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Nucleic Acids Research Advance Access originally published online on February 24, 2008
Nucleic Acids Research 2008 36(7):2353-2365; doi:10.1093/nar/gkn076
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Nucleic Acids Research, 2008, Vol. 36, No. 7 2353-2365
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element{dagger}

Dominique L. Ouellet1,2, Isabelle Plante1,2, Patricia Landry1,2, Corinne Barat2,3, Marie-Ève Janelle1,2, Louis Flamand1,2, Michel J. Tremblay2,3 and Patrick Provost1,2,*

1Centre de Recherche en Rhumatologie et Immunologie, 2Faculty of Medicine, Université Laval, Quebec, QC, G1V 0A6 and 3Centre de Recherche en Infectiologie, CHUL Research Center, CHUQ, 2705 Blvd Laurier, Quebec, QC, G1V 4G2, Canada

*To whom correspondence should be addressed. Tel: 1 418 654 2772; Fax: 1 418 654 2765; Email: patrick.provost{at}crchul.ulaval.ca

Received January 11, 2008. Revised February 6, 2008. Accepted February 8, 2008.

The interaction between human immunodeficiency virus type 1 (HIV-1) and RNA silencing pathways is complex and multifaceted. Essential for efficient viral transcription and supporting Tat-mediated transactivation of viral gene expression, the trans-activation responsive (TAR) element is a structured RNA located at the 5' end of all transcripts derived from HIV-1. Here, we report that this element is a source of microRNAs (miRNAs) in cultured HIV-1-infected cell lines and in HIV-1-infected human CD4+ T lymphocytes. Using primer extension and ribonuclease (RNase) protection assays, we delineated both strands of the TAR miRNA duplex deriving from a model HIV-1 transcript, namely miR-TAR-5p and miR-TAR-3p. In vitro RNase assays indicate that the lack of a free 3' extremity at the base of TAR may contribute to its low processing reactivity in vivo. Both miR-TAR-5p and miR-TAR-3p down-regulated TAR miRNA sensor activity in a process that required an integral miRNA-guided RNA silencing machinery. miR-TAR-3p exerted superior gene downregulatory effects, probably due to its preferential release from HIV-1 TAR RNA by the RNase III Dicer. Our study suggests that the TAR element of HIV-1 transcripts releases functionally competent miRNAs upon asymmetrical processing by Dicer, thereby providing novel insights into viral miRNA biogenesis.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

{dagger}Nucleic Acid Sequence Information: The nucleotide sequence of miR-TAR-5p and miR-TAR-3p have been deposited to the miRBase registry at http://microrna.sanger.ac.uk


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