev/RRE Pathway Is Essential for Efficient Inhibition of Human Immunodeficiency Virus Type 1 by an Antisense RNA Derived from the Envelope Gene {triangledown}

Alex M. Ward, David Rekosh, and Marie-Louise Hammarskjold*

Myles H. Thaler Center for AIDS and Human Retrovirus Research and the Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908

Received 18 July 2008/ Accepted 23 October 2008

A human immunodeficiency virus type 1 (HIV-1)-based vector expressing an antisense RNA directed against HIV-1 is currently in clinical trials. This vector has shown a remarkable ability to inhibit HIV-1 replication, in spite of the fact that therapeutic use of unmodified antisense RNAs has generally been disappointing. To further analyze the basis for this, we examined the effects of different plasmid-based HIV-1 long-terminal-repeat-driven constructs expressing antisense RNA to the same target region in HIV-1 but containing different export elements. Two of these vectors were designed to express antisense RNA containing either a Rev response element (RRE) or a Mason-Pfizer monkey virus (MPMV) constitutive transport element (CTE). In the third vector, no specific transport element was provided. Efficient inhibition of HIV-1 virus production was obtained with the RRE-driven antisense RNA. This construct also efficiently inhibited p24 production from a pNL4-3 provirus that used the MPMV CTE for RNA export. In contrast, little inhibition was observed with the constructs lacking an RRE. Furthermore, when the RRE-driven antisense RNA was redirected to the Tap/Nxf1 pathway, utilized by the MPMV CTE, through the expression of a RevM10-Tap fusion protein, the efficiency of antisense inhibition was greatly reduced. These results indicate that efficient inhibition requires trafficking of the antisense RNA through the Rev/RRE pathway. Mechanistic studies indicated that the Rev/RRE-mediated inhibition did not involve either nuclear retention or degradation of target mRNA, since target RNA was found to export and associate normally with polyribosomes. However, protein levels were significantly reduced. Taken together, our results suggest a new mechanism for antisense inhibition of HIV mediated by Rev/RRE.

* Corresponding author. Mailing address: University of Virginia, Department of Microbiology, Jordan Hall Room 7087, P.O. Box 800734, Charlottesville, VA 22908. Phone: (434) 982-1598. Fax: (434) 982-1590. E-mail: mh7g{at}virginia.edu

{triangledown} Published ahead of print on 29 October 2008.

Journal of Virology, January 2009, p. 940-952, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01520-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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