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A Bidirectional SF2/ASF- and SRp40-Dependent Splicing Enhancer Regulates Human Immunodeficiency Virus Type 1 rev, env, vpu, and nef Gene Expression

Massimo Caputi ,^1,, Marcel Freund,^2, Susanne Kammler,² Corinna Asang,² and Heiner Schaal^2*

Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218,¹ Institut für Virologie, Heinrich-Heine-Universität Düsseldorf, D-40225 Düsseldorf, Germany²

Received 8 October 2003/ Accepted 18 February 2004

The integrated human immunodeficiency virus type 1 (HIV-1) genome is transcribed in a single pre-mRNA that is alternatively spliced into more than 40 mRNAs. We characterized a novel bidirectional exonic splicing enhancer (ESE) that regulates the expression of the HIV-1 env, vpu, rev, and nef mRNAs. The ESE is localized downstream of the vpu-, env-, and nef-specific 3' splice site no. 5. SF2/ASF and SRp40 activate the ESE and are required for efficient 3' splice site usage and binding of the U1 snRNP to the downstream 5' splice site no. 4. U1 snRNP binding to the 5' splice site no. 4 is required for splicing of the rev and nef mRNAs and to increase expression of the partially spliced env mRNA. Finally, our results indicate that this ESE is necessary for the recruitment of the U1 snRNP to the 5' splice site no. 4, even when the 5' splice site and the U1 snRNA have been mutated to obtain a perfect complementary match. The ESE characterized here is highly conserved in most viral subtypes.

M.C. and M.F. contributed equally to this work.

Present address: Biomedical Science Department, Florida Atlantic University, Boca Raton, FL 33431.

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