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Journal of Virology, March 2008, p. 3090-3098, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01479-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

RNA Structure Modulates Splicing Efficiency at the Human Immunodeficiency Virus Type 1 Major Splice Donor{triangledown}

Truus E. M. Abbink and Ben Berkhout*

Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Amsterdam, The Netherlands

Received 6 July 2007/ Accepted 13 December 2007

The untranslated leader of the human immunodeficiency virus type 1 (HIV-1) RNA genome encodes essential sequence and structural motifs that control various replication steps. The 5' splice site or splice donor (SD) is embedded in a semistable hairpin, but the function of this structure is unknown. We stabilized this SD hairpin by creating an additional base pair and demonstrated a severe HIV-1 replication defect. A splicing defect was apparent in RNA analyses of virus-infected cells and cells transfected with appropriate reporter constructs. We selected multiple virus revertants in search for interesting second-site escape pathways. Most revertants acquired an additional mutation that modulated the stability of the mutant SD hairpin. One revertant acquired a single nucleotide change in the upstream DIS hairpin. We demonstrate that a novel SD site is created by this upstream mutation, which obviously reduces the number of leader nucleotides that are included in spliced HIV-1 transcripts. These results suggest a novel role of RNA structure in the regulation of HIV-1 splicing.

* Corresponding author. Mailing address: Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone: 31 20 566 4822. Fax: 31 20 691 6531. E-mail: b.berkhout{at}amc.uva.nl

{triangledown} Published ahead of print on 26 December 2007.

Journal of Virology, March 2008, p. 3090-3098, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01479-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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